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  1. A case of cervical radiation radiculopathy resembling motor neuron disease

    International Nuclear Information System (INIS)

    Mitsunaga, Yoshihiro; Yoshimura, Takeo; Hara, Hideo; Yamada, Takeshi; Kira, Jun-ichi; Kobayashi, Takuro

    1998-01-01

    A 67-year-old man developed slowly progressive muscular weakness in the bilateral upper extremities (C5-7 regions) without signs of sensory deficit following the cervical radiation therapy (70.5 Gy) for right laryngeal cancer 4 years before. These clinical signs resembled those of lower motor neuron disease. MRI with gadolinium-DTPA, however, showed enhancement in the bilateral C5 and C6 anterior roots, suggesting the cervical radiculopathy due to radiotherapy. It is known that radiation to the spinal cord can lead to ''selective anterior horn cell injury''. This is the first case report of the cervical radiation radiculopathy, which, if without MRI, might be classified into selective anterior horn cell injury. Suggestion is made for the hypothesis that the spinal motoneuron loss in radiation myelopathy would be caused by retrograde degeneration due to anterior root damages. (author)

  2. A case of cervical radiation radiculopathy resembling motor neuron disease

    Energy Technology Data Exchange (ETDEWEB)

    Mitsunaga, Yoshihiro; Yoshimura, Takeo; Hara, Hideo; Yamada, Takeshi; Kira, Jun-ichi; Kobayashi, Takuro [Kyushu Univ., Fukuoka (Japan). Faculty of Medicine

    1998-05-01

    A 67-year-old man developed slowly progressive muscular weakness in the bilateral upper extremities (C5-7 regions) without signs of sensory deficit following the cervical radiation therapy (70.5 Gy) for right laryngeal cancer 4 years before. These clinical signs resembled those of lower motor neuron disease. MRI with gadolinium-DTPA, however, showed enhancement in the bilateral C5 and C6 anterior roots, suggesting the cervical radiculopathy due to radiotherapy. It is known that radiation to the spinal cord can lead to ``selective anterior horn cell injury``. This is the first case report of the cervical radiation radiculopathy, which, if without MRI, might be classified into selective anterior horn cell injury. Suggestion is made for the hypothesis that the spinal motoneuron loss in radiation myelopathy would be caused by retrograde degeneration due to anterior root damages. (author)

  3. Gait analysis in a mouse model resembling Leigh disease.

    Science.gov (United States)

    de Haas, Ria; Russel, Frans G; Smeitink, Jan A

    2016-01-01

    Leigh disease (LD) is one of the clinical phenotypes of mitochondrial OXPHOS disorders and also known as sub-acute necrotizing encephalomyelopathy. The disease has an incidence of 1 in 77,000 live births. Symptoms typically begin early in life and prognosis for LD patients is poor. Currently, no clinically effective treatments are available. Suitable animal and cellular models are necessary for the understanding of the neuropathology and the development of successful new therapeutic strategies. In this study we used the Ndufs4 knockout (Ndufs4(-/-)) mouse, a model of mitochondrial complex I deficiency. Ndusf4(-/-) mice exhibit progressive neurodegeneration, which closely resemble the human LD phenotype. When dissecting behavioral abnormalities in animal models it is of great importance to apply translational tools that are clinically relevant. To distinguish gait abnormalities in patients, simple walking tests can be assessed, but in animals this is not easy. This study is the first to demonstrate automated CatWalk gait analysis in the Ndufs4(-/-) mouse model. Marked differences were noted between Ndufs4(-/-) and control mice in dynamic, static, coordination and support parameters. Variation of walking speed was significantly increased in Ndufs4(-/-) mice, suggesting hampered and uncoordinated gait. Furthermore, decreased regularity index, increased base of support and changes in support were noted in the Ndufs4(-/-) mice. Here, we report the ability of the CatWalk system to sensitively assess gait abnormalities in Ndufs4(-/-) mice. This objective gait analysis can be of great value for intervention and drug efficacy studies in animal models for mitochondrial disease. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Neurons other than motor neurons in motor neuron disease.

    Science.gov (United States)

    Ruffoli, Riccardo; Biagioni, Francesca; Busceti, Carla L; Gaglione, Anderson; Ryskalin, Larisa; Gambardella, Stefano; Frati, Alessandro; Fornai, Francesco

    2017-11-01

    Amyotrophic lateral sclerosis (ALS) is typically defined by a loss of motor neurons in the central nervous system. Accordingly, morphological analysis for decades considered motor neurons (in the cortex, brainstem and spinal cord) as the neuronal population selectively involved in ALS. Similarly, this was considered the pathological marker to score disease severity ex vivo both in patients and experimental models. However, the concept of non-autonomous motor neuron death was used recently to indicate the need for additional cell types to produce motor neuron death in ALS. This means that motor neuron loss occurs only when they are connected with other cell types. This concept originally emphasized the need for resident glia as well as non-resident inflammatory cells. Nowadays, the additional role of neurons other than motor neurons emerged in the scenario to induce non-autonomous motor neuron death. In fact, in ALS neurons diverse from motor neurons are involved. These cells play multiple roles in ALS: (i) they participate in the chain of events to produce motor neuron loss; (ii) they may even degenerate more than and before motor neurons. In the present manuscript evidence about multi-neuronal involvement in ALS patients and experimental models is discussed. Specific sub-classes of neurons in the whole spinal cord are reported either to degenerate or to trigger neuronal degeneration, thus portraying ALS as a whole spinal cord disorder rather than a disease affecting motor neurons solely. This is associated with a novel concept in motor neuron disease which recruits abnormal mechanisms of cell to cell communication.

  5. Motor neuron disease in blacks

    African Journals Online (AJOL)

    1989-08-19

    Aug 19, 1989 ... We reported earlier that motor neuron disease occurs more commonly among blacks than Parkinson's disease, which is relatively rare in this race group.! The hypothesis that these conditions, and other neuronal abiotrophies, are the result of previous subclinical neuronal insult and subsequent age-related.

  6. Motor neuron disease in blacks

    African Journals Online (AJOL)

    1989-08-19

    Aug 19, 1989 ... A series of 86 black, Indian and white patients with motor neuron disease were analysed retrospectively. Although the material does not allow statistically valid conclusions, there are sufficient cases among blacks to allow two prima facie observations in this population group: (~ motor neuron disease.

  7. Rapid generation of mitochondrial superoxide induces mitochondrion-dependent but caspase-independent cell death in hippocampal neuronal cells that morphologically resembles necroptosis

    Energy Technology Data Exchange (ETDEWEB)

    Fukui, Masayuki; Choi, Hye Joung; Zhu, Bao Ting, E-mail: BTZhu@kumc.edu

    2012-07-15

    Studies in recent years have revealed that excess mitochondrial superoxide production is an important etiological factor in neurodegenerative diseases, resulting from oxidative modifications of cellular lipids, proteins, and nucleic acids. Hence, it is important to understand the mechanism by which mitochondrial oxidative stress causes neuronal death. In this study, the immortalized mouse hippocampal neuronal cells (HT22) in culture were used as a model and they were exposed to menadione (also known as vitamin K{sub 3}) to increase intracellular superoxide production. We found that menadione causes preferential accumulation of superoxide in the mitochondria of these cells, along with the rapid development of mitochondrial dysfunction and cellular ATP depletion. Neuronal death induced by menadione is independent of the activation of the MAPK signaling pathways and caspases. The lack of caspase activation is due to the rapid depletion of cellular ATP. It was observed that two ATP-independent mitochondrial nucleases, namely, AIF and Endo G, are released following menadione exposure. Silencing of their expression using specific siRNAs results in transient suppression (for ∼ 12 h) of mitochondrial superoxide-induced neuronal death. While suppression of the mitochondrial superoxide dismutase expression markedly sensitizes neuronal cells to mitochondrial superoxide-induced cytotoxicity, its over-expression confers strong protection. Collectively, these findings showed that many of the observed features associated with mitochondrial superoxide-induced cell death, including caspase independency, rapid depletion of ATP level, mitochondrial release of AIF and Endo G, and mitochondrial swelling, are distinctly different from those of apoptosis; instead they resemble some of the known features of necroptosis. -- Highlights: ► Menadione causes mitochondrial superoxide accumulation and injury. ► Menadione-induced cell death is caspase-independent, due to rapid depletion of

  8. Neuronal oscillations in Parkinson's disease.

    Science.gov (United States)

    Witcher, Mark; Moran, Rosalyn; Tatter, Stephen B; Laxton, Adrian W

    2014-06-01

    Parkinson's Disease (PD), characterized by tremor, rigidity, and bradykinesia, is one of the most prevalent neurodegenerative disorders in the world. The pathological hallmark of PD is the loss of dopaminergic cells in the substantia nigra and other brain regions. The pathophysiological mechanisms by which dopaminergic cell loss leads to the motor manifestations of PD are yet to be fully elucidated. A growing body of evidence has revealed abnormal neuronal oscillations within and between multiple brain regions in PD. Unique oscillatory patterns are associated with specific motor abnormalities in PD. Therapies, such as dopaminergic medication and deep brain stimulation that disrupt these abnormal neuronal oscillatory patterns produce symptomatic improvement in PD patients. These findings emphasize the importance of abnormal neuronal oscillations in the pathophysiology of PD, making the disruption of these oscillatory patterns a promising target in the development of effective PD treatments.

  9. Prion disease resembling frontotemporal dementia and parkinsonism linked to chromosome 17

    Directory of Open Access Journals (Sweden)

    Nitrini Ricardo

    2001-01-01

    Full Text Available OBJECTIVE: To compare the clinical features of a familial prion disease with those of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17. BACKGROUND: Prion diseases are not usually considered in the differential diagnosis of FTDP-17, since familial Creutzfeldt-Jakob disease (CJD, the most common inherited prion disease, often manifests as a rapidly progressive dementia. Conversely, FTDP-17 usually has an insidious onset in the fifth decade, with abnormal behavior and parkinsonian features. METHOD: We present the clinical features of 12 patients from a family with CJD associated with a point mutation at codon 183 of the prion protein gene. RESULTS: The mean age at onset was 44.0 ± 3.7; the duration of the symptoms until death ranged from two to nine years. Behavioral disturbances were the predominant presenting symptoms. Nine patients were first seen by psychiatrists. Eight patients manifested parkinsonian signs. CONCLUSION: These clinical features bear a considerable resemblance to those described in FTDP-17.

  10. Cognition and behavior in motor neuron disease

    NARCIS (Netherlands)

    Raaphorst, J.

    2015-01-01

    Motor neuron disease (MND) is a devastating neurodegenerative disorder characterized by progressive motor neuron loss, leading to weakness of the muscles of arms and legs, bulbar and respiratory muscles. Depending on the involvement of the lower and the upper motor neuron, amyotrophic lateral

  11. Imaging manifestations of acquired elastopathy resembling pseudoxanthoma elasticum in patients with beta thalassaemia major and sickle cell disease

    International Nuclear Information System (INIS)

    Narayana, Harish; Cheng, Ken; Lau, Ken; Harish, Radhika; Bowden, Donald K.

    2016-01-01

    Development of an acquired systemic elastopathy resembling pseudoxanthoma elasticum in patients with chronic haemoglobinopathies such as beta thalassaemia major and sickle cell disease is well documented. There is paucity of any comprehensive literature on the radiological manifestations of this entity. This pictorial review aims to describe and illustrate the multi system and multi modality imaging findings of this condition.

  12. Sleep disordered breathing in motor neurone disease

    OpenAIRE

    D’Cruz, Rebecca F.; Murphy, Patrick B.; Kaltsakas, Georgios

    2018-01-01

    Motor neurone disease (MND) is a neurodegenerative disease defined by axonal loss and gliosis of upper and lower motor neurones in the motor cortex, lower brainstem nuclei and ventral horn of the spinal cord. MND is currently incurable and has a poor prognosis, with death typically occurring 3 to 5 years after disease onset. The disease is characterised by rapidly progressive weakness leading to paralysis, fasciculations, bulbar symptoms (including dysarthria and dysphagia) and respiratory co...

  13. Intracellular acidification by inhibition of the Na+/H+-exchanger leads to caspase-independent death of cerebellar granule neurons resembling paraptosis.

    Science.gov (United States)

    Schneider, D; Gerhardt, E; Bock, J; Müller, M M; Wolburg, H; Lang, F; Schulz, J B

    2004-07-01

    Potassium withdrawal is commonly used to induce caspase-mediated apoptosis in cerebellar granule neurons in vitro. However, the underlying and cell death-initiating mechanisms are unknown. We firstly investigated potassium efflux through the outward delayed rectifier K+ current (Ik) as a potential mediator. However, tetraethylammoniumchloride, an inhibitor of Ik, was ineffective to block apoptosis after potassium withdrawal. Since potassium withdrawal reduced intracellular pH (pHi) from 7.4 to 7.2, we secondly investigated the effects of intracellular acidosis. To study intracellular acidosis in cerebellar granule neurons, we inhibited the Na+/H+ exchanger (NHE) with 4-isopropyl-3-methylsulfonylbenzoyl-guanidine methanesulfonate (HOE 642) and 5-(N-ethyl-N-isopropyl)-amiloride. Both inhibitors concentration-dependently induced cell death and potentiated cell death after potassium withdrawal. Although inhibition of the NHE induced cell death with morphological criteria of apoptosis in light and electron microscopy including chromatin condensation, positive TUNEL staining and cell shrinkage, no internucleosomal DNA cleavage or activation of caspases was detected. In contrast to potassium withdrawal-induced apoptosis, cell death induced by intracellular acidification was not prevented by insulin-like growth factor-1, cyclo-adenosine-monophosphate, caspase inhibitors and transfection with an adenovirus expressing Bcl-XL. However, cycloheximide protected cerebellar granule neurons from death induced by potassium withdrawal as well as from death after treatment with HOE 642. Therefore, the molecular mechanisms leading to cell death after acidification appear to be different from the mechanisms after potassium withdrawal and resemble the biochemical but not the morphological characteristics of paraptosis.

  14. 'Hair-on-end' skull changes resembling thalassemia caused by marrow expansion in uncorrected complex cyanotic heart disease

    Energy Technology Data Exchange (ETDEWEB)

    Walor, David M.; Berdon, Walter E. [Columbia University Medical Center, Department of Radiology Children' s Hospital of New York, New York, NY (United States); Westra, Sjirk J. [Massachusetts General Hospital, Department of Radiology, Boston, MA (United States)

    2005-07-01

    ''Hair-on-end'' skull changes resembling thalassemia were rarely described in the 1950s and 1960s in children with cyanotic congenital heart diseases; these changes were described almost entirely in patients with tetralogy of Fallot or D-transposition of the great arteries. As these lesions have become correctable, the osseous changes, never common, seem now only to exist in a small number of patients with uncorrectable complex cyanotic congenital heart disease who survive in a chronic hypoxic state. We present two cases: a case of marked marrow expansion in the skull of a 5-year-old boy with uncorrectable cyanotic heart disease studied by CT, and a second case of an 8-year-old with tetralogy of Fallot and pulmonary atresia studied by plain skull radiographs. The true incidence of these findings is unknown. (orig.)

  15. 'Hair-on-end' skull changes resembling thalassemia caused by marrow expansion in uncorrected complex cyanotic heart disease

    International Nuclear Information System (INIS)

    Walor, David M.; Berdon, Walter E.; Westra, Sjirk J.

    2005-01-01

    ''Hair-on-end'' skull changes resembling thalassemia were rarely described in the 1950s and 1960s in children with cyanotic congenital heart diseases; these changes were described almost entirely in patients with tetralogy of Fallot or D-transposition of the great arteries. As these lesions have become correctable, the osseous changes, never common, seem now only to exist in a small number of patients with uncorrectable complex cyanotic congenital heart disease who survive in a chronic hypoxic state. We present two cases: a case of marked marrow expansion in the skull of a 5-year-old boy with uncorrectable cyanotic heart disease studied by CT, and a second case of an 8-year-old with tetralogy of Fallot and pulmonary atresia studied by plain skull radiographs. The true incidence of these findings is unknown. (orig.)

  16. Absence of the SRC-2 Coactivator Results in a Glycogenopathy Resembling Von Gierke's Disease

    OpenAIRE

    Chopra, Atul R.; Louet, Jean-Francois; Saha, Pradip; An, Jie; DeMayo, Franco; Xu, Jianming; York, Brian; Karpen, Saul; Finegold, Milton; Moore, David; Chan, Lawrence; Newgard, Christopher B.; O'Malley, Bert W.

    2008-01-01

    Hepatic glucose production is critical for basal brain function and survival when dietary glucose is unavailable. Glucose-6-phosphatase (G6Pase) is an essential, rate-limiting enzyme that serves as a terminal gatekeeper for hepatic glucose release into the plasma. Mutations in G6Pase result in Von Gierke's disease (glycogen storage disease–1a), a potentially fatal genetic disorder. We have identified the transcriptional coactivator SRC-2 as a regulator of fasting hepatic glucose release, a fu...

  17. Clinical Presentation Resembling Mucosal Disease Associated with 'HoBi'-like Pestivirus in a Field Outbreak.

    Science.gov (United States)

    Weber, M N; Mósena, A C S; Simões, S V D; Almeida, L L; Pessoa, C R M; Budaszewski, R F; Silva, T R; Ridpath, J F; Riet-Correa, F; Driemeier, D; Canal, C W

    2016-02-01

    The genus Pestivirus of the family Flaviviridae consists of four recognized species: Bovine viral diarrhoea virus 1 (BVDV-1), Bovine viral diarrhoea virus 2 (BVDV-2), Classical swine fever virus (CSFV) and Border disease virus (BDV). Recently, atypical pestiviruses ('HoBi'-like pestiviruses) were identified in batches of contaminated foetal calf serum and in naturally infected cattle with and without clinical symptoms. Here, we describe the first report of a mucosal disease-like clinical presentation (MD) associated with a 'HoBi'-like pestivirus occurring in a cattle herd. The outbreak was investigated using immunohistochemistry, antibody detection, viral isolation and RT-PCR. The sequence and phylogenetic analysis of 5'NCR, N(pro) and E2 regions of the RT-PCR positive samples showed that four different 'HoBi'-like strains were circulating in the herd. The main clinical signs and lesions were observed in the respiratory and digestive systems, but skin lesions and corneal opacity were also observed. MD characteristic lesions and a pestivirus with cytopathic biotype were detected in one calf. The present study is the first report of a MD like presentation associated with natural infection with 'HoBi'-like pestivirus. This report describes the clinical signs and provides a pathologic framework of an outbreak associated with at least two different 'HoBi'-like strains. Based on these observations, it appears that these atypical pestiviruses are most likely underdiagnosed in Brazilian cattle. © 2014 Blackwell Verlag GmbH.

  18. Suicide in patients with motor neuron disease

    DEFF Research Database (Denmark)

    Bak, Søren; Stenager, E N; Stenager, Egon

    1994-01-01

    The aim of the present study was to assess, through an epidemiological study, whether suicide risk is increased in patients with motor neuron disease (MND). The study involved 116 patients with MND. In the study period 92 patients died, 47 males and 45 females. No patients committed suicide...

  19. Orofacial Apraxia in Motor Neuron Disease

    OpenAIRE

    Patrícia Pita Lobo; Susana Pinto; Luz Rocha; Sofia Reimão; Mamede de Carvalho

    2013-01-01

    Introduction: Cognitive and behavioral impairments are considered to occur frequently in amyotrophic lateral sclerosis/motor neuron disease (MND). Rarely, apraxia has been reported in MND. Orofacial, or buccofacial, apraxia is characterized by a loss of voluntary control of facial, lingual, pharyngeal and masticatory muscles in the presence of preserved reflexive and automatic functions of the same muscles. Methods: We report a patient with MND who presented with spastic dysarthria and asymme...

  20. Combined exposure to bacteria and cigarette smoke resembles characteristic phenotypes of human COPD in a murine disease model.

    Science.gov (United States)

    Herr, Christian; Han, Gang; Li, Dong; Tschernig, Thomas; Dinh, Quoc Thai; Beißwenger, Christoph; Bals, Robert

    2015-03-01

    Abundant microbial colonization is a hallmark of COPD and smoke exposure likely increases the susceptibility to colonization and infection. The aim of the present study was to characterize the pulmonary changes of a combined exposure to cigarette smoke (CS) and microbial challenge in a preclinical murine COPD model. Animals were exposed to CS for 2 weeks, 3, and 6 months. Low and high doses of heat inactivated nontypeable Haemophilus influenzae (NTHi) were administered by inhalation during the whole exposure time. Pulmonary changes were analyzed by stereology, pulmonary function tests, measurements of inflammatory cells and mediators, and histopathology. Exposure of smoke in a relatively low concentration caused COPD-like changes of pulmonary function and only little inflammation. The coadministration of low dose NTHi (ld-NTHi) augmented a macrophage dominated inflammatory profile, while high dose NTHi (hd-NTHi) induced a neutrophilic inflammatory pattern. IL-17A secretion was solely dependent on the exposure to NTHi. Also goblet cell metaplasia and the formation of lymphoid aggregates depended on exposure to bacteria. In conclusion, the combination of exposure to smoke and bacterial compounds resulted in a mouse model that resembles several aspects of human disease. Exposure to microbial structural components appears necessary to model important pathologic features of the disease and the quantity of the exposure with microorganisms has a strong effect on the phenotype. Copyright © 2015 Elsevier GmbH. All rights reserved.

  1. The frontotemporal dementia-motor neuron disease continuum.

    Science.gov (United States)

    Burrell, James R; Halliday, Glenda M; Kril, Jillian J; Ittner, Lars M; Götz, Jürgen; Kiernan, Matthew C; Hodges, John R

    2016-08-27

    Early reports of cognitive and behavioural deficits in motor neuron disease might have been overlooked initially, but the concept of a frontotemporal dementia-motor neuron disease continuum has emerged during the past decade. Frontotemporal dementia-motor neuron disease is now recognised as an important dementia syndrome, which presents substantial challenges for diagnosis and management. Frontotemporal dementia, motor neuron disease, and frontotemporal dementia-motor neuron disease are characterised by overlapping patterns of TAR DNA binding protein (TDP-43) pathology, while the chromosome 9 open reading frame 72 (C9orf72) repeat expansion is common across the disease spectrum. Indeed, the C9orf72 repeat expansion provides important clues to disease pathogenesis and suggests potential therapeutic targets. Variable diagnostic criteria identify motor, cognitive, and behavioural deficits, but further refinement is needed to define the clinical syndromes encountered in frontotemporal dementia-motor neuron disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  2. A RAB3GAP1 SINE Insertion in Alaskan Huskies with Polyneuropathy, Ocular Abnormalities, and Neuronal Vacuolation (POANV Resembling Human Warburg Micro Syndrome 1 (WARBM1

    Directory of Open Access Journals (Sweden)

    Michaela Wiedmer

    2016-02-01

    Full Text Available We observed a hereditary phenotype in Alaskan Huskies that was characterized by polyneuropathy with ocular abnormalities and neuronal vacuolation (POANV. The affected dogs developed a progressive severe ataxia, which led to euthanasia between 8 and 16 months of age. The pedigrees were consistent with a monogenic autosomal recessive inheritance. We localized the causative genetic defect to a 4 Mb interval on chromosome 19 by a combined linkage and homozygosity mapping approach. Whole genome sequencing of one affected dog, an obligate carrier, and an unrelated control revealed a 218-bp SINE insertion into exon 7 of the RAB3GAP1 gene. The SINE insertion was perfectly associated with the disease phenotype in a cohort of 43 Alaskan Huskies, and it was absent from 541 control dogs of diverse other breeds. The SINE insertion induced aberrant splicing and led to a transcript with a greatly altered exon 7. RAB3GAP1 loss-of-function variants in humans cause Warburg Micro Syndrome 1 (WARBM1, which is characterized by additional developmental defects compared to canine POANV, whereas Rab3gap1-deficient mice have a much milder phenotype than either humans or dogs. Thus, the RAB3GAP1 mutant Alaskan Huskies provide an interesting intermediate phenotype that may help to better understand the function of RAB3GAP1 in development. Furthermore, the identification of the presumed causative genetic variant will enable genetic testing to avoid the nonintentional breeding of affected dogs.

  3. Neuronal Ca(2+) dyshomeostasis in Huntington disease.

    Science.gov (United States)

    Giacomello, Marta; Oliveros, Juan C; Naranjo, Jose R; Carafoli, Ernesto

    2013-01-01

    The expansion of the N-terminal poly-glutamine tract of the huntingtin (Htt) protein is responsible for Huntington disease (HD). A large number of studies have explored the neuronal phenotype of HD, but the molecular aethiology of the disease is still very poorly understood. This has hampered the development of an appropriate therapeutical strategy to at least alleviate its symptoms. In this short review, we have focused our attention on the alteration of a specific cellular mechanism common to all HD models, either genetic or induced by treatment with 3-NPA, i.e. the cellular dyshomeostasis of Ca(2+). We have highlighted the direct and indirect (i.e. transcriptionally mediated) effects of mutated Htt on the maintenance of the intracellular Ca(2+) balance, the correct modulation of which is fundamental to cell survival and the disturbance of which plays a key role in the death of the cell.

  4. Household and familial resemblance in risk factors for type 2 diabetes and related cardiometabolic diseases in rural Uganda sample

    DEFF Research Database (Denmark)

    Nielsen, Jannie; Bahendeka, Silver K.; Whyte, Susan R.

    2017-01-01

    (ICC=0.24), HbA1c (ICC=0.18) and systolic blood pressure (ICC=0.11). Regarding dyadic resemblance, the highest standardised regression coefficient was seen in fitness status for spouses (0.54, 95% CI 0.32 to 0.76), parent–offspring (0.41, 95% CI 0.28 0.54) and siblings (0.41, 95% CI 0.25 to 0.......57). Overall, parent–offspring and sibling pairs were the dyads with strongest resemblance, followed by spouses. Conclusions The marked degree of resemblance in T2D risk factors at household level and between spouses, parent–offspring and sibling dyads suggest that shared behavioural and environmental factors...

  5. Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases

    Science.gov (United States)

    2015-08-24

    Spinal Muscular Atrophy; Charcot-Marie-Tooth Disease; Muscular Dystrophy; Spinal Muscular Atrophy With Respiratory Distress 1; Amyotrophic Lateral Sclerosis; Motor Neuron Disease; Neuromuscular Disease; Peroneal Muscular Atrophy; Fragile X Syndrome

  6. Orofacial Apraxia in Motor Neuron Disease

    Science.gov (United States)

    Lobo, Patrícia Pita; Pinto, Susana; Rocha, Luz; Reimão, Sofia; de Carvalho, Mamede

    2013-01-01

    Introduction Cognitive and behavioral impairments are considered to occur frequently in amyotrophic lateral sclerosis/motor neuron disease (MND). Rarely, apraxia has been reported in MND. Orofacial, or buccofacial, apraxia is characterized by a loss of voluntary control of facial, lingual, pharyngeal and masticatory muscles in the presence of preserved reflexive and automatic functions of the same muscles. Methods We report a patient with MND who presented with spastic dysarthria and asymmetric orofacial apraxia. She progressed to frontotemporal dementia (FTD). Results Clinical and neurophysiological examinations were suggestive of bulbar-onset MND-FTD. Tractography showed a reduction of fractional anisotropy in the centrum semiovale, corona radiata, corticomedullary pathway and inferior aspect of the medulla; the changes were more severe on the left side. To our knowledge, this is the first report of an asymmetric presentation of an apraxic syndrome in MND-FTD. PMID:23569452

  7. Orofacial Apraxia in Motor Neuron Disease

    Directory of Open Access Journals (Sweden)

    Patrícia Pita Lobo

    2013-03-01

    Full Text Available Introduction: Cognitive and behavioral impairments are considered to occur frequently in amyotrophic lateral sclerosis/motor neuron disease (MND. Rarely, apraxia has been reported in MND. Orofacial, or buccofacial, apraxia is characterized by a loss of voluntary control of facial, lingual, pharyngeal and masticatory muscles in the presence of preserved reflexive and automatic functions of the same muscles. Methods: We report a patient with MND who presented with spastic dysarthria and asymmetric orofacial apraxia. She progressed to frontotemporal dementia (FTD. Results: Clinical and neurophysiological examinations were suggestive of bulbar-onset MND-FTD. Tractography showed a reduction of fractional anisotropy in the centrum semiovale, corona radiata, corticomedullary pathway and inferior aspect of the medulla; the changes were more severe on the left side. To our knowledge, this is the first report of an asymmetric presentation of an apraxic syndrome in MND-FTD.

  8. Heavy metals in locus ceruleus and motor neurons in motor neuron disease.

    Science.gov (United States)

    Pamphlett, Roger; Kum Jew, Stephen

    2013-12-12

    The causes of sporadic amyotrophic lateral sclerosis (SALS) and other types of motor neuron disease (MND) remain largely unknown. Heavy metals have long been implicated in MND, and it has recently been shown that inorganic mercury selectively enters human locus ceruleus (LC) and motor neurons. We therefore used silver nitrate autometallography (AMG) to look for AMG-stainable heavy metals (inorganic mercury and bismuth) in LC and motor neurons of 24 patients with MND (18 with SALS and 6 with familial MND) and in the LC of 24 controls. Heavy metals in neurons were found in significantly more MND patients than in controls when comparing: (1) the presence of any versus no heavy metal-containing LC neurons (MND 88%, controls 42%), (2) the median percentage of heavy metal-containing LC neurons (MND 9.5%, control 0.0%), and (3) numbers of individuals with heavy metal-containing LC neurons in the upper half of the percentage range (MND 75%, controls 25%). In MND patients, 67% of remaining spinal motor neurons contained heavy metals; smaller percentages were found in hypoglossal, nucleus ambiguus and oculomotor neurons, but none in cortical motor neurons. The majority of MND patients had heavy metals in both LC and spinal motor neurons. No glia or other neurons, including neuromelanin-containing neurons of the substantia nigra, contained stainable heavy metals. Uptake of heavy metals by LC and lower motor neurons appears to be fairly common in humans, though heavy metal staining in the LC, most likely due to inorganic mercury, was seen significantly more often in MND patients than in controls. The LC innervates many cell types that are affected in MND, and it is possible that MND is triggered by toxicant-induced interactions between LC and motor neurons.

  9. Heavy metals in locus ceruleus and motor neurons in motor neuron disease

    Science.gov (United States)

    2013-01-01

    Background The causes of sporadic amyotrophic lateral sclerosis (SALS) and other types of motor neuron disease (MND) remain largely unknown. Heavy metals have long been implicated in MND, and it has recently been shown that inorganic mercury selectively enters human locus ceruleus (LC) and motor neurons. We therefore used silver nitrate autometallography (AMG) to look for AMG-stainable heavy metals (inorganic mercury and bismuth) in LC and motor neurons of 24 patients with MND (18 with SALS and 6 with familial MND) and in the LC of 24 controls. Results Heavy metals in neurons were found in significantly more MND patients than in controls when comparing: (1) the presence of any versus no heavy metal-containing LC neurons (MND 88%, controls 42%), (2) the median percentage of heavy metal-containing LC neurons (MND 9.5%, control 0.0%), and (3) numbers of individuals with heavy metal-containing LC neurons in the upper half of the percentage range (MND 75%, controls 25%). In MND patients, 67% of remaining spinal motor neurons contained heavy metals; smaller percentages were found in hypoglossal, nucleus ambiguus and oculomotor neurons, but none in cortical motor neurons. The majority of MND patients had heavy metals in both LC and spinal motor neurons. No glia or other neurons, including neuromelanin-containing neurons of the substantia nigra, contained stainable heavy metals. Conclusions Uptake of heavy metals by LC and lower motor neurons appears to be fairly common in humans, though heavy metal staining in the LC, most likely due to inorganic mercury, was seen significantly more often in MND patients than in controls. The LC innervates many cell types that are affected in MND, and it is possible that MND is triggered by toxicant-induced interactions between LC and motor neurons. PMID:24330485

  10. associated neuron disease carCInoma Motor with

    African Journals Online (AJOL)

    1983-02-19

    Feb 19, 1983 ... re\\'ealed wasting of the temporalis muscle, upper motor neuron weakness of the ... left, there was bilateral wasting ofthe small muscles of the hands, .... disease with associated rectal adenocarcinoma and benign pros- tatic hypertrophy. Discussion. Motor neuron disease occurs in all parts of the world, with a.

  11. Motor neuron disease in blacks | Cosnett | South African Medical ...

    African Journals Online (AJOL)

    Motor neuron disease in blacks. JE Cosnett, PLA Bill, AI Bhigjee. Abstract. A series of 86 black, Indian and white patients with motor neuron disease were analysed retrospectively. Although the material does not allow statistically valid conclusions, there are sufficient cases among blacks to allow two prima facie observations ...

  12. Motor neuron disease associated with carcinoma | Gritzman | South ...

    African Journals Online (AJOL)

    Paraneoplastic complications are obscure and difficult to understand. The association of motor neuron disease and carcinoma may sometimes be more than coincidental, and 2 cases are described. One patient had motor neuron disease, limbic encephalitis (a recognized paraneoplastic disorder) and carcinoma of the ...

  13. Failure of Neuronal Maturation in Alzheimer Disease Dentate Gyrus

    Science.gov (United States)

    Li, Bin; Yamamori, Hidenaga; Tatebayashi, Yoshitaka; Shafit-Zagardo, Bridget; Tanimukai, Hitoshi; Chen, She; Iqbal, Khalid; Grundke-Iqbal, Inge

    2011-01-01

    The dentate gyrus, an important anatomic structure of the hippocampal formation, is one of the major areas in which neurogenesis takes place in the adult mammalian brain. Neurogenesis in the dentate gyrus is thought to play an important role in hippocampus-dependent learning and memory. Neurogenesis has been reported to be increased in the dentate gyrus of patients with Alzheimer disease, but it is not known whether the newly generated neurons differentiate into mature neurons. In this study, the expression of the mature neuronal marker high molecular weight microtubule-associated protein (MAP) isoforms MAP2a and b was found to be dramatically decreased in Alzheimer disease dentate gyrus, as determined by immunohistochemistry and in situ hybridization. The total MAP2, including expression of the immature neuronal marker, the MAP2c isoform, was less affected. These findings suggest that newly generated neurons in Alzheimer disease dentate gyrus do not become mature neurons, although neuroproliferation is increased. PMID:18091557

  14. Assessing neuronal networks: understanding Alzheimer's disease.

    LENUS (Irish Health Repository)

    Bokde, Arun L W

    2012-02-01

    Findings derived from neuroimaging of the structural and functional organization of the human brain have led to the widely supported hypothesis that neuronal networks of temporally coordinated brain activity across different regional brain structures underpin cognitive function. Failure of integration within a network leads to cognitive dysfunction. The current discussion on Alzheimer\\'s disease (AD) argues that it presents in part a disconnection syndrome. Studies using functional magnetic resonance imaging, positron emission tomography and electroencephalography demonstrate that synchronicity of brain activity is altered in AD and correlates with cognitive deficits. Moreover, recent advances in diffusion tensor imaging have made it possible to track axonal projections across the brain, revealing substantial regional impairment in fiber-tract integrity in AD. Accumulating evidence points towards a network breakdown reflecting disconnection at both the structural and functional system level. The exact relationship among these multiple mechanistic variables and their contribution to cognitive alterations and ultimately decline is yet unknown. Focused research efforts aimed at the integration of both function and structure hold great promise not only in improving our understanding of cognition but also of its characteristic progressive metamorphosis in complex chronic neurodegenerative disorders such as AD.

  15. Distortion of neuronal geometry and formation of aberrant synapses in neuronal storage disease.

    Science.gov (United States)

    Purpura, D P; Suzuki, K

    1976-10-29

    Golgi and electron microscope studies of cortical neurons in several lysosomal storage diseases were carried out to elucidate structural features of the large neural processes (meganeurites) that develop as storage sites for accumulated undigestible substrates. Meganeurites occur preferentially in pyramidal neurons wherein they develop between the base of the perikaryon and the initial portion of the axon. They frequently give rise to secondary neurites which bear filopodium-like processes. Meganeurites may possess spines some of which are contacted by presynaptic processes containing synaptic vesicles. The extent of meganeurite development is related to the onset, severity and clinical course of neuronal storage disease. Extensive development of bizarre and pleomorphic meganeurites occurs in classical Tay-Sachs disease (infantile GM2-gangliosidosis, B variant), whereas a smaller proportion of neurons exhibits meganeurites in juvenile GM2-hangliosidosis and Hurler's disease. Meganeurites with spines and spine synapses were prominent in GM2-gangliosidosis, AB variant. It is proposed that meganeurites and meganeurite synapses contribute to the onset and progression of neuronal dysfunction in storage diseases by altering electrical properties of the neuron and modifying integrative operations of somadendritic synaptic inputs.

  16. Direct Neuronal Reprogramming for Disease Modeling Studies Using Patient-Derived Neurons: What Have We Learned?

    Directory of Open Access Journals (Sweden)

    Janelle Drouin-Ouellet

    2017-09-01

    Full Text Available Direct neuronal reprogramming, by which a neuron is formed via direct conversion from a somatic cell without going through a pluripotent intermediate stage, allows for the possibility of generating patient-derived neurons. A unique feature of these so-called induced neurons (iNs is the potential to maintain aging and epigenetic signatures of the donor, which is critical given that many diseases of the CNS are age related. Here, we review the published literature on the work that has been undertaken using iNs to model human brain disorders. Furthermore, as disease-modeling studies using this direct neuronal reprogramming approach are becoming more widely adopted, it is important to assess the criteria that are used to characterize the iNs, especially in relation to the extent to which they are mature adult neurons. In particular: i what constitutes an iN cell, ii which stages of conversion offer the earliest/optimal time to assess features that are specific to neurons and/or a disorder and iii whether generating subtype-specific iNs is critical to the disease-related features that iNs express. Finally, we discuss the range of potential biomedical applications that can be explored using patient-specific models of neurological disorders with iNs, and the challenges that will need to be overcome in order to realize these applications.

  17. Diagnosis and management of motor neurone disease.

    Science.gov (United States)

    Orrell, Richard W

    2016-09-01

    Motor neurone disease is a rapidly progressive and fatal neurodegenerative condition which causes progressive weakness, with normal sensation. It can occur at any age but is more frequent with increasing age. Key clinical presentations include bulbar (slurred or difficult speech, problems swallowing, tongue fasciculation), limb (typically in one limb with weakness and muscle wasting), respiratory (breathlessness, chest muscle fasciculation) and cognitive features (behavioural change, emotional lability, features of frontotemporal dementia). Although survival is typically three to five years from symptom onset, there is significant individual variation. Rarely, survival may be 20 years or longer. Favourable features include a limb rather than a bulbar presentation, preserved weight and respiratory function, younger age of onset and longer time from fist symptom to diagnosis. The patient should be linked to a multidisciplinary team able to provide support from the start with a designated individual as the point of contact, with regular, coordinated assessments, as the patient's needs change and their condition progresses. Gastrostomy is an important supportive intervention which maximizes nutrition, and minimizes aspiration and chest infection. Adequate nutrition and hydration is key to maximizing health and survival. It is possible for a patient to control a computer and speech by eye. movement alone. An important consideration is voice banking where the patient may store their voice before there is difficulty with speech so that it can be used at a later stage if they need a communication aid. Impaired cough and retention of respiratory secretions is frequent in the later stages, and may be managed with physiotherapy. The patient should be referred for expert respiratory assessment if needed.

  18. Neuronal and glial purinergic receptors functions in neuron development and brain disease.

    Directory of Open Access Journals (Sweden)

    Ana edel Puerto

    2013-10-01

    Full Text Available Brain development requires the interaction of complex signalling pathways, involving different cell types and molecules. For a long time, most attention has focused on neurons in a neuronocentric conceptualization of CNS development, these cells fulfilling an intrinsic programme that establishes the brain’s morphology and function. By contrast, glia have mainly been studied as support cells, offering guidance or as the cells that react to brain injury. However, new evidence is appearing that demonstrates a more fundamental role of glial cells in the control of different aspects of neuronal development and function, events in which the influence of neurons is at best weak. Moreover, it is becoming clear that the function and organization of the nervous system depends heavily on reciprocal neuron-glia interactions. During development, neurons are often generated far from their final destination and while intrinsic mechanisms are responsible for neuronal migration and growth, they need support and regulatory influences from glial cells in order to migrate correctly. Similarly, the axons emitted by neurons often have to reach faraway targets and in this sense, glia help define the way that axons grow. Moreover, oligodendrocytes and Schwann cells ultimately envelop axons, contributing to the generation of Nodes of Ranvier. Finally, recent publications show that astrocytes contribute to the modulation of synaptic transmission. In this sense, purinergic receptors are expressed widely by glial cells and neurons, and recent evidence points to multiple roles of purines and purinergic receptors in neuronal development and function, from neurogenesis to axon growth and functional axonal maturation, as well as in pathological conditions in the brain. This review will focus on the role of glial and neuronal secreted purines, and on the purinergic receptors, fundamentally in the control of neuronal development and function, as well as in diseases of the

  19. Familial resemblance on the Thurstone Activity Scale, systolic blood pressure, and total cholesterol among first degree relatives of subjects with and without coronary heart disease.

    Science.gov (United States)

    Carmelli, D; Rosenman, R

    1985-01-01

    An investigation of the pattern of familial resemblance of three different risk factors assessed in families of coronary heart disease (CHD) patients and controls is presented. The fathers of these families participated in the Western Collaborative Group Study that first established the type A/B behavior pattern as an independent risk factor for CHD. A recently developed methodology, the Structured Exploratory Data Analysis (SEDA), was implemented to examine parental interaction, parent-offspring closeness, asymmetries in transmission, and other differences in the pattern of familial similarities among family members of case and control subjects. The analysis performed revealed pronounced parent-child similarity for total serum cholesterol values in both case and control families; spouse closeness and parent-child resemblance for systolic blood pressure measurements only in control families; and sex asymmetries in the parent-child closeness on pace of activity, which also differed between case and control families. The results of this investigation underscore the value of examining the joint pattern of familial resemblance of a number of risk factors as a means for differentiating between cultural and biological factors affecting familial aggregation of CHD.

  20. Disseminated Alveolar Hydatid Disease Resembling a Metastatic Malignancy: A Diagnostic Challenge—A Report of Two Cases

    Directory of Open Access Journals (Sweden)

    Mesut Bulakci

    2014-01-01

    Full Text Available Alveolar hydatid disease or alveolar echinococcosis is a disease of the parasite Echinococcus multilocularis that is potentially fatal if left untreated. It primarily involves the liver but can be disseminated to other organs like the lungs and the brain by hematogenous route. Multiorgan involvement and the aggressive appearance of lesions make alveolar hydatid disease easy to confuse with a metastatic malignancy. For this reason, histopathological confirmation is essential for definite diagnosis. We present the imaging features of this disease in two patients in order to emphasize that these lesions can be easily misdiagnosed as malignancies.

  1. Neuronal histamine and cognitive symptoms in Alzheimer's disease.

    Science.gov (United States)

    Zlomuzica, Armin; Dere, Dorothea; Binder, Sonja; De Souza Silva, Maria Angelica; Huston, Joseph P; Dere, Ekrem

    2016-07-01

    Alzheimer's disease is a neurodegenerative disorder characterized by extracellular amyloid plaque deposits, mainly composed of amyloid-beta peptide and intracellular neurofibrillary tangles consisting of aggregated hyperphosphorylated tau protein. Amyloid-beta represents a neurotoxic proteolytic cleavage product of amyloid precursor protein. The progressive cognitive decline that is associated with Alzheimer's disease has been mainly attributed to a deficit in cholinergic neurotransmission due to the continuous degeneration of cholinergic neurons e.g. in the basal forebrain. There is evidence suggesting that other neurotransmitter systems including neuronal histamine also contribute to the development and maintenance of Alzheimer's disease-related cognitive deficits. Pathological changes in the neuronal histaminergic system of such patients are highly predictive of ensuing cognitive deficits. Furthermore, histamine-related drugs, including histamine 3 receptor antagonists, have been demonstrated to alleviate cognitive symptoms in Alzheimer's disease. This review summarizes findings from animal and clinical research on the relationship between the neuronal histaminergic system and cognitive deterioration in Alzheimer's disease. The significance of the neuronal histaminergic system as a promising target for the development of more effective drugs for the treatment of cognitive symptoms is discussed. Furthermore, the option to use histamine-related agents as neurogenesis-stimulating therapy that counteracts progressive brain atrophy in Alzheimer's disease is considered. This article is part of a Special Issue entitled 'Histamine Receptors'. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Dysarthria of Motor Neuron Disease: Clinician Judgments of Severity.

    Science.gov (United States)

    Seikel, J. Anthony; And Others

    1990-01-01

    This study investigated the relationship between the temporal-acoustic parameters of the speech of 15 adults with motor neuron disease. Differences in predictions of the progression of the disease and clinician judgments of dysarthria severity were found to relate to the linguistic systems of both speaker and judge. (Author/JDD)

  3. Communications Technology and Motor Neuron Disease: An Australian Survey of People With Motor Neuron Disease

    Science.gov (United States)

    2016-01-01

    Background People with Motor Neuron Disease (MND), of which amyotrophic lateral sclerosis (ALS) is the most common form in adults, typically experience difficulties with communication and disabilities associated with movement. Assistive technology is essential to facilitate everyday activities, promote social support and enhance quality of life. Objective This study aimed to explore the types of mainstream and commonly available communication technology used by people with MND including software and hardware, to identify the levels of confidence and skill that people with MND reported in using technology, to determine perceived barriers to the use of technology for communication, and to investigate the willingness of people with MND to adopt alternative modes of communication. Methods An on-line survey was distributed to members of the New South Wales Motor Neuron Disease Association (MND NSW). Descriptive techniques were used to summarize frequencies of responses and cross tabulate data. Free-text responses to survey items and verbal comments from participants who chose to undertake the survey by telephone were analyzed using thematic analysis. Results Responses from 79 MND NSW members indicated that 15-21% had difficulty with speaking, writing and/or using a keyboard. Commonly used devices were desktop computers, laptops, tablets and mobile phones. Most participants (84%) were connected to the Internet and used it for email (91%), to find out more about MND (59%), to follow the news (50%) or for on-line shopping (46%). A third of respondents used Skype or its equivalent, but few used this to interact with health professionals. Conclusions People with MND need greater awareness of technology options to access the most appropriate solutions. The timing for people with MND to make decisions about technology is critical. Health professionals need skills and knowledge about the application of technology to be able to work with people with MND to select the best

  4. Communications Technology and Motor Neuron Disease: An Australian Survey of People With Motor Neuron Disease.

    Science.gov (United States)

    Mackenzie, Lynette; Bhuta, Prarthna; Rusten, Kim; Devine, Janet; Love, Anna; Waterson, Penny

    2016-01-25

    People with Motor Neuron Disease (MND), of which amyotrophic lateral sclerosis (ALS) is the most common form in adults, typically experience difficulties with communication and disabilities associated with movement. Assistive technology is essential to facilitate everyday activities, promote social support and enhance quality of life. This study aimed to explore the types of mainstream and commonly available communication technology used by people with MND including software and hardware, to identify the levels of confidence and skill that people with MND reported in using technology, to determine perceived barriers to the use of technology for communication, and to investigate the willingness of people with MND to adopt alternative modes of communication. An on-line survey was distributed to members of the New South Wales Motor Neuron Disease Association (MND NSW). Descriptive techniques were used to summarize frequencies of responses and cross tabulate data. Free-text responses to survey items and verbal comments from participants who chose to undertake the survey by telephone were analyzed using thematic analysis. Responses from 79 MND NSW members indicated that 15-21% had difficulty with speaking, writing and/or using a keyboard. Commonly used devices were desktop computers, laptops, tablets and mobile phones. Most participants (84%) were connected to the Internet and used it for email (91%), to find out more about MND (59%), to follow the news (50%) or for on-line shopping (46%). A third of respondents used Skype or its equivalent, but few used this to interact with health professionals. People with MND need greater awareness of technology options to access the most appropriate solutions. The timing for people with MND to make decisions about technology is critical. Health professionals need skills and knowledge about the application of technology to be able to work with people with MND to select the best communication technology options as early as possible

  5. Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease.

    Science.gov (United States)

    Scher, Jose U; Ubeda, Carles; Artacho, Alejandro; Attur, Mukundan; Isaac, Sandrine; Reddy, Soumya M; Marmon, Shoshana; Neimann, Andrea; Brusca, Samuel; Patel, Tejas; Manasson, Julia; Pamer, Eric G; Littman, Dan R; Abramson, Steven B

    2015-01-01

    To characterize the diversity and taxonomic relative abundance of the gut microbiota in patients with never-treated, recent-onset psoriatic arthritis (PsA). High-throughput 16S ribosomal RNA pyrosequencing was utilized to compare the community composition of gut microbiota in patients with PsA (n = 16), patients with psoriasis of the skin (n = 15), and healthy, matched control subjects (n = 17). Samples were further assessed for the presence and levels of fecal and serum secretory IgA (sIgA), proinflammatory proteins, and fatty acids. The gut microbiota observed in patients with PsA and patients with skin psoriasis was less diverse when compared to that in healthy controls. This could be attributed to the reduced presence of several taxa. Samples from both patient groups showed a relative decrease in abundance of Coprococcus species, while samples from PsA patients were also characterized by a significant reduction in Akkermansia, Ruminococcus, and Pseudobutyrivibrio. Supernatants of fecal samples from PsA patients revealed an increase in sIgA levels and decrease in RANKL levels. Analysis of fatty acids revealed low fecal quantities of hexanoate and heptanoate in both patients with PsA and patients with psoriasis. Patients with PsA and patients with skin psoriasis had a lower relative abundance of multiple intestinal bacteria. Although some genera were concomitantly decreased in both conditions, PsA samples had a lower abundance of reportedly beneficial taxa. This gut microbiota profile in PsA was similar to that previously described in patients with inflammatory bowel disease and was associated with changes in specific inflammatory proteins unique to this group, and distinct from that in patients with skin psoriasis and healthy controls. Thus, the role of the gut microbiome in the continuum of psoriasis-PsA pathogenesis and the associated immune response merits further study. Copyright © 2015 by the American College of Rheumatology.

  6. Human endogenous retrovirus-K contributes to motor neuron disease.

    Science.gov (United States)

    Li, Wenxue; Lee, Myoung-Hwa; Henderson, Lisa; Tyagi, Richa; Bachani, Muzna; Steiner, Joseph; Campanac, Emilie; Hoffman, Dax A; von Geldern, Gloria; Johnson, Kory; Maric, Dragan; Morris, H Douglas; Lentz, Margaret; Pak, Katherine; Mammen, Andrew; Ostrow, Lyle; Rothstein, Jeffrey; Nath, Avindra

    2015-09-30

    The role of human endogenous retroviruses (HERVs) in disease pathogenesis is unclear. We show that HERV-K is activated in a subpopulation of patients with sporadic amyotrophic lateral sclerosis (ALS) and that its envelope (env) protein may contribute to neurodegeneration. The virus was expressed in cortical and spinal neurons of ALS patients, but not in neurons from control healthy individuals. Expression of HERV-K or its env protein in human neurons caused retraction and beading of neurites. Transgenic animals expressing the env gene developed progressive motor dysfunction accompanied by selective loss of volume of the motor cortex, decreased synaptic activity in pyramidal neurons, dendritic spine abnormalities, nucleolar dysfunction, and DNA damage. Injury to anterior horn cells in the spinal cord was manifested by muscle atrophy and pathological changes consistent with nerve fiber denervation and reinnervation. Expression of HERV-K was regulated by TAR (trans-activation responsive) DNA binding protein 43, which binds to the long terminal repeat region of the virus. Thus, HERV-K expression within neurons of patients with ALS may contribute to neurodegeneration and disease pathogenesis. Copyright © 2015, American Association for the Advancement of Science.

  7. What is happening to motor neuron disease in Nigeria? | Imam ...

    African Journals Online (AJOL)

    Conclusions: The frequency of motor neuron disease appears to have declined considerably. While the onset remains in the younger age group, the male predominance has remarkably increased. The proportion of amyotrophic lateral sclerosis has increased from 80 to 100% of cases. Trauma, previously reported to be an ...

  8. Modeling motor neuron disease : the matter of time

    NARCIS (Netherlands)

    Arbab, Mandana; Baars, Susanne; Geijsen, Niels

    2014-01-01

    Stem cell technologies have created new opportunities to generate unlimited numbers of human neurons in the lab and study neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Although some disease hallmarks have been reported in patient-derived

  9. Spinal Muscular Atrophy: More than a Disease of Motor Neurons?

    Science.gov (United States)

    Nash, L A; Burns, J K; Chardon, J Warman; Kothary, R; Parks, R J

    2016-01-01

    Spinal muscular atrophy (SMA) is the most common genetically inherited neurodegenerative disease resulting in infant mortality. SMA is caused by genetic deletion or mutation in the survival of motor neuron 1 (SMN1) gene, which results in reduced levels of the survival of motor neuron (SMN) protein. SMN protein deficiency preferentially affects α- motor neurons, leading to their degeneration and subsequent atrophy of limb and trunk muscles, progressing to death in severe forms of the disease. More recent studies have shown that SMN protein depletion is detrimental to the functioning of other tissues including skeletal muscle, heart, autonomic and enteric nervous systems, metabolic/endocrine (e.g. pancreas), lymphatic, bone and reproductive system. In this review, we summarize studies discussing SMN protein's function in various cell and tissue types and their involvement in the context of SMA disease etiology. Taken together, these studies indicate that SMA is a multi-organ disease, which suggests that truly effective disease intervention may require body-wide correction of SMN protein levels. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Glutamate and Neurotrophic Factors in Neuronal Plasticity and Disease

    Science.gov (United States)

    Mattson, Mark P.

    2008-01-01

    Glutamate’s role as a neurotransmitter at synapses has been known for 40 years, but glutamate has since been shown to regulate neurogenesis, neurite outgrowth, synaptogenesis and neuron survival in the developing and adult mammalian nervous system. Cell surface glutamate receptors are coupled to Ca2+ influx and release from endoplasmic reticulum stores which causes rapid (kinase- and protease-mediated) and delayed (transcription-dependent) responses that change the structure and function of neurons. Neurotrophic factors and glutamate interact to regulate developmental and adult neuroplasticity. For example, glutamate stimulates the production of brain-derived neurotrophic factor (BDNF) which, in turn, modifies neuronal glutamate sensitivity, Ca2+ homeostasis and plasticity. Neurotrophic factors may modify glutamate signalling directly, by changing the expression of glutamate receptor subunits and Ca2+-regulating proteins, and also indirectly by inducing the production of antioxidant enzymes, energy-regulating proteins and anti-apoptotic Bcl2 family members. Excessive activation of glutamate receptors, under conditions of oxidative and metabolic stress, may contribute to neuronal dysfunction and degeneration in diseases ranging from stroke and Alzheimer’s disease to psychiatric disorders. By enhancing neurotrophic factor signalling, environmental factors such as exercise and dietary energy restriction, and chemicals such as antidepressants may optimize glutamatergic signalling and protect against neurological disorders. PMID:19076369

  11. Alloxan-Induced Diabetes Causes Morphological and Ultrastructural Changes in Rat Liver that Resemble the Natural History of Chronic Fatty Liver Disease in Humans

    Directory of Open Access Journals (Sweden)

    Amanda Natália Lucchesi

    2015-01-01

    Full Text Available Purpose. This study evaluated the long-term effects of alloxan-induced diabetes in rat liver. Methods. Thirty nondiabetic control rats (NC and 30 untreated diabetic (UD rats were divided into three subgroups sacrificed after 6, 14, or 26 weeks. Clinical and laboratory parameters were assessed. Fresh liver weight and its relationship with body weight were obtained, and liver tissue was analyzed. Results. UD rats showed sustained hyperglycemia, high glycosylated hemoglobin, and low plasma insulin. High serum levels of AST and ALT were observed in UD rats after 2 weeks, but only ALT remained elevated throughout the experiment. Fresh liver weight was equal between NC and UD rats, but the fresh liver weight/body weight ratio was significantly higher in UD rats after 14 and 26 weeks. UD rats showed liver morphological changes characterized by hepatic sinusoidal enlargement and micro- and macrovesicular hepatocyte fatty degeneration with progressive liver structure loss, steatohepatitis, and periportal fibrosis. Ultrastructural changes of hepatocytes, such as a decrease in the number of intracytoplasmic organelles and degeneration of mitochondria, rough endoplasmic reticulum, and nuclei, were also observed. Conclusion. Alloxan-induced diabetes triggered liver morphological and ultrastructural changes that closely resembled human disease, ranging from steatosis to steatohepatitis and liver fibrosis.

  12. Metals and Neuronal Metal Binding Proteins Implicated in Alzheimer's Disease

    Science.gov (United States)

    2016-01-01

    Alzheimer's disease (AD) is the most prevalent age-related dementia affecting millions of people worldwide. Its main pathological hallmark feature is the formation of insoluble protein deposits of amyloid-β and hyperphosphorylated tau protein into extracellular plaques and intracellular neurofibrillary tangles, respectively. Many of the mechanistic details of this process remain unknown, but a well-established consequence of protein aggregation is synapse dysfunction and neuronal loss in the AD brain. Different pathways including mitochondrial dysfunction, oxidative stress, inflammation, and metal metabolism have been suggested to be implicated in this process. In particular, a body of evidence suggests that neuronal metal ions such as copper, zinc, and iron play important roles in brain function in health and disease states and altered homeostasis and distribution as a common feature across different neurodegenerative diseases and aging. In this focused review, we overview neuronal proteins that are involved in AD and whose metal binding properties may underlie important biochemical and regulatory processes occurring in the brain during the AD pathophysiological process. PMID:26881049

  13. Firing patterns of muscle vasoconstrictor neurones in respiratory disease

    Directory of Open Access Journals (Sweden)

    Vaughan G Macefield

    2012-05-01

    Full Text Available Because the cardiovascular system and respiration are so intimately coupled, disturbances in respiratory control often lead to disturbances in cardiovascular control. Obstructive Sleep Apnoea (OSA, Chronic Obstructive Pulmonary Disease (COPD and Bronchiectasis (BE are all associated with a greatly elevated muscle vasoconstrictor drive (muscle sympathetic nerve activity; MSNA. Indeed, the increase in MSNA is comparable to that seen in congestive heart failure (CHF, in which the increase in MSNA compensates for the reduced cardiac output and thereby assists in maintaining blood pressure. However, in OSA – but not COPD or BE – the increase in MSNA can lead to hypertension. Here, the features of the sympathoexcitation in OSA, COPD and BE are reviewed in terms of the firing properties of post-ganglionic muscle vasoconstrictor neurones. Compared to healthy subjects with low levels of resting MSNA, single-unit recordings revealed that the augmented MSNA seen in OSA, BE, COPD and CHF were each associated with an increase in firing probability and mean firing rates of individual neurones. However, unlike patients with heart failure, all patients with respiratory disease exhibited an increase in multiple within-burst firing which, it is argued, reflects an increase in central sympathetic drive. Similar patterns to those seen in OSA, COPD and BE were seen in healthy subjects during an acute increase in muscle vasoconstrictor drive. These observations emphasise the differences by which the sympathetic nervous system grades its output in health and disease, with an increase in firing probability of active neurones and recruitment of additional neurones being the dominant mechanisms.

  14. Nonmotor symptoms in patients suffering from motor neuron diseases

    Directory of Open Access Journals (Sweden)

    Rene Günther

    2016-07-01

    Full Text Available Background: The recently postulated disease spreading hypothesis has gained much attention, especially for Parkinson’s disease (PD. The various nonmotor symptoms (NMS in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND is primarily known as a group of diseases with a selective loss of motor function. Recent evidence, however, suggests disease spreading into nonmotor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND.Methods: We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric and sleep complaints (NMSQuest which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls.Results: In total, MND patients reported significantly higher NMS scores (median: 7 points in comparison to controls (median: 4 points. Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression.Conclusions: NMS in MND patients seemed to increase with disease progression which would fit with the recently postulated disease spreading hypothesis. The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.

  15. Electron microscopic examination of skin and conjunctival biopsy specimens in neuronal storage diseases.

    Science.gov (United States)

    Yamano, T; Shimada, M; Okada, S; Yutaka, T; Yabuuchi, H; Nakao, Y

    1979-01-01

    Skin and conjunctival biopsy specimens from fourteen patients with neuronal storage diseases were investigated using an electron microscope. The diseases were Tay-Sachs disease, ceroid-lipofuscinosis (Jansky-Bielschowsky type), Niemann-Pick disease (type B), highly suspected adrenoleukodystrophy, I-cell disease, mucolipidosis of the beta-galactosidase deficient type, Hurler disease, Hunter disease and Morquio disease. This examination provided valuable diagnostic information on some neuronal storage diseases but not on Morquio disease or highly suspected adrenoleukodystrophy. False negative results may sometimes occur using this examination method. However, this examination suggests the usefulness of skin and conjunctival biopsy specimens as a diagnostic tool in some neuronal storage diseases.

  16. Lack of Neuronal IFN-β-IFNAR Causes Lewy Body- and Parkinson's Disease-like Dementia

    DEFF Research Database (Denmark)

    Ejlerskov, Patrick; Hultberg, Jeanette Göransdotter; Wang, JunYang

    2015-01-01

    defects in neuronal autophagy prior to α-synucleinopathy, which was associated with accumulation of senescent mitochondria. Recombinant IFN-β promoted neurite growth and branching, autophagy flux, and α-synuclein degradation in neurons. In addition, lentiviral IFN-β overexpression prevented dopaminergic...... neuron loss in a familial Parkinson's disease model. These results indicate a protective role for IFN-β in neuronal homeostasis and validate Ifnb mutant mice as a model for sporadic Lewy body and Parkinson's disease dementia....

  17. The in vivo contribution of motor neuron TrkB receptors to mutant SOD1 motor neuron disease.

    Science.gov (United States)

    Zhai, Jinbin; Zhou, Weiguo; Li, Jian; Hayworth, Christopher R; Zhang, Lei; Misawa, Hidemi; Klein, Rudiger; Scherer, Steven S; Balice-Gordon, Rita J; Kalb, Robert Gordon

    2011-11-01

    Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) are widely expressed in the vertebrate nervous system and play a central role in mature neuronal function. In vitro BDNF/TrkB signaling promotes neuronal survival and can help neurons resist toxic insults. Paradoxically, BDNF/TrkB signaling has also been shown, under certain in vitro circumstances, to render neurons vulnerable to insults. We show here that in vivo conditional deletion of TrkB from mature motor neurons attenuates mutant superoxide dismutase 1 (SOD1) toxicity. Mutant SOD1 mice lacking motor neuron TrkB live a month longer than controls and retain motor function for a longer period, particularly in the early phase of the disease. These effects are subserved by slowed motor neuron loss, persistence of neuromuscular junction integrity and reduced astrocytic and microglial reactivity within the spinal cord. These results suggest that manipulation of BDNF/TrkB signaling might have therapeutic efficacy in motor neuron diseases.

  18. Progressive neuronal degeneration of childhood with liver disease

    International Nuclear Information System (INIS)

    Kendall, B.E.; Boyd, S.G.; Egger, J.; Harding, B.N.

    1987-01-01

    The clinical, electrophysiological and neuroradiological features of thirteen patients suffering from progressive neuronal degeneration of childhood with liver failure are presented. The disease commonly presents very early in life with progressive mental retardation, followed by intractable epilepsy, and should be suspected clinically especially if there is a family history of similar disorder in a sibling. On computed tomography there are low density regions, particularly in the occipital and posterior temporal lobes, involving both cortex and white matter, combined with or followed by progressive atrophy. Typical EEG findings may be confirmatory. (orig.)

  19. Neuromuscular ultrasound in polyneuropathies and motor neuron disease.

    Science.gov (United States)

    Hobson-Webb, Lisa D

    2013-06-01

    Current standards for diagnosing polyneuropathies (PN) and motor neuron disease (MND) sometimes lack early sensitivity and result in delayed diagnosis and treatment. Neuromuscular ultrasound (NMUS), already established in the diagnosis of entrapment neuropathies, may offer another means of diagnosis and monitoring response to therapy. This review of current evidence discusses diffuse nerve hypertrophy in hereditary demyelinating neuropathies, multifocal nerve enlargement in acquired demyelinating PN and the lack of readily apparent structural change in axonal neuropathies. NMUS detection of fasciculations and muscular change in MND is also reviewed, along with the need for further research to better define the role of nerve imaging in patients with PN. Copyright © 2013 Wiley Periodicals, Inc.

  20. Does facial resemblance enhance cooperation?

    Directory of Open Access Journals (Sweden)

    Trang Giang

    Full Text Available Facial self-resemblance has been proposed to serve as a kinship cue that facilitates cooperation between kin. In the present study, facial resemblance was manipulated by morphing stimulus faces with the participants' own faces or control faces (resulting in self-resemblant or other-resemblant composite faces. A norming study showed that the perceived degree of kinship was higher for the participants and the self-resemblant composite faces than for actual first-degree relatives. Effects of facial self-resemblance on trust and cooperation were tested in a paradigm that has proven to be sensitive to facial trustworthiness, facial likability, and facial expression. First, participants played a cooperation game in which the composite faces were shown. Then, likability ratings were assessed. In a source memory test, participants were required to identify old and new faces, and were asked to remember whether the faces belonged to cooperators or cheaters in the cooperation game. Old-new recognition was enhanced for self-resemblant faces in comparison to other-resemblant faces. However, facial self-resemblance had no effects on the degree of cooperation in the cooperation game, on the emotional evaluation of the faces as reflected in the likability judgments, and on the expectation that a face belonged to a cooperator rather than to a cheater. Therefore, the present results are clearly inconsistent with the assumption of an evolved kin recognition module built into the human face recognition system.

  1. Beta-band intermuscular coherence: a novel biomarker of upper motor neuron dysfunction in motor neuron disease.

    Science.gov (United States)

    Fisher, Karen M; Zaaimi, Boubker; Williams, Timothy L; Baker, Stuart N; Baker, Mark R

    2012-09-01

    In motor neuron disease, the focus of therapy is to prevent or slow neuronal degeneration with neuroprotective pharmacological agents; early diagnosis and treatment are thus essential. Incorporation of needle electromyographic evidence of lower motor neuron degeneration into diagnostic criteria has undoubtedly advanced diagnosis, but even earlier diagnosis might be possible by including tests of subclinical upper motor neuron disease. We hypothesized that beta-band (15-30 Hz) intermuscular coherence could be used as an electrophysiological marker of upper motor neuron integrity in such patients. We measured intermuscular coherence in eight patients who conformed to established diagnostic criteria for primary lateral sclerosis and six patients with progressive muscular atrophy, together with 16 age-matched controls. In the primary lateral sclerosis variant of motor neuron disease, there is selective destruction of motor cortical layer V pyramidal neurons and degeneration of the corticospinal tract, without involvement of anterior horn cells. In progressive muscular atrophy, there is selective degeneration of anterior horn cells but a normal corticospinal tract. All patients with primary lateral sclerosis had abnormal motor-evoked potentials as assessed using transcranial magnetic stimulation, whereas these were similar to controls in progressive muscular atrophy. Upper and lower limb intermuscular coherence was measured during a precision grip and an ankle dorsiflexion task, respectively. Significant beta-band coherence was observed in all control subjects and all patients with progressive muscular atrophy tested, but not in the patients with primary lateral sclerosis. We conclude that intermuscular coherence in the 15-30 Hz range is dependent on an intact corticospinal tract but persists in the face of selective anterior horn cell destruction. Based on the distributions of coherence values measured from patients with primary lateral sclerosis and control

  2. Amyotrophic lateral sclerosis – a motor neuron disease. Case report

    Directory of Open Access Journals (Sweden)

    Maja Rubinowicz-Zasada

    2015-03-01

    Full Text Available Amyotrophic lateral sclerosis, also known as Charcot’s disease and motor neuron disease, is a progressive neurodegenerative disease that causes muscle weakness, paralysis, and ultimately, respiratory failure. The aetiology and the pathogenesis of the syndrome remain unknown. Most people live 2–5 years after their first signs of the disease. There is no cure or effective treatment. We present a case of a female patient affected by progressing Charcot’s disease. On the Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised (ALSFRS-R, the patient obtained 21 points. Atrophy and muscle spasm were very extended. Electromyography revealed features of coexisting denervation and reinnervation in the examined muscles. A growing number of Charcot’s disease cases require multidirectional actions to meet patient’s physical, emotional, and nutritional needs. Amyotrophic lateral sclerosis is an incurable disease. However, it is possible to relieve its symptoms by applying systematic physical rehabilitation.

  3. Magnetic resonance imaging applied to motor neuron disease

    International Nuclear Information System (INIS)

    Markarian, Maria F.; Villarroal, Gonzalo M.; Giavitto, Enrique; Nagel, Jorge

    2005-01-01

    Objective: Differentiate Motor Neuron Disease by MRI. Material and Methods: 10 patients were studied, 7 patients had a diagnosis of definite ALS by the El Escorial criteria, 2 patients had lower motor neuron signs (LMN) and hyperreflexia and one patient had LMN signs without pain. MRI was performed: slices brain: Sagittal T1-weighted, sagittal and axial FSE T2, axial and coronal FLAIR, diffusion, singlevoxel spectroscopy in protuberances. Functional MRI with motor test; slices in cervical spine: Sagittal T1-weighted, sagittal and axial FSE T2, sagittal FSIR. Results: The 7 patients with definite ALS by El Escorial criteria and 2 patients with LMN signs and hyperreflexia: hyperintensity signal in FSE T2 and FLAIR extending from the motor cortex down to the corona radiate, posterior limb of internal capsules, cerebral peduncles and protuberance base; FSE T2: hypointensity sign in motor cortex; elevation in diffusivity and hyperintensity signal in ADC in posterior limb of internal capsule; reduction of NAA, high levels of Glutamine-Glutamate and of Colina. One of these 9 patients showed disc hernia in C4-5, and other patient in C3-C4, C4-C5 without cord lesion. The patient with LMN signs without pain showed normal brain and disc hernia C5-C6, hypertrophy yellow ligament, anterior-posterior diminution of medullar canal, hyperintensity signal in spine cord in the same level in sagittal FSIR. fMRI: increase signal in contralateral, ipsilateral motor area, and areas involved in initiation and planning movement. Conclusion: MRI allow differentiation between ALS and myelopathy cervical spondylitis and others motor neuron disease. (author) [es

  4. Selective disruption of acetylcholine synthesis in subsets of motor neurons: a new model of late-onset motor neuron disease.

    Science.gov (United States)

    Lecomte, Marie-José; Bertolus, Chloé; Santamaria, Julie; Bauchet, Anne-Laure; Herbin, Marc; Saurini, Françoise; Misawa, Hidemi; Maisonobe, Thierry; Pradat, Pierre-François; Nosten-Bertrand, Marika; Mallet, Jacques; Berrard, Sylvie

    2014-05-01

    Motor neuron diseases are characterized by the selective chronic dysfunction of a subset of motor neurons and the subsequent impairment of neuromuscular function. To reproduce in the mouse these hallmarks of diseases affecting motor neurons, we generated a mouse line in which ~40% of motor neurons in the spinal cord and the brainstem become unable to sustain neuromuscular transmission. These mice were obtained by conditional knockout of the gene encoding choline acetyltransferase (ChAT), the biosynthetic enzyme for acetylcholine. The mutant mice are viable and spontaneously display abnormal phenotypes that worsen with age including hunched back, reduced lifespan, weight loss, as well as striking deficits in muscle strength and motor function. This slowly progressive neuromuscular dysfunction is accompanied by muscle fiber histopathological features characteristic of neurogenic diseases. Unexpectedly, most changes appeared with a 6-month delay relative to the onset of reduction in ChAT levels, suggesting that compensatory mechanisms preserve muscular function for several months and then are overwhelmed. Deterioration of mouse phenotype after ChAT gene disruption is a specific aging process reminiscent of human pathological situations, particularly among survivors of paralytic poliomyelitis. These mutant mice may represent an invaluable tool to determine the sequence of events that follow the loss of function of a motor neuron subset as the disease progresses, and to evaluate therapeutic strategies. They also offer the opportunity to explore fundamental issues of motor neuron biology. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Finger extension weakness and downbeat nystagmus motor neuron disease syndrome: A novel motor neuron disorder?

    Science.gov (United States)

    Delva, Aline; Thakore, Nimish; Pioro, Erik P; Poesen, Koen; Saunders-Pullman, Rachel; Meijer, Inge A; Rucker, Janet C; Kissel, John T; Van Damme, Philip

    2017-12-01

    Disturbances of eye movements are infrequently encountered in motor neuron diseases (MNDs) or motor neuropathies, and there is no known syndrome that combines progressive muscle weakness with downbeat nystagmus. To describe the core clinical features of a syndrome of MND associated with downbeat nystagmus, clinical features were collected from 6 patients. All patients had slowly progressive muscle weakness and wasting in combination with downbeat nystagmus, which was clinically most obvious in downward and lateral gaze. Onset was in the second to fourth decade with finger extension weakness, progressing to other distal and sometimes more proximal muscles. Visual complaints were not always present. Electrodiagnostic testing showed signs of regional motor axonal loss in all patients. The etiology of this syndrome remains elusive. Because finger extension weakness and downbeat nystagmus are the discriminating clinical features of this MND, we propose the name FEWDON-MND syndrome. Muscle Nerve 56: 1164-1168, 2017. © 2017 The Authors Muscle & Nerve Published by Wiley Periodicals, Inc.

  6. Controlling the Regional Identity of hPSC-Derived Neurons to Uncover Neuronal Subtype Specificity of Neurological Disease Phenotypes

    Directory of Open Access Journals (Sweden)

    Kent Imaizumi

    2015-12-01

    Full Text Available The CNS contains many diverse neuronal subtypes, and most neurological diseases target specific subtypes. However, the mechanism of neuronal subtype specificity of disease phenotypes remains elusive. Although in vitro disease models employing human pluripotent stem cells (PSCs have great potential to clarify the association of neuronal subtypes with disease, it is currently difficult to compare various PSC-derived subtypes. This is due to the limited number of subtypes whose induction is established, and different cultivation protocols for each subtype. Here, we report a culture system to control the regional identity of PSC-derived neurons along the anteroposterior (A-P and dorsoventral (D-V axes. This system was successfully used to obtain various neuronal subtypes based on the same protocol. Furthermore, we reproduced subtype-specific phenotypes of amyotrophic lateral sclerosis (ALS and Alzheimer’s disease (AD by comparing the obtained subtypes. Therefore, our culture system provides new opportunities for modeling neurological diseases with PSCs.

  7. The Impact of Exercise on the Vulnerability of Dopamine Neurons to Cell Death in Animal Models of Parkinson's Disease

    National Research Council Canada - National Science Library

    Zigmond, Michael J; Smith, Amanda; Liou, Anthony

    2006-01-01

    Parkinson's disease results in part from the loss of dopamine neurons. We hypothesize that exercise reduces the vulnerability of dopamine neurons to neurotoxin exposure, whereas stress increases vulnerability...

  8. Patterns of symptom development in patients with motor neuron disease.

    Science.gov (United States)

    Walhout, Renée; Verstraete, Esther; van den Heuvel, Martijn P; Veldink, Jan H; van den Berg, Leonard H

    2018-02-01

    To investigate whether symptom development in motor neuron disease (MND) is a random or organized process. Six hundred patients with amyotrophic lateral sclerosis (ALS), upper motor neuron (UMN) or lower motor neuron (LMN) phenotypes were invited for a questionnaire concerning symptom development. A binomial test was used to examine distribution of symptoms from site of onset. Development of symptoms over time was evaluated by Kaplan-Meier analysis. There were 470 respondents (ALS = 254; LMN = 100; UMN = 116). Subsequent symptoms were more often in the contralateral limb following unilateral limb onset (ALS: arms p = 1.05 × 10 -8 , legs p < 2.86 × 10 -15 ; LMN phenotype: arms p = 6.74 × 10 -9 , legs p = 6.26 × 10 -6 ; UMN phenotype: legs p = 4.07 × 10 -14 ). In patients with limb onset, symptoms occurred significantly faster in the contralateral limb, followed by the other limbs and lastly by the bulbar region. Patterns of non-contiguous symptom development were also reported: leg symptoms followed bulbar onset in 30%, and bulbar symptoms followed leg onset in 11% of ALS patients. Preferred spread of symptoms from one limb to the contralateral limb, and to adjacent sites appears to be a characteristic of MND phenotypes, suggesting that symptom spread is organized, possibly involving axonal connectivity. Non-contiguous symptom development, however, is not uncommon, and may involve other factors.

  9. Patterns of Weakness, Classification of Motor Neuron Disease, and Clinical Diagnosis of Sporadic Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Statland, Jeffrey M; Barohn, Richard J; McVey, April L; Katz, Jonathan S; Dimachkie, Mazen M

    2015-11-01

    When approaching a patient with suspected motor neuron disease (MND), the pattern of weakness on examination helps distinguish MND from other diseases of peripheral nerves, the neuromuscular junction, or muscle. MND is a clinical diagnosis supported by findings on electrodiagnostic testing. MNDs exist on a spectrum, from a pure lower motor neuron to mixed upper and lower motor neuron to a pure upper motor neuron variant. Amyotrophic lateral sclerosis (ALS) is a progressive mixed upper and lower motor neuron disorder, most commonly sporadic, which is invariably fatal. This article describes a pattern approach to identifying MND and clinical features of sporadic ALS. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Changes in Ionic Conductance Signature of Nociceptive Neurons Underlying Fabry Disease Phenotype

    Science.gov (United States)

    Namer, Barbara; Ørstavik, Kirstin; Schmidt, Roland; Mair, Norbert; Kleggetveit, Inge Petter; Zeidler, Maximillian; Martha, Theresa; Jorum, Ellen; Schmelz, Martin; Kalpachidou, Theodora; Kress, Michaela; Langeslag, Michiel

    2017-01-01

    The first symptom arising in many Fabry patients is neuropathic pain due to changes in small myelinated and unmyelinated fibers in the periphery, which is subsequently followed by a loss of sensory perception. Here we studied changes in the peripheral nervous system of Fabry patients and a Fabry mouse model induced by deletion of α-galactosidase A (Gla−/0). The skin innervation of Gla−/0 mice resembles that of the human Fabry patients. In Fabry diseased humans and Gla−/0 mice, we observed similar sensory abnormalities, which were also observed in nerve fiber recordings in both patients and mice. Electrophysiological recordings of cultured Gla−/0 nociceptors revealed that the conductance of voltage-gated Na+ and Ca2+ currents was decreased in Gla−/0 nociceptors, whereas the activation of voltage-gated K+ currents was at more depolarized potentials. Conclusively, we have observed that reduced sensory perception due to small-fiber degeneration coincides with altered electrophysiological properties of sensory neurons. PMID:28769867

  11. Changes in Ionic Conductance Signature of Nociceptive Neurons Underlying Fabry Disease Phenotype

    Directory of Open Access Journals (Sweden)

    Barbara Namer

    2017-07-01

    Full Text Available The first symptom arising in many Fabry patients is neuropathic pain due to changes in small myelinated and unmyelinated fibers in the periphery, which is subsequently followed by a loss of sensory perception. Here we studied changes in the peripheral nervous system of Fabry patients and a Fabry mouse model induced by deletion of α-galactosidase A (Gla−/0. The skin innervation of Gla−/0 mice resembles that of the human Fabry patients. In Fabry diseased humans and Gla−/0 mice, we observed similar sensory abnormalities, which were also observed in nerve fiber recordings in both patients and mice. Electrophysiological recordings of cultured Gla−/0 nociceptors revealed that the conductance of voltage-gated Na+ and Ca2+ currents was decreased in Gla−/0 nociceptors, whereas the activation of voltage-gated K+ currents was at more depolarized potentials. Conclusively, we have observed that reduced sensory perception due to small-fiber degeneration coincides with altered electrophysiological properties of sensory neurons.

  12. Intracerebroventricular Delivery in Mice for Motor Neuron Diseases.

    Science.gov (United States)

    Nizzardo, M; Rizzuti, M

    2017-01-01

    The use of antisense oligonucleotides to target specific mRNA sequences represents a promising therapeutic strategy for neurological disorders. Recent advances in antisense technology enclose the development of phosphorodiamidate morpholino oligomers (MO), which is one of the best candidates for molecular therapies due to MO's excellent pharmacological profile.Nevertheless, the route of administration of antisense compounds represents a critical issue in the neurological field. Particularly, as regards motor neuron diseases, intracerebroventricular (ICV) injection is undoubtedly the most efficient procedure to directly deliver therapeutic molecules in the central nervous system (CNS). Indeed, we recently demonstrated the outstanding efficacy of the MO antisense approach by its direct administration to CNS of the transgenic mouse models of Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS).Here, we describe methods to perform the ICV delivery of MO in neonatal SMA mice and in adult ALS mice.

  13. Multimodal structural MRI in the diagnosis of motor neuron diseases

    Directory of Open Access Journals (Sweden)

    Pilar M. Ferraro

    2017-01-01

    Full Text Available This prospective study developed an MRI-based method for identification of individual motor neuron disease (MND patients and test its accuracy at the individual patient level in an independent sample compared with mimic disorders. 123 patients with amyotrophic lateral sclerosis (ALS, 44 patients with predominantly upper motor neuron disease (PUMN, 20 patients with ALS-mimic disorders, and 78 healthy controls were studied. The diagnostic accuracy of precentral cortical thickness and diffusion tensor (DT MRI metrics of corticospinal and motor callosal tracts were assessed in a training cohort and externally proved in a validation cohort using a random forest analysis. In the training set, precentral cortical thickness showed 0.86 and 0.89 accuracy in differentiating ALS and PUMN patients from controls, while DT MRI distinguished the two groups from controls with 0.78 and 0.92 accuracy. In ALS vs controls, the combination of cortical thickness and DT MRI metrics (combined model improved the classification pattern (0.91 accuracy. In the validation cohort, the best accuracy was reached by DT MRI (0.87 and 0.95 accuracy in ALS and PUMN vs mimic disorders. The combined model distinguished ALS and PUMN patients from mimic syndromes with 0.87 and 0.94 accuracy. A multimodal MRI approach that incorporates motor cortical and white matter alterations yields statistically significant improvement in accuracy over using each modality separately in the individual MND patient classification. DT MRI represents the most powerful tool to distinguish MND from mimic disorders.

  14. α-Internexin aggregates are abundant in neuronal intermediate filament inclusion disease (NIFID) but rare in other neurodegenerative diseases

    Science.gov (United States)

    Cairns, Nigel J.; Uryu, Kunihiro; Bigio, Eileen H.; Mackenzie, Ian R. A.; Gearing, Marla; Duyckaerts, Charles; Yokoo, Hideaki; Nakazato, Yoichi; Jaros, Evelyn; Perry, Robert H.; Arnold, Steven E.; Lee, Virginia M.-Y.; Trojanowski, John Q.

    2009-01-01

    Abnormal neuronal aggregates of α-internexin and the three neurofilament (NF) subunits, NF-L, NF-M, and NF-H have recently been identified as the pathological hallmarks of neuronal intermediate filament (IF) inclusion disease (NIFID), a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal and extrapyramidal signs. α-Internexin, a class IV IF protein, a major component of inclusions in NIFID, has not previously been identified as a component of the pathological protein aggregates of any other neurodegenerative disease. Therefore, to determine the specificity of this protein, α-internexin immunohistochemistry was undertaken on cases of NIFID, non-tau frontotemporal dementias, motor neuron disease, α-synucleinopathies, tauopathies, and normal aged control brains. Our results indicate that class IV IF proteins are present within the pleomorphic inclusions of all cases of NIFID. Small subsets of abnormal neuronal inclusions in Alzheimer's disease, Lewy body diseases, and motor neuron disease also contain epitopes of α-internexin. Thus, α-internexin is a major component of the neuronal inclusions in NIFID and a relatively minor component of inclusions in other neurodegenerative diseases. The discovery of α-internexin in neuronal cytoplasmic inclusions implicates novel mechanisms of pathogenesis in NIFID and other neurological diseases with pathological filamentous neuronal inclusions. PMID:15170578

  15. Dysregulation of striatal projection neurons in Parkinson's disease.

    Science.gov (United States)

    Beck, Goichi; Singh, Arun; Papa, Stella M

    2018-03-01

    The loss of nigrostriatal dopamine (DA) is the primary cause of motor dysfunction in Parkinson's disease (PD), but the underlying striatal mechanisms remain unclear. In spite of abundant literature portraying structural, biochemical and plasticity changes of striatal projection neurons (SPNs), in the past there has been a data vacuum from the natural human disease and its close model in non-human primates. Recently, single-cell recordings in advanced parkinsonian primates have generated new insights into the altered function of SPNs. Currently, there are also human data that provide direct evidence of profoundly dysregulated SPN activity in PD. Here, we review primate recordings that are impacting our understanding of the striatal dysfunction after DA loss, particularly through the analysis of physiologic correlates of parkinsonian motor behaviors. In contrast to recordings in rodents, data obtained in primates and patients demonstrate similar major abnormalities of the spontaneous SPN firing in the alert parkinsonian state. Furthermore, these studies also show altered SPN responses to DA replacement in the advanced parkinsonian state. Clearly, there is yet much to learn about the striatal discharges in PD, but studies using primate models are contributing unique information to advance our understanding of pathophysiologic mechanisms.

  16. A Dutch family with autosomal recessively inherited lower motor neuron predominant motor neuron disease due to optineurin mutations

    NARCIS (Netherlands)

    Beeldman, Emma; van der Kooi, Anneke J.; de Visser, Marianne; van Maarle, Merel C.; van Ruissen, Fred; Baas, Frank

    2015-01-01

    Approximately 10% of motor neuron disease (MND) patients report a familial predisposition for MND. Autosomal recessively inherited MND is less common and is most often caused by mutations in the superoxide dismutase 1 (SOD1) gene. In 2010, autosomal recessively inherited mutations in the optineurin

  17. Neuronal Ceroid Lipofuscinosis: The Increasing Spectrum of an Old Disease.

    Science.gov (United States)

    Simonati, A; Pezzini, F; Moro, F; Santorelli, F M

    2014-10-13

    Neuronal Ceroid Lipofuscinoses (NCL) are genetically heterogeneous heritable neurodegenerative disorders with worldwide distribution. They are considered as childhood diseases; however rare adult onset forms are known. NCL have a progressive course, affecting visual, motor and cognitive functions, and are associated with myoclonic epilepsy; behavioural problems can be observed at the onset. The outcome is invariably fatal, mostly during the second or third decade. The denomination is based on pathological criteria, i.e. the presence of intralysosomal storage of autofluorescent lipopigment of glycoprotein origin with characteristic ultrastructural features. The NCL are autosomal recessive diseases (but a rare autosomal dominant form of adult onset). Thirteen NCL associated genes have been identified so far, which allow a definite diagnosis to be reached and provide genetic counselling to the families. Still unidentified NCL genes are foreseen. Allelic heterogeneity is observed in some mutated genes; likewise phenotypic heterogeneity is seen in several NCL. The gene products are either soluble proteins (such as lysosomal enzymes) or membrane proteins related to lysosomes, endoplasmic reticulum, synaptic vesicles. Little is known about pathogenetic mechanisms, leading to storage formation and cell death. Current research is focusing on intracellular trafficking, neurotransmission and storage removal. No cure is available for any form. Innovative treatments led to some results in mouse models related to lysosome hydrolase defects. Evidences that autophagy, oxidative stress, excitotoxicity play roles in NCL cell pathology raise the possibility that selected steps of these processes might become target of treatments, and therefore modify the disease course. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Economic Studies in Motor Neurone Disease: A Systematic Methodological Review.

    Science.gov (United States)

    Moore, Alan; Young, Carolyn A; Hughes, Dyfrig A

    2017-04-01

    Motor neurone disease (MND) is a devastating condition which greatly diminishes patients' quality of life and limits life expectancy. Health technology appraisals of future interventions in MND need robust data on costs and utilities. Existing economic evaluations have been noted to be limited and fraught with challenges. The aim of this study was to identify and critique methodological aspects of all published economic evaluations, cost studies, and utility studies in MND. We systematically reviewed all relevant published studies in English from 1946 until January 2016, searching the databases of Medline, EMBASE, Econlit, NHS Economic Evaluation Database (NHS EED) and the Health Economics Evaluation Database (HEED). Key data were extracted and synthesised narratively. A total of 1830 articles were identified, of which 15 economic evaluations, 23 cost and 3 utility studies were included. Most economic studies focused on riluzole (n = 9). Six studies modelled the progressive decline in motor function using a Markov design but did not include mutually exclusive health states. Cost estimates for a number of evaluations were based on expert opinion and were hampered by high variability and location-specific characteristics. Few cost studies reported disease-stage-specific costs (n = 3) or fully captured indirect costs. Utilities in three studies of MND patients used the EuroQol EQ-5D questionnaire or standard gamble, but included potentially unrepresentative cohorts and did not consider any health impacts on caregivers. Economic evaluations in MND suffer from significant methodological issues such as a lack of data, uncertainty with the disease course and use of inappropriate modelling framework. Limitations may be addressed through the collection of detailed and representative data from large cohorts of patients.

  19. Direct Lineage Reprogramming Reveals Disease-Specific Phenotypes of Motor Neurons from Human ALS Patients

    Directory of Open Access Journals (Sweden)

    Meng-Lu Liu

    2016-01-01

    Full Text Available Subtype-specific neurons obtained from adult humans will be critical to modeling neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS. Here, we show that adult human skin fibroblasts can be directly and efficiently converted into highly pure motor neurons without passing through an induced pluripotent stem cell stage. These adult human induced motor neurons (hiMNs exhibit the cytological and electrophysiological features of spinal motor neurons and form functional neuromuscular junctions (NMJs with skeletal muscles. Importantly, hiMNs converted from ALS patient fibroblasts show disease-specific degeneration manifested through poor survival, soma shrinkage, hypoactivity, and an inability to form NMJs. A chemical screen revealed that the degenerative features of ALS hiMNs can be remarkably rescued by the small molecule kenpaullone. Taken together, our results define a direct and efficient strategy to obtain disease-relevant neuronal subtypes from adult human patients and reveal their promising value in disease modeling and drug identification.

  20. Transcranial magnetic stimulation in lower motor neuron diseases.

    Science.gov (United States)

    Attarian, S; Azulay, J-Ph; Lardillier, D; Verschueren, A; Pouget, J

    2005-01-01

    To study the diagnostic value of transcranial magnetic stimulation (TMS) in a group of patients with lower motor neuron disease (LMND). Among LMND, several chronic immune mediate motor neuropathies may simulate amyotrophic lateral sclerosis (ALS). Forty patients with LMND were included TMS was performed at the first visit. The patients were seen prospectively every 3 months for a period of 1-4 years. Three different groups were distinguished at the end of follow-up: (1) ALS group with 7 patients, (2) Pure motor neuropathy with 14 patients and (3) Other LMND including 12 patients with hereditary spinal amyotrophy, 3 patients with Kennedy's disease and 4 patients with post-poliomyelitis. On the basis of the results of TMS variables, 6 out of 7 ALS patients had abnormality of silent period (SP) associated or not with abnormality of excitatory threshold or amplitude ratio. Patients with pure motor neuropathy had normal SP and amplitude ratio. Four out of 14 patients had increased central motor conduction time (CMCT), one had increased CMCT and excitatory threshold, and one patient had a slightly increased excitatory threshold. Considering the abnormality of TMS variables in the groups, SP, excitatory threshold, and amplitude ratio were chosen in a post-hoc attempt to select variables yielding high sensitivity and specificity. The overall sensitivity of TMS for diagnosis of ALS among LMND was 85.7%, its specificity was 93.9%. When only the abnormality of SP was taken into account, the sensitivity was unchanged. But the specificity was improved to 100%. TMS helped to distinguish suspected ALS from pure motor neuropathy.

  1. Farming and incidence of motor neuron disease: French nationwide study.

    Science.gov (United States)

    Kab, S; Moisan, F; Elbaz, A

    2017-09-01

    The association of farming with motor neuron disease (MND) is unclear, with conflicting studies. We performed a French nationwide study of the association of farming with MND incidence, and compared findings with those for Parkinson's disease (PD), which has been shown to be more frequent in farmers. We used the French national health insurance and hospital discharge databases to identify MND/PD incident cases. The Mutualité Sociale Agricole (MSA) guarantees health insurance for farmers and agricultural workers. We compared the incidence of MND (2010-2014) and PD (2011-2012) in MSA farmers, MSA workers and non-MSA affiliates, and estimated relative risks (RRs) and 95% confidence intervals (CIs). Probabilistic sensitivity analyses were used for external smoking adjustment. Analyses relied on 8931 MND (MSA, 9%) and 45 409 PD (MSA,11%) cases. There was a trend towards higher MND incidence in MSA farmers compared with non-MSA affiliates (RR,1.08; 95% CI,0.99-1.18) and MSA workers (RR, 1.13; 95% CI, 0.97-1.31) that strengthened after smoking adjustment (if associated with MND). PD incidence was higher in MSA farmers than non-MSA affiliates (RR, 1.13; 95% CI, 1.08-1.17) and MSA workers (RR, 1.10; 95% CI, 1.02-1.18); this association remained after smoking adjustment (RR, 1.09; 95% CI, 1.05-1.14). This French nationwide study suggested an association between farming and MND, and confirmed higher PD incidence in farmers in France, a country with high pesticide use. © 2017 EAN.

  2. Multiple factors interact to produce responses resembling spectrum of human disease in Campylobacter jejuni infected C57BL/6 IL-10-/- mice

    Directory of Open Access Journals (Sweden)

    Wolf John E

    2009-03-01

    Full Text Available Abstract Background Campylobacter jejuni infection produces a spectrum of clinical presentations in humans – including asymptomatic carriage, watery diarrhea, and bloody diarrhea – and has been epidemiologically associated with subsequent autoimmune neuropathies. This microorganism is genetically variable and possesses genetic mechanisms that may contribute to variability in nature. However, relationships between genetic variation in the pathogen and variation in disease manifestation in the host are not understood. We took a comparative experimental approach to explore differences among different C. jejuni strains and studied the effect of diet on disease manifestation in an interleukin-10 deficient mouse model. Results In the comparative study, C57BL/6 interleukin-10-/- mice were infected with seven genetically distinct C. jejuni strains. Four strains colonized the mice and caused disease; one colonized with no disease; two did not colonize. A DNA:DNA microarray comparison of the strain that colonized mice without disease to C. jejuni 11168 that caused disease revealed that putative virulence determinants, including loci encoding surface structures known to be involved in C. jejuni pathogenesis, differed from or were absent in the strain that did not cause disease. In the experimental study, the five colonizing strains were passaged four times in mice. For three strains, serial passage produced increased incidence and degree of pathology and decreased time to develop pathology; disease shifted from watery to bloody diarrhea. Mice kept on an ~6% fat diet or switched from an ~12% fat diet to an ~6% fat diet just before infection with a non-adapted strain also exhibited increased incidence and severity of disease and decreased time to develop disease, although the effects of diet were only statistically significant in one experiment. Conclusion C. jejuni strain genetic background and adaptation of the strain to the host by serial passage

  3. Cognitive dysfunction in lower motor neuron disease: executive and memory deficits in progressive muscular atrophy

    NARCIS (Netherlands)

    Raaphorst, J.; de Visser, M.; van Tol, M.-J.; Linssen, W.H.J.P.; van der Kooi, A.J.; de Haan, R.J.; van den Berg, L.H.; Schmand, B.

    2011-01-01

    Aim In contrast with findings in amyotrophic lateral sclerosis (ALS), cognitive impairments have as yet not been shown in the lower motor neuron variant of motor neuron disease, progressive spinal muscular atrophy (PMA). The objective of this study was to investigate cognitive function in PMA and to

  4. The storm before the quiet : neuronal hyperactivity and Aβ in the presymptomatic stages of Alzheimer's disease

    NARCIS (Netherlands)

    Stargardt, Anita; Swaab, Dick F; Bossers, K.

    Neuronal activity directly promotes the production and secretion of amyloid β (Aβ). Interestingly, neuronal hyperactivity can be observed in presymptomatic stages of both sporadic and familial Alzheimer's disease (AD) and in several AD mouse models. In this review, we will highlight the recent

  5. Single photon emission computed tomography in motor neuron disease with dementia.

    Science.gov (United States)

    Sawada, H; Udaka, F; Kishi, Y; Seriu, N; Mezaki, T; Kameyama, M; Honda, M; Tomonobu, M

    1988-01-01

    Single photon emission computed tomography with [123 I] isopropylamphetamine was carried out on a patient with motor neuron disease with dementia. [123 I] uptake was decreased in the frontal lobes. This would reflect the histopathological findings such as neuronal loss and gliosis in the frontal lobes.

  6. Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases.

    Science.gov (United States)

    Kline, Rachel A; Kaifer, Kevin A; Osman, Erkan Y; Carella, Francesco; Tiberi, Ariana; Ross, Jolill; Pennetta, Giuseppa; Lorson, Christian L; Murray, Lyndsay M

    2017-03-01

    The term "motor neuron disease" encompasses a spectrum of disorders in which motor neurons are the primary pathological target. However, in both patients and animal models of these diseases, not all motor neurons are equally vulnerable, in that while some motor neurons are lost very early in disease, others remain comparatively intact, even at late stages. This creates a valuable system to investigate the factors that regulate motor neuron vulnerability. In this study, we aim to use this experimental paradigm to identify potential transcriptional modifiers. We have compared the transcriptome of motor neurons from healthy wild-type mice, which are differentially vulnerable in the childhood motor neuron disease Spinal Muscular Atrophy (SMA), and have identified 910 transcriptional changes. We have compared this data set with published microarray data sets on other differentially vulnerable motor neurons. These neurons were differentially vulnerable in the adult onset motor neuron disease Amyotrophic Lateral Sclerosis (ALS), but the screen was performed on the equivalent population of neurons from neurologically normal human, rat and mouse. This cross species comparison has generated a refined list of differentially expressed genes, including CELF5, Col5a2, PGEMN1, SNCA, Stmn1 and HOXa5, alongside a further enrichment for synaptic and axonal transcripts. As an in vivo validation, we demonstrate that the manipulation of a significant number of these transcripts can modify the neurodegenerative phenotype observed in a Drosophila line carrying an ALS causing mutation. Finally, we demonstrate that vector-mediated expression of alpha-synuclein (SNCA), a transcript decreased in selectively vulnerable motor neurons in all four screens, can extend life span, increase weight and decrease neuromuscular junction pathology in a mouse model of SMA. In summary, we have combined multiple data sets to identify transcripts, which are strong candidates for being phenotypic modifiers

  7. Diversity matters - heterogeneity of dopaminergic neurons in the ventral mesencephalon and its relation to Parkinson's Disease.

    Science.gov (United States)

    Vogt Weisenhorn, Daniela Maria; Giesert, Florian; Wurst, Wolfgang

    2016-10-01

    Dopaminergic neurons in the ventral mesencephalon (the ventral mesencephalic dopaminergic complex) are known for their role in a multitude of behaviors, including cognition, reward, addiction and voluntary movement. Dysfunctions of these neurons are the underlying cause of various neuropsychiatric disorders, such as depression, addiction and schizophrenia. In addition, Parkinson's disease (PD), which is the second most common degenerative disease in developed countries, is characterized by the degeneration of dopaminergic neurons, leading to the core motor symptoms of the disease. However, only a subset of dopaminergic neurons in the ventral mesencephalon is highly vulnerable to the disease process. Indeed, research over several decades revealed that the neurons in the ventral mesencephalic dopaminergic complex do not form a homogeneous group with respect to anatomy, physiology, function, molecular identity or vulnerability/dysfunction in different diseases. Here, we review how the concept of dopaminergic neuron diversity, assisted by the advent and application of new technologies, evolved and was refined over time and how it shaped our understanding of PD pathogenesis. Understanding this diversity of neurons in the ventral mesencephalic dopaminergic complex at all levels is imperative for the development of new and more selective drugs for both PD and various other neuropsychiatric diseases. Several decades of research revealed that the neurons in the ventral mesencephalic dopaminergic complex do not form a homogeneous group in respect to anatomy, physiology, function, molecular identity or vulnerability/dysfunction in diseases like Parkinson's disease (PD). Here, we review how this concept evolved and was refined over time and how it shaped our understanding of the pathogenesis of PD. Source of the midbrain image: www.wikimd.org/wiki/index.php/The_Midbrain_or_Mesencephalon; downloaded 28.01.2016. See also Figures and of the paper. This article is part of a

  8. Primary Lateral Sclerosis and Early Upper Motor Neuron Disease: Characteristics of a Cross-Sectional Population.

    Science.gov (United States)

    Fournier, Christina N; Murphy, Alyssa; Loci, Lorena; Mitsumoto, Hiroshi; Lomen-Hoerth, Catherine; Kisanuki, Yasushi; Simmons, Zachary; Maragakis, Nicholas J; McVey, April L; Al-Lahham, Tawfiq; Heiman-Patterson, Terry D; Andrews, Jinsy; McDonnell, Erin; Cudkowicz, Merit; Atassi, Nazem

    2016-03-01

    The goals of this study were to characterize clinical and electrophysiologic findings of subjects with upper motor neuron disease and to explore feasibility of clinical trials in this population. Twenty northeast amyotrophic lateral sclerosis consortium (northeast amyotrophic lateral sclerosis) sites performed chart reviews to identify active clinical pure upper motor neuron disease patients. Patients with hereditary spastic paraplegia or meeting revised El Escorial electrodiagnostic criteria for amyotrophic lateral sclerosis were excluded. Patients were classified into 2 groups according to the presence or absence of minor electromyography (EMG) abnormalities. Two hundred thirty-three subjects with upper motor neuron disease were identified; 217 had available EMG data. Normal EMGs were seen in 140 subjects, and 77 had minor denervation. Mean disease duration was 84 (±80) months for the entire cohort with no difference seen between the 2 groups. No difference was seen in clinical symptoms, disability, or outcome measures between the 2 groups after correcting for multiple comparisons. Minor EMG abnormalities were not associated with phenotypic differences in a clinical upper motor neuron disease population. These findings suggest that subtle EMG abnormalities can not necessarily be used as a prognostic tool in patients with clinical upper motor neuron disease. This study also demonstrates the availability of a large number of patients with upper motor neuron diseases within the northeast amyotrophic lateral sclerosis network and suggests feasibility for conducting clinical trials in this population.

  9. The critical role of membralin in postnatal motor neuron survival and disease.

    Science.gov (United States)

    Yang, Bo; Qu, Mingliang; Wang, Rengang; Chatterton, Jon E; Liu, Xiao-Bo; Zhu, Bing; Narisawa, Sonoko; Millan, Jose Luis; Nakanishi, Nobuki; Swoboda, Kathryn; Lipton, Stuart A; Zhang, Dongxian

    2015-05-15

    Hitherto, membralin has been a protein of unknown function. Here, we show that membralin mutant mice manifest a severe and early-onset motor neuron disease in an autosomal recessive manner, dying by postnatal day 5-6. Selective death of lower motor neurons, including those innervating the limbs, intercostal muscles, and diaphragm, is predominantly responsible for this fatal phenotype. Neural expression of a membralin transgene completely rescues membralin mutant mice. Mechanistically, we show that membralin interacts with Erlin2, an endoplasmic reticulum (ER) membrane protein that is located in lipid rafts and known to be important in ER-associated protein degradation (ERAD). Accordingly, the degradation rate of ERAD substrates is attenuated in cells lacking membralin. Membralin mutations or deficiency in mouse models induces ER stress, rendering neurons more vulnerable to cell death. Our study reveals a critical role of membralin in motor neuron survival and suggests a novel mechanism for early-onset motor neuron disease.

  10. Respiratory management of motor neurone disease: a review of current practice and new developments.

    Science.gov (United States)

    Rafiq, Muhammad Khizar; Proctor, Alison Ruth; McDermott, Christopher J; Shaw, Pamela J

    2012-06-01

    Motor neurone disease is a neurodegenerative condition with a significant morbidity and shortened life expectancy. Hypoventilatory respiratory failure is the most common cause of death and respiratory function significantly predicts both survival and quality of life in patients with motor neurone disease. Accordingly, supporting and maintaining respiratory function is important in caring for these patients. The most significant advance in motor neurone disease care of recent years has been the domiciliary provision of non-invasive ventilation for treating respiratory failure. Neuromuscular respiratory weakness also leads to ineffective cough and retained airways secretions, predisposing to recurrent chest infections. In this review, we discuss current practice and recent developments in the respiratory management of motor neurone disease, in terms of ventilatory support and cough augmentation.

  11. Dopamine neurons implanted into people with Parkinson's disease survive without pathology for 14 years

    DEFF Research Database (Denmark)

    Mendez, Ivar; Viñuela, Angel; Astradsson, Arnar

    2008-01-01

    Postmortem analysis of five subjects with Parkinson's disease 9-14 years after transplantation of fetal midbrain cell suspensions revealed surviving grafts that included dopamine and serotonin neurons without pathology. These findings are important for the understanding of the etiopathogenesis...

  12. Knockdown of GAD67 protein levels normalizes neuronal activity in a rat model of Parkinson's disease

    DEFF Research Database (Denmark)

    Horvath, Lazlo; van Marion, Ingrid; Taï, Khalid

    2011-01-01

    Dopamine depletion of the striatum is one of the hallmarks of Parkinson's disease. The loss of dopamine upregulates GAD67 expression in the striatal projection neurons and causes other changes in the activity of the basal ganglia circuit.......Dopamine depletion of the striatum is one of the hallmarks of Parkinson's disease. The loss of dopamine upregulates GAD67 expression in the striatal projection neurons and causes other changes in the activity of the basal ganglia circuit....

  13. Look Out before Polypectomy in Patients with Diverticular Disease – A Case of a Large, Inverted Diverticulum of the Colon Resembling a Pedunculated Polyp

    Directory of Open Access Journals (Sweden)

    Omero Alessandro Paoluzi

    2010-01-01

    Full Text Available Diverticular disease of the colon may be responsible for abdominal symptoms requiring colonoscopy, which may reveal the presence of concomitant polyps. A polyp found during colonoscopy in patients with colonic diverticular disease may be removed by endoscopic polypectomy with electrosurgical snare, a procedure associated with an incidence of perforation of less than 0.05%. The risk of such a complication may be higher in the event of an inverted colonic diverticulum, which may be misinterpreted as a polypoid lesion at colonoscopy. To date, fewer than 20 cases of inverted colonic diverticula, diagnosed at colonoscopy or following air contrast barium enema, have been reported in the literature. The present report describes a 68-year-old woman who underwent a screening colonoscopy, which revealed a voluminous pedunculated polyp that was recognized to be an inverted giant colonic diverticulum before endoscopic polypectomy.

  14. Neuronal phosphorylated RNA-dependent protein kinase in Creutzfeldt-Jakob disease.

    LENUS (Irish Health Repository)

    Paquet, Claire

    2009-02-01

    The mechanisms of neuronal apoptosis in Creutzfeldt-Jakob disease (CJD) and their relationship to accumulated prion protein (PrP) are unclear. A recent cell culture study showed that intracytoplasmic PrP may induce phosphorylated RNA-dependent protein kinase (PKR(p))-mediated cell stress. The double-stranded RNA protein kinase PKR is a proapoptotic and stress kinase that accumulates in degenerating neurons in Alzheimer disease. To determine whether neuronal apoptosis in human CJD is associated with activation of the PKR(p) signaling pathway, we assessed in situ end labeling and immunocytochemistry for PrP, glial fibrillary acidic protein, CD68, activated caspase 3, and phosphorylated PKR (Thr451) in samples of frontal, occipital, and temporal cortex, striatum, and cerebellum from 6 patients with sporadic CJD and 5 controls. Neuronal immunostaining for activated PKR was found in all CJD cases. The most staining was in nuclei and, in contrast to findings in Alzheimer disease, cytoplasmic labeling was not detected. Both the number and distribution of PKR(p)-positive neurons correlated closely with the extent of neuronal apoptosis, spongiosis, astrocytosis, and microglial activation and with the phenotype and disease severity. There was no correlation with the type, topography, or amount of extracellular PrP deposits. These findings suggest that neuronal apoptosis in human CJD may result from PKR(p)-mediated cell stress and are consistent with recent studies supporting a pathogenic role for intracellular or transmembrane PrP.

  15. Regenerative therapy for neuronal diseases with transplantation of somatic stem cells.

    Science.gov (United States)

    Kanno, Hiroshi

    2013-10-26

    Pluripotent stem cells, which are capable of differentiating in various species of cells, are hoped to be donor cells in transplantation in regenerative medicine. Embryonic stem (ES) cells and induced pluripotent stem cells have the potential to differentiate in approximately all species of cells. However, the proliferating ability of these cells is high and the cancer formation ability is also recognized. In addition, ethical problems exist in using ES cells. Somatic stem cells with the ability to differentiate in various species of cells have been used as donor cells for neuronal diseases, such as amyotrophic lateral sclerosis, spinal cord injury, Alzheimer disease, cerebral infarction and congenital neuronal diseases. Human mesenchymal stem cells derived from bone marrow, adipose tissue, dermal tissue, umbilical cord blood and placenta are usually used for intractable neuronal diseases as somatic stem cells, while neural progenitor/stem cells and retinal progenitor/stem cells are used for a few congenital neuronal diseases and retinal degenerative disease, respectively. However, non-treated somatic stem cells seldom differentiate to neural cells in recipient neural tissue. Therefore, the contribution to neuronal regeneration using non-treated somatic stem cells has been poor and various differential trials, such as the addition of neurotrophic factors, gene transfer, peptide transfer for neuronal differentiation of somatic stem cells, have been performed. Here, the recent progress of regenerative therapies using various somatic stem cells is described.

  16. Malignant catarrhal fever-like disease in Barbary red deer (Cervus elaphus barbarus) naturally infected with a virus resembling alcelaphine herpesvirus 2.

    Science.gov (United States)

    Klieforth, Robert; Maalouf, Gabriel; Stalis, Ilse; Terio, Karen; Janssen, Donald; Schrenzel, Mark

    2002-09-01

    Eight Barbary red deer (Cervus elaphus barbarus) developed clinical signs suggestive of malignant catarrhal fever (MCF) over a 28-day period. These animals were housed outdoors with four other species of ruminants. Affected red deer had lethargy, ocular signs, and nasal discharge and were euthanatized within 48 h. Lesions included ulcers of the muzzle, lips, and oral cavity associated with infiltrates of neutrophils and lymphocytes. Serologically, six of seven red deer tested during the outbreak were positive by competitive enzyme-linked immunosorbent assay for antibodies to a shared MCF virus antigen. PCR using oligonucleotide primers designed for a conserved protein of alcelaphine herpesviruses 1 (AlHV-1) and 2 (AlHV-2) and for conserved regions of a herpesvirus DNA polymerase gene was positive for tissues from all eight clinically affected animals and negative for eight out of eight red deer without clinical signs of MCF. DNA sequencing of PCR amplicons from the diseased red deer indicated that they were infected with a novel herpesvirus closely related to AlHV-2; immunohistochemistry using polyclonal anti-AlHV-2 serum and in situ hybridization demonstrated the presence of virus within salivary glands adjacent to oral lesions of affected animals. A survey of other ruminants near the outbreak subsequently showed that normal Jackson's hartebeest (Alcelaphus buselaphus jacksoni) that were cohoused with the diseased red deer were infected with the same virus and were shedding the virus in nasal excretions. These findings suggest that a herpesvirus closely related to AlHV-2 caused the MCF-like disease epizootic in Barbary red deer and that the virus may have originated from Jackson's hartebeest.

  17. Malignant Catarrhal Fever-Like Disease in Barbary Red Deer (Cervus elaphus barbarus) Naturally Infected with a Virus Resembling Alcelaphine Herpesvirus 2†

    Science.gov (United States)

    Klieforth, Robert; Maalouf, Gabriel; Stalis, Ilse; Terio, Karen; Janssen, Donald; Schrenzel, Mark

    2002-01-01

    Eight Barbary red deer (Cervus elaphus barbarus) developed clinical signs suggestive of malignant catarrhal fever (MCF) over a 28-day period. These animals were housed outdoors with four other species of ruminants. Affected red deer had lethargy, ocular signs, and nasal discharge and were euthanatized within 48 h. Lesions included ulcers of the muzzle, lips, and oral cavity associated with infiltrates of neutrophils and lymphocytes. Serologically, six of seven red deer tested during the outbreak were positive by competitive enzyme-linked immunosorbent assay for antibodies to a shared MCF virus antigen. PCR using oligonucleotide primers designed for a conserved protein of alcelaphine herpesviruses 1 (AlHV-1) and 2 (AlHV-2) and for conserved regions of a herpesvirus DNA polymerase gene was positive for tissues from all eight clinically affected animals and negative for eight out of eight red deer without clinical signs of MCF. DNA sequencing of PCR amplicons from the diseased red deer indicated that they were infected with a novel herpesvirus closely related to AlHV-2; immunohistochemistry using polyclonal anti-AlHV-2 serum and in situ hybridization demonstrated the presence of virus within salivary glands adjacent to oral lesions of affected animals. A survey of other ruminants near the outbreak subsequently showed that normal Jackson's hartebeest (Alcelaphus buselaphus jacksoni) that were cohoused with the diseased red deer were infected with the same virus and were shedding the virus in nasal excretions. These findings suggest that a herpesvirus closely related to AlHV-2 caused the MCF-like disease epizootic in Barbary red deer and that the virus may have originated from Jackson's hartebeest. PMID:12202582

  18. Phenotypic Features of Circulating Leukocytes from Non-human Primates Naturally Infected with Trypanosoma cruzi Resemble the Major Immunological Findings Observed in Human Chagas Disease

    Science.gov (United States)

    Mattoso-Barbosa, Armanda Moreira; Perdigão-de-Oliveira, Marcelo; Costa, Ronaldo Peres; Elói-Santos, Silvana Maria; Gomes, Matheus de Souza; do Amaral, Laurence Rodrigues; Teixeira-Carvalho, Andréa; Martins-Filho, Olindo Assis; Dick, Edward J.; Hubbard, Gene B.; VandeBerg, Jane F.; VandeBerg, John L.

    2016-01-01

    Background Cynomolgus macaques (Macaca fascicularis) represent a feasible model for research on Chagas disease since natural T. cruzi infection in these primates leads to clinical outcomes similar to those observed in humans. However, it is still unknown whether these clinical similarities are accompanied by equivalent immunological characteristics in the two species. We have performed a detailed immunophenotypic analysis of circulating leukocytes together with systems biology approaches from 15 cynomolgus macaques naturally infected with T. cruzi (CH) presenting the chronic phase of Chagas disease to identify biomarkers that might be useful for clinical investigations. Methods and Findings Our data established that CH displayed increased expression of CD32+ and CD56+ in monocytes and enhanced frequency of NK Granzyme A+ cells as compared to non-infected controls (NI). Moreover, higher expression of CD54 and HLA-DR by T-cells, especially within the CD8+ subset, was the hallmark of CH. A high level of expression of Granzyme A and Perforin underscored the enhanced cytotoxicity-linked pattern of CD8+ T-lymphocytes from CH. Increased frequency of B-cells with up-regulated expression of Fc-γRII was also observed in CH. Complex and imbricate biomarker networks demonstrated that CH showed a shift towards cross-talk among cells of the adaptive immune system. Systems biology analysis further established monocytes and NK-cell phenotypes and the T-cell activation status, along with the Granzyme A expression by CD8+ T-cells, as the most reliable biomarkers of potential use for clinical applications. Conclusions Altogether, these findings demonstrated that the similarities in phenotypic features of circulating leukocytes observed in cynomolgus macaques and humans infected with T. cruzi further supports the use of these monkeys in preclinical toxicology and pharmacology studies applied to development and testing of new drugs for Chagas disease. PMID:26808481

  19. Phenotypic Features of Circulating Leukocytes from Non-human Primates Naturally Infected with Trypanosoma cruzi Resemble the Major Immunological Findings Observed in Human Chagas Disease.

    Directory of Open Access Journals (Sweden)

    Renato Sathler-Avelar

    2016-01-01

    Full Text Available Cynomolgus macaques (Macaca fascicularis represent a feasible model for research on Chagas disease since natural T. cruzi infection in these primates leads to clinical outcomes similar to those observed in humans. However, it is still unknown whether these clinical similarities are accompanied by equivalent immunological characteristics in the two species. We have performed a detailed immunophenotypic analysis of circulating leukocytes together with systems biology approaches from 15 cynomolgus macaques naturally infected with T. cruzi (CH presenting the chronic phase of Chagas disease to identify biomarkers that might be useful for clinical investigations.Our data established that CH displayed increased expression of CD32+ and CD56+ in monocytes and enhanced frequency of NK Granzyme A+ cells as compared to non-infected controls (NI. Moreover, higher expression of CD54 and HLA-DR by T-cells, especially within the CD8+ subset, was the hallmark of CH. A high level of expression of Granzyme A and Perforin underscored the enhanced cytotoxicity-linked pattern of CD8+ T-lymphocytes from CH. Increased frequency of B-cells with up-regulated expression of Fc-γRII was also observed in CH. Complex and imbricate biomarker networks demonstrated that CH showed a shift towards cross-talk among cells of the adaptive immune system. Systems biology analysis further established monocytes and NK-cell phenotypes and the T-cell activation status, along with the Granzyme A expression by CD8+ T-cells, as the most reliable biomarkers of potential use for clinical applications.Altogether, these findings demonstrated that the similarities in phenotypic features of circulating leukocytes observed in cynomolgus macaques and humans infected with T. cruzi further supports the use of these monkeys in preclinical toxicology and pharmacology studies applied to development and testing of new drugs for Chagas disease.

  20. Endosomal accumulation of APP in wobbler motor neurons reflects impaired vesicle trafficking: implications for human motor neuron disease.

    Science.gov (United States)

    Palmisano, Ralf; Golfi, Panagiota; Heimann, Peter; Shaw, Christopher; Troakes, Claire; Schmitt-John, Thomas; Bartsch, Jörg W

    2011-03-07

    The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown but hypotheses about disease mechanisms include oxidative stress, defective axonal transport, mitochondrial dysfunction and disrupted RNA processing. Whereas familial ALS is well represented by transgenic mutant SOD1 mouse models, the mouse mutant wobbler (WR) develops progressive motor neuron degeneration due to a point mutation in the Vps54 gene, and provides an animal model for sporadic ALS. VPS54 protein as a component of a protein complex is involved in vesicular Golgi trafficking; impaired vesicle trafficking might also be mechanistic in the pathogenesis of human ALS. In motor neurons of homozygous symptomatic WR mice, a massive number of endosomal vesicles significantly enlarged (up to 3 μm in diameter) were subjected to ultrastructural analysis and immunohistochemistry for the endosome-specific small GTPase protein Rab7 and for amyloid precursor protein (APP). Enlarged vesicles were neither detected in heterozygous WR nor in transgenic SOD1(G93A) mice; in WR motor neurons, numerous APP/Rab7-positive vesicles were observed which were mostly LC3-negative, suggesting they are not autophagosomes. We conclude that endosomal APP/Rab7 staining reflects impaired vesicle trafficking in WR mouse motor neurons. Based on these findings human ALS tissues were analysed for APP in enlarged vesicles and were detected in spinal cord motor neurons in six out of fourteen sporadic ALS cases. These enlarged vesicles were not detected in any of the familial ALS cases. Thus our study provides the first evidence for wobbler-like aetiologies in human ALS and suggests that the genes encoding proteins involved in vesicle trafficking should be screened for pathogenic mutations.

  1. The Impact of Exercise on the Vulnerability of Dopamine Neurons to Cell Death in Animal Models of Parkinson's Disease

    National Research Council Canada - National Science Library

    Zigmond, Michael J; Smith, Amanda

    2005-01-01

    Parkinson's disease (PD) results in part from the loss of dopamine (DA) neurons. We hypothesize that exercise reduces the vulnerability of DA neurons to neurotoxin exposure, whereas stress increases vulnerability...

  2. The Impact of Exercise on the Vulnerability of Dopamine Neurons to Cell Death in Animal Models of Parkinson's Disease

    National Research Council Canada - National Science Library

    Zpgmond, Michael J; Smith, Amanda; Liou, Anthony

    2007-01-01

    Parkinson's disease results in part from the loss of dopamine neurons. We hypothesize that exercise reduces the vulnerability of dopamine neurons to neurotoxin exposure, which is modulated by stress...

  3. Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Ditsworth, Dara; Maldonado, Marcus; McAlonis-Downes, Melissa; Sun, Shuying; Seelman, Amanda; Drenner, Kevin; Arnold, Eveline; Ling, Shuo-Chien; Pizzo, Donald; Ravits, John; Cleveland, Don W; Da Cruz, Sandrine

    2017-06-01

    Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43 Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43 Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types.

  4. The role of the intestinal microvasculature in inflammatory bowel disease: studies with a modified Caco-2 model including endothelial cells resembling the intestinal barrier in vitro

    Science.gov (United States)

    Kasper, Jennifer Y; Hermanns, Maria Iris; Cavelius, Christian; Kraegeloh, Annette; Jung, Thomas; Danzebrink, Rolf; Unger, Ronald E; Kirkpatrick, Charles James

    2016-01-01

    The microvascular endothelium of the gut barrier plays a crucial role during inflammation in inflammatory bowel disease. We have modified a commonly used intestinal cell model based on the Caco-2 cells by adding microvascular endothelial cells (ISO-HAS-1). Transwell filters were used with intestinal barrier-forming Caco-2 cells on top and the ISO-HAS-1 on the bottom of the filter. The goal was to determine whether this coculture mimics the in vivo situation more closely, and whether the model is suitable to evaluate interactions of, for example, prospective nanosized drug vehicles or contrast agents with this coculture in a physiological and inflamed state as it would occur in inflammatory bowel disease. We monitored the inflammatory responsiveness of the cells (release of IL-8, soluble intercellular adhesion molecule 1, and soluble E-selectin) after exposure to inflammatory stimuli (lipopolysaccharide, TNF-α, INF-γ, IL1-β) and a nanoparticle (Ba/Gd: coprecipitated BaSO4 and Gd(OH)3), generally used as contrast agents. The barrier integrity of the coculture was evaluated via the determination of transepithelial electrical resistance and the apparent permeability coefficient (Papp) of NaFITC. The behavior of the coculture Caco-1/ISO-HAS-1 was compared to the respective monocultures Caco-2 and ISO-HAS-1. Based on transepithelial electrical resistance, the epithelial barrier integrity of the coculture remained stable during incubation with all stimuli, whereas the Papp decreased after exposure to the cytokine mixture (TNF-α, INF-γ, IL1-β, and Ba/Gd). Both the endothelial and epithelial monocultures showed a high inflammatory response in both the upper and lower transwell-compartments. However, in the coculture, inflammatory mediators were only detected on the epithelial side and not on the endothelial side. Thus in the coculture, based on the Papp, the epithelial barrier appears to prevent a potential inflammatory overreaction in the underlying endothelial cells

  5. TRPV1 on astrocytes rescues nigral dopamine neurons in Parkinson’s disease via CNTF

    Science.gov (United States)

    Nam, Jin H.; Park, Eun S.; Won, So-Yoon; Lee, Yu A.; Kim, Kyoung I.; Jeong, Jae Y.; Baek, Jeong Y.; Cho, Eun J.; Jin, Minyoung; Chung, Young C.; Lee, Byoung D.; Kim, Sung Hyun; Kim, Eung-Gook; Byun, Kyunghee; Lee, Bonghee; Woo, Dong Ho; Lee, C. Justin; Kim, Sang R.; Bok, Eugene; Kim, Yoon-Seong; Ahn, Tae-Beom; Ko, Hyuk Wan; Brahmachari, Saurav; Pletinkova, Olga; Troconso, Juan C.; Dawson, Valina L.; Dawson, Ted M.

    2015-01-01

    Currently there is no neuroprotective or neurorestorative therapy for Parkinson’s disease. Here we report that transient receptor potential vanilloid 1 (TRPV1) on astrocytes mediates endogenous production of ciliary neurotrophic factor (CNTF), which prevents the active degeneration of dopamine neurons and leads to behavioural recovery through CNTF receptor alpha (CNTFRα) on nigral dopamine neurons in both the MPP+-lesioned or adeno-associated virus α-synuclein rat models of Parkinson’s disease. Western blot and immunohistochemical analysis of human post-mortem substantia nigra from Parkinson’s disease suggests that this endogenous neuroprotective system (TRPV1 and CNTF on astrocytes, and CNTFRα on dopamine neurons) might have relevance to human Parkinson’s disease. Our results suggest that activation of astrocytic TRPV1 activates endogenous neuroprotective machinery in vivo and that it is a novel therapeutic target for the treatment of Parkinson’s disease. PMID:26490328

  6. Dysregulation of TBX1 dosage in the anterior heart field results in congenital heart disease resembling the 22q11.2 duplication syndrome.

    Science.gov (United States)

    Hasten, Erica; McDonald-McGinn, Donna M; Crowley, Terrence B; Zackai, Elaine; Emanuel, Beverly S; Morrow, Bernice E; Racedo, Silvia E

    2018-03-02

    Non-allelic homologous recombination events on chromosome 22q11.2 during meiosis can result in either the deletion (22q11.2DS) or duplication (22q11.2DupS) syndrome. Although the spectrum and frequency of congenital heart disease (CHD) are known for 22q11.2DS, there is less known for 22q11.2DupS. We now evaluated cardiac phenotypes in 235 subjects with 22q11.2DupS including 102 subjects we collected and 133 subjects that were previously reported as a confirmation and found 25% have CHD, mostly affecting the cardiac outflow tract (OFT). Previous studies have shown that global loss or gain of function (LOF; GOF) of mouse Tbx1, encoding a T-box transcription factor mapping to the region of synteny to 22q11.2, results in similar OFT defects. To further evaluate Tbx1 function in the progenitor cells forming the cardiac OFT, termed the anterior heart field, Tbx1 was overexpressed using the Mef2c-AHF-Cre driver (Tbx1 GOF). Here we found that all resulting conditional GOF embryos had a persistent truncus arteriosus (PTA), similar to what was previously reported for conditional Tbx1 LOF mutant embryos. To understand the basis for the PTA in the conditional GOF embryos, we found that proliferation in the Mef2c-AHF-Cre lineage cells before migrating to the heart, was reduced and critical genes were oppositely changed in this tissue in Tbx1 GOF embryos versus conditional LOF embryos. These results suggest that a major function of TBX1 in the AHF is to maintain the normal balance of expression of key cardiac developmental genes required to form the aorta and pulmonary trunk, which is disrupted in 22q11.2DS and 22q11.2DupS.

  7. Monoclonal antibody identification of subpopulations of cerebral cortical neurons affected in Alzheimer's disease

    International Nuclear Information System (INIS)

    Miller, C.A.; Rudnicka, M.; Hinton, D.R.; Blanks, J.C.; Kozlowski, M.

    1987-01-01

    Neuronal degeneration is one of the hallmarks of Alzheimer's disease (AD). Given the paucity of molecular markers available for the identification of neuronal subtypes, the specificity of neuronal loss within the cerebral cortex has been difficult to evaluate. With a panel of four monoclonal antibodies (mAbs) applied to central nervous system tissues from AD patients, the authors have immunocytochemically identified a population of vulnerable cortical neurons; a subpopulation of pyramidal neurons is recognized by mAbs 3F12 and 44.1 in the hippocampus and neocortex, and clusters of multipolar neurons in the entorhinal cortex reactive with mAb 44.1 show selective degeneration. Closely adjacent stellate-like neurons in these regions, identified by mAb 6A2, show striking preservation in AD. The neurons recognized by mAbs 3F12 and 44.1 do not comprise a single known neurotransmitter system. mAb 3A4 identifies a phosphorylated antigen that is undetectable in normal brain but accumulates early in the course of AD in somas of vulnerable neurons. Antigen 3A4 is distinct from material reactive with thioflavin S or antibody generated against paired helical filaments. Initially, antigen 3A4 is localized to neurons in the entorhinal cortex and subiculum, later in the association neocortex, and, ultimately in cases of long duration, in primary sensory cortical regions. mAb 3F12 recognizes multiple bands of immunoblots of homogenates of normal and AD cortical tissues, whereas mAb 3A4 does not bind to immunoblots containing neurofilament proteins or brain homogenates from AD patients. Ultrastructurally, antigen 3A4 is localized to paired-helical filaments. Using these mAbs, further molecular characterization of the affected cortical neurons is now possible

  8. Neuronal activity patterns in the ventral thalamus: Comparison between Parkinson's disease and cervical dystonia.

    Science.gov (United States)

    Devetiarov, Dmitriy; Semenova, Ulia; Usova, Svetlana; Tomskiy, Alexey; Tyurnikov, Vladimir; Nizametdinova, Dinara; Gushcha, Artem; Belova, Elena; Sedov, Alexey

    2017-12-01

    The aim of this study was to distinguish neuronal activity patterns in the human ventral thalamus and reveal common and disease-specific features in patients with Parkinson's disease (PD) and cervical dystonia (CD). Single unit activity of neurons was recorded during microelectrode-guided thalamotomies. We classified neurons of surgical target and surrounding area into patterns and compared their characteristics and responsiveness to voluntary movement between PD and CD patients. We distinguished five patterns of neuronal activity: single, LTS burst, mixed, non-LTS burst and longburst patterns. The burst and mixed patterns showed significant differences in several basic and burst characteristics. We showed that there were no disease-specific patterns or significant differences in pattern distribution between studied patients. However, burst patterns had an unbalanced distribution between disease conditions. In addition, we found difference in LTS burst characteristics between surgical targets and surrounding nuclei. All identified patterns, except the long burst pattern, were reactive to the motor tasks and to contraction of the pathological muscles. The ventral thalamus was characterised by common neuronal activity patterns which differed in characteristics between PD and CD. Our findings highlight patterns of neuronal activity of the human ventral thalamus and specific pathological features. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

  9. Widespread heterogeneous neuronal loss across the cerebral cortex in Huntington's disease.

    Science.gov (United States)

    Nana, Alissa L; Kim, Eric H; Thu, Doris C V; Oorschot, Dorothy E; Tippett, Lynette J; Hogg, Virginia M; Synek, Beth J; Roxburgh, Richard; Waldvogel, Henry J; Faull, Richard L M

    2014-01-01

    Huntington's disease is an autosomal dominant neurodegenerative disease characterized by neuronal degeneration in the basal ganglia and cerebral cortex, and a variable symptom profile. Although progressive striatal degeneration is known to occur and is related to symptom profile, little is known about the cellular basis of symptom heterogeneity across the entire cerebral cortex. To investigate this, we have undertaken a double blind study using unbiased stereological cell counting techniques to determine the pattern of cell loss in six representative cortical regions from the frontal, parietal, temporal, and occipital lobes in the brains of 14 Huntington's disease cases and 15 controls. The results clearly demonstrate a widespread loss of total neurons and pyramidal cells across all cortical regions studied, except for the primary visual cortex. Importantly, the results show that cell loss is remarkably variable both within and between Huntington's disease cases. The results also show that neuronal loss in the primary sensory and secondary visual cortices relate to Huntington's disease motor symptom profiles, and neuronal loss across the associational cortices in the frontal, parietal and temporal lobes is related to both Huntington's disease motor and to mood symptom profiles. This finding considerably extends a previous study (Thu et al., Brain, 2010; 133:1094-1110) which showed that neuronal loss in the primary motor cortex was related specifically to the motor symptom profiles while neuronal loss in the anterior cingulate cortex was related specifically to mood symptom profiles. The extent of cortical cell loss in the current study was generally related to the striatal neuropathological grade, but not to CAG repeat length on the HTT gene. Overall our findings show that Huntington's disease is characterized by a heterogeneous pattern of neuronal cell loss across the entire cerebrum which varies with symptom profile.

  10. Mechanical ventilation for amyotrophic lateral sclerosis/motor neuron disease.

    Science.gov (United States)

    Radunovic, Aleksandar; Annane, Djillali; Rafiq, Muhammad K; Brassington, Ruth; Mustfa, Naveed

    2017-10-06

    Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is a fatal neurodegenerative disease. Neuromuscular respiratory failure is the most common cause of death, which usually occurs within two to five years of the disease onset. Supporting respiratory function with mechanical ventilation may improve survival and quality of life. This is the second update of a review first published in 2009. To assess the effects of mechanical ventilation (tracheostomy-assisted ventilation and non-invasive ventilation (NIV)) on survival, functional measures of disease progression, and quality of life in ALS, and to evaluate adverse events related to the intervention. We searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL Plus, and AMED on 30 January 2017. We also searched two clinical trials registries for ongoing studies. Randomised controlled trials (RCTs) and quasi-RCTs involving non-invasive or tracheostomy-assisted ventilation in participants with a clinical diagnosis of ALS, independent of the reported outcomes. We included comparisons with no intervention or the best standard care. For the original review, four review authors independently selected studies for assessment. Two review authors reviewed searches for this update. All review authors independently extracted data from the full text of selected studies and assessed the risk of bias in studies that met the inclusion criteria. We attempted to obtain missing data where possible. We planned to collect adverse event data from the included studies. For the original Cochrane Review, the review authors identified two RCTs involving 54 participants with ALS receiving NIV. There were no new RCTs or quasi-RCTs at the first update. One new RCT was identified in the second update but was excluded for the reasons outlined below.Incomplete data were available for one published study comparing early and late initiation of

  11. Basal ganglia neuronal activity during scanning eye movements in Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Tomáš Sieger

    Full Text Available The oculomotor role of the basal ganglia has been supported by extensive evidence, although their role in scanning eye movements is poorly understood. Nineteen Parkinsońs disease patients, which underwent implantation of deep brain stimulation electrodes, were investigated with simultaneous intraoperative microelectrode recordings and single channel electrooculography in a scanning eye movement task by viewing a series of colored pictures selected from the International Affective Picture System. Four patients additionally underwent a visually guided saccade task. Microelectrode recordings were analyzed selectively from the subthalamic nucleus, substantia nigra pars reticulata and from the globus pallidus by the WaveClus program which allowed for detection and sorting of individual neurons. The relationship between neuronal firing rate and eye movements was studied by crosscorrelation analysis. Out of 183 neurons that were detected, 130 were found in the subthalamic nucleus, 30 in the substantia nigra and 23 in the globus pallidus. Twenty percent of the neurons in each of these structures showed eye movement-related activity. Neurons related to scanning eye movements were mostly unrelated to the visually guided saccades. We conclude that a relatively large number of basal ganglia neurons are involved in eye motion control. Surprisingly, neurons related to scanning eye movements differed from neurons activated during saccades suggesting functional specialization and segregation of both systems for eye movement control.

  12. Basal ganglia neuronal activity during scanning eye movements in Parkinson's disease.

    Science.gov (United States)

    Sieger, Tomáš; Bonnet, Cecilia; Serranová, Tereza; Wild, Jiří; Novák, Daniel; Růžička, Filip; Urgošík, Dušan; Růžička, Evžen; Gaymard, Bertrand; Jech, Robert

    2013-01-01

    The oculomotor role of the basal ganglia has been supported by extensive evidence, although their role in scanning eye movements is poorly understood. Nineteen Parkinsońs disease patients, which underwent implantation of deep brain stimulation electrodes, were investigated with simultaneous intraoperative microelectrode recordings and single channel electrooculography in a scanning eye movement task by viewing a series of colored pictures selected from the International Affective Picture System. Four patients additionally underwent a visually guided saccade task. Microelectrode recordings were analyzed selectively from the subthalamic nucleus, substantia nigra pars reticulata and from the globus pallidus by the WaveClus program which allowed for detection and sorting of individual neurons. The relationship between neuronal firing rate and eye movements was studied by crosscorrelation analysis. Out of 183 neurons that were detected, 130 were found in the subthalamic nucleus, 30 in the substantia nigra and 23 in the globus pallidus. Twenty percent of the neurons in each of these structures showed eye movement-related activity. Neurons related to scanning eye movements were mostly unrelated to the visually guided saccades. We conclude that a relatively large number of basal ganglia neurons are involved in eye motion control. Surprisingly, neurons related to scanning eye movements differed from neurons activated during saccades suggesting functional specialization and segregation of both systems for eye movement control.

  13. Neuronal Entropy-Rate Feature of Entopeduncular Nucleus in Rat Model of Parkinson's Disease.

    Science.gov (United States)

    Darbin, Olivier; Jin, Xingxing; Von Wrangel, Christof; Schwabe, Kerstin; Nambu, Atsushi; Naritoku, Dean K; Krauss, Joachim K; Alam, Mesbah

    2016-03-01

    The function of the nigro-striatal pathway on neuronal entropy in the basal ganglia (BG) output nucleus, i.e. the entopeduncular nucleus (EPN) was investigated in the unilaterally 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD). In both control subjects and subjects with 6-OHDA lesion of dopamine (DA) the nigro-striatal pathway, a histological hallmark for parkinsonism, neuronal entropy in EPN was maximal in neurons with firing rates ranging between 15 and 25 Hz. In 6-OHDA lesioned rats, neuronal entropy in the EPN was specifically higher in neurons with firing rates above 25 Hz. Our data establishes that the nigro-striatal pathway controls neuronal entropy in motor circuitry and that the parkinsonian condition is associated with abnormal relationship between firing rate and neuronal entropy in BG output nuclei. The neuronal firing rates and entropy relationship provide putative relevant electrophysiological information to investigate the sensory-motor processing in normal condition and conditions such as movement disorders.

  14. Modeling Neurological Disease by Rapid Conversion of Human Urine Cells into Functional Neurons

    Directory of Open Access Journals (Sweden)

    Shu-Zhen Zhang

    2016-01-01

    Full Text Available Somatic cells can be directly converted into functional neurons by ectopic expression of defined factors and/or microRNAs. Since the first report of conversion mouse embryonic fibroblasts into functional neurons, the postnatal mouse, and human fibroblasts, astroglia, hepatocytes, and pericyte-derived cells have been converted into functional dopaminergic and motor neurons both in vitro and in vivo. However, it is invasive to get all these materials. In the current study, we provide a noninvasive approach to obtain directly reprogrammed functional neurons by overexpression of the transcription factors Ascl1, Brn2, NeuroD, c-Myc, and Myt1l in human urine cells. These induced neuronal (iN cells could express multiple neuron-specific proteins and generate action potentials. Moreover, urine cells from Wilson’s disease (WD patient could also be directly converted into neurons. In conclusion, generation of iN cells from nonneural lineages is a feasible and befitting approach for neurological disease modeling.

  15. Late onset GM2 gangliosidosis presenting with motor neuron disease: an autopsy case.

    Science.gov (United States)

    Yokoyama, Teruo; Nakamura, Seigo; Horiuchi, Emiko; Ishiyama, Miyako; Kawashima, Rei; Nakamura, Kazuo; Hasegawa, Kazuko; Yagishita, Saburo

    2014-06-01

    Adult-onset GM2 gangliosidosis is very rare and only three autopsy cases have been reported up to now. We report herein an autopsy case of adult-onset GM2 gangliosidosis. The patient developed slowly progressive motor neuron disease-like symptoms after longstanding mood disorder and cognitive dysfunction. He developed gait disturbance and weakness of lower limbs at age 52 years. Because of progressive muscle weakness and atrophy, he became bed-ridden at age 65. At age of 68, he died. His neurological findings presented slight cognitive disturbance, slight manic state, severe muscle weakness, atrophy of four limbs and no extrapyramidal signs and symptoms, and cerebellar ataxia. Neuropathologically, mild neuronal loss and abundant lipid deposits were noted in the neuronal cytoplasm throughout the nervous system, including peripheral autonomic neurons. The most outstanding findings were marked neuronal loss and distended neurons in the anterior horn of the spinal cord, which supports his clinical symptomatology of lower motor neuron disease in this case. The presence of lipofuscin, zebra bodies and membranous cytoplasmic bodies (MCB) and the increase of GM2 ganglioside by biochemistry led to diagnosis of GM2 gangliosidosis. © 2013 Japanese Society of Neuropathology.

  16. MotomiRs: miRNAs in Motor Neuron Function and Disease.

    Science.gov (United States)

    Hawley, Zachary C E; Campos-Melo, Danae; Droppelmann, Cristian A; Strong, Michael J

    2017-01-01

    MiRNAs are key regulators of the mammalian transcriptome that have been increasingly linked to degenerative diseases of the motor neurons. Although many of the miRNAs currently incriminated as participants in the pathogenesis of these diseases are also important to the normal development and function of motor neurons, at present there is no knowledge of the complete miRNA profile of motor neurons. In this review, we examine the current understanding with respect to miRNAs that are specifically required for motor neuron development, function and viability, and provide evidence that these should be considered as a functional network of miRNAs which we have collectively termed MotomiRs. We will also summarize those MotomiRs currently known to be associated with both amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), and discuss their potential use as biomarkers.

  17. Human-induced pluripotent stem cells pave the road for a better understanding of motor neuron disease.

    Science.gov (United States)

    Winner, Beate; Marchetto, Maria C; Winkler, Jürgen; Gage, Fred H

    2014-09-15

    While motor neuron diseases are currently incurable, induced pluripotent stem cell research has uncovered some disease-relevant phenotypes. We will discuss strategies to model different aspects of motor neuron disease and the specific neurons involved in the disease. We will then describe recent progress to investigate common forms of motor neuron disease: amyotrophic lateral sclerosis, hereditary spastic paraplegia and spinal muscular atrophy. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  18. Is spinal muscular atrophy a disease of the motor neurons only: pathogenesis and therapeutic implications?

    Science.gov (United States)

    Simone, Chiara; Ramirez, Agnese; Bucchia, Monica; Rinchetti, Paola; Rideout, Hardy; Papadimitriou, Dimitra; Re, Diane B; Corti, Stefania

    2016-03-01

    Spinal muscular atrophy (SMA) is a genetic neurological disease that causes infant mortality; no effective therapies are currently available. SMA is due to homozygous mutations and/or deletions in the survival motor neuron 1 gene and subsequent reduction of the SMN protein, leading to the death of motor neurons. However, there is increasing evidence that in addition to motor neurons, other cell types are contributing to SMA pathology. In this review, we will discuss the involvement of non-motor neuronal cells, located both inside and outside the central nervous system, in disease onset and progression. Even if SMN restoration in motor neurons is needed, it has been shown that optimal phenotypic amelioration in animal models of SMA requires a more widespread SMN correction. It has been demonstrated that non-motor neuronal cells are also involved in disease pathogenesis and could have important therapeutic implications. For these reasons it will be crucial to take this evidence into account for the clinical translation of the novel therapeutic approaches.

  19. Progressive Apraxia of Speech as a Sign of Motor Neuron Disease

    Science.gov (United States)

    Duffy, Joseph R.; Peach, Richard K.; Strand, Edythe A.

    2007-01-01

    Purpose: To document and describe in detail the occurrence of apraxia of speech (AOS) in a group of individuals with a diagnosis of motor neuron disease (MND). Method: Seven individuals with MND and AOS were identified from among 80 patients with a variety of neurodegenerative diseases and AOS (J. R. Duffy, 2006). The history, presenting…

  20. The utility of cerebral blood flow imaging in patients with the unique syndrome of progressive dementia with motor neuron disease

    International Nuclear Information System (INIS)

    Ohnishi, T.; Hoshi, H.; Jinnouchi, S.; Nagamachi, S.; Watanabe, K.; Mituyama, Y.

    1990-01-01

    Two patients presenting with progressive dementia coupled with motor neuron disease underwent brain SPECT using N-isopropyl-p iodine-123-iodoamphetamine [( 123 I]IMP). The characteristic clinical features of progressive dementia and motor neuron disease were noted. IMP SPECT also revealed reduced uptake in the bilateral frontal and temporal regions, with no reduction of uptake in the parietal, parietal-occipital regions. We conclude that IMP SPECT has potential for the evaluation of progressive dementia with motor neuron disease

  1. Long-Term Health of Dopaminergic Neuron Transplants in Parkinson's Disease Patients

    Directory of Open Access Journals (Sweden)

    Penelope J. Hallett

    2014-06-01

    Full Text Available To determine the long-term health and function of transplanted dopamine neurons in Parkinson’s disease (PD patients, the expression of dopamine transporters (DATs and mitochondrial morphology were examined in human fetal midbrain cellular transplants. DAT was robustly expressed in transplanted dopamine neuron terminals in the reinnervated host putamen and caudate for at least 14 years after transplantation. The transplanted dopamine neurons showed a healthy and nonatrophied morphology at all time points. Labeling of the mitochondrial outer membrane protein Tom20 and α-synuclein showed a typical cellular pathology in the patients’ own substantia nigra, which was not observed in transplanted dopamine neurons. These results show that the vast majority of transplanted neurons remain healthy for the long term in PD patients, consistent with clinical findings that fetal dopamine neuron transplants maintain function for up to 15–18 years in patients. These findings are critically important for the rational development of stem-cell-based dopamine neuronal replacement therapies for PD.

  2. Signaling pathways regulating neuron-glia interaction and their implications in Alzheimer's disease.

    Science.gov (United States)

    Lian, Hong; Zheng, Hui

    2016-02-01

    Astrocytes are the most abundant cells in the central nervous system. They play critical roles in neuronal homeostasis through their physical properties and neuron-glia signaling pathways. Astrocytes become reactive in response to neuronal injury and this process, referred to as reactive astrogliosis, is a common feature accompanying neurodegenerative conditions, particularly Alzheimer's disease. Reactive astrogliosis represents a continuum of pathobiological processes and is associated with morphological, functional, and gene expression changes of varying degrees. There has been a substantial growth of knowledge regarding the signaling pathways regulating glial biology and pathophysiology in recent years. Here, we attempt to provide an unbiased review of some of the well-known players, namely calcium, proteoglycan, transforming growth factor β, NFκB, and complement, in mediating neuron-glia interaction under physiological conditions as well as in Alzheimer's disease. This review discusses the role of astrocytic NFκB and calcium as well as astroglial secreted factors, including proteoglycans, TGFβ, and complement in mediating neuronal function and AD pathogenesis through direct interaction with neurons and through cooperation with microglia. © 2015 International Society for Neurochemistry.

  3. Axonal Charcot-Marie-Tooth disease patient-derived motor neurons demonstrate disease-specific phenotypes including abnormal electrophysiological properties.

    Science.gov (United States)

    Saporta, Mario A; Dang, Vu; Volfson, Dmitri; Zou, Bende; Xie, Xinmin Simon; Adebola, Adijat; Liem, Ronald K; Shy, Michael; Dimos, John T

    2015-01-01

    Charcot-Marie-Tooth (CMT) disease is a group of inherited peripheral neuropathies associated with mutations or copy number variations in over 70 genes encoding proteins with fundamental roles in the development and function of Schwann cells and peripheral axons. Here, we used iPSC-derived cells to identify common pathophysiological mechanisms in axonal CMT. iPSC lines from patients with two distinct forms of axonal CMT (CMT2A and CMT2E) were differentiated into spinal cord motor neurons and used to study axonal structure and function and electrophysiological properties in vitro. iPSC-derived motor neurons exhibited gene and protein expression, ultrastructural and electrophysiological features of mature primary spinal cord motor neurons. Cytoskeletal abnormalities were found in neurons from a CMT2E (NEFL) patient and corroborated by a mouse model of the same NEFL point mutation. Abnormalities in mitochondrial trafficking were found in neurons derived from this patient, but were only mildly present in neurons from a CMT2A (MFN2) patient. Novel electrophysiological abnormalities, including reduced action potential threshold and abnormal channel current properties were observed in motor neurons derived from both of these patients. Human iPSC-derived motor neurons from axonal CMT patients replicated key pathophysiological features observed in other models of MFN2 and NEFL mutations, including abnormal cytoskeletal and mitochondrial dynamics. Electrophysiological abnormalities found in axonal CMT iPSC-derived human motor neurons suggest that these cells are hyperexcitable and have altered sodium and calcium channel kinetics. These findings may provide a new therapeutic target for this group of heterogeneous inherited neuropathies. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease?

    Science.gov (United States)

    Shababi, Monir; Lorson, Christian L; Rudnik-Schöneborn, Sabine S

    2014-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death. SMA is characterized by loss of motor neurons in the ventral horn of the spinal cord, leading to weakness and muscle atrophy. SMA occurs as a result of homozygous deletion or mutations in Survival Motor Neuron-1 (SMN1). Loss of SMN1 leads to a dramatic reduction in SMN protein, which is essential for motor neuron survival. SMA disease severity ranges from extremely severe to a relatively mild adult onset form of proximal muscle atrophy. Severe SMA patients typically die mostly within months or a few years as a consequence of respiratory insufficiency and bulbar paralysis. SMA is widely known as a motor neuron disease; however, there are numerous clinical reports indicating the involvement of additional peripheral organs contributing to the complete picture of the disease in severe cases. In this review, we have compiled clinical and experimental reports that demonstrate the association between the loss of SMN and peripheral organ deficiency and malfunction. Whether defective peripheral organs are a consequence of neuronal damage/muscle atrophy or a direct result of SMN loss will be discussed. © 2013 Anatomical Society.

  5. Advance care planning in motor neuron disease: A qualitative study of caregiver perspectives.

    Science.gov (United States)

    Murray, Leigh; Butow, Phyllis N; White, Kate; Kiernan, Matthew C; D'Abrew, Natalie; Herz, Helen

    2016-05-01

    Motor neuron disease is a fatal disease, characterised by progressive loss of motor function, often associated with cognitive deterioration and, in some, the development of frontotemporal dementia. Life-sustaining technologies are available (e.g. non-invasive ventilation and enteral nutrition) but may compromise quality of life for some patients. Timely commencement of 'Advance Care Planning' enables patients to participate in future care choices; however, this approach has rarely been explored in motor neuron disease. We aimed to investigate caregiver perspectives on the acceptability and impact of advance care planning, documented in a letter format, for patients with motor neuron disease and caregivers. This is a qualitative cross-sectional study. Data were analysed by a narrative synthesis approach. Structured interviews were held with 18 former caregivers of deceased patients with motor neuron disease. A total of 10 patients had created a disease-specific advanced directive, 'Letter of Future Care', and 8 had not. A total of four global themes emerged: Readiness for death, Empowerment, Connections and Clarifying decisions and choices. Many felt the letter of future care was or would be beneficial, engendering autonomy and respect for patients, easing difficult decision-making and enhancing communication within families. However, individuals' 'readiness' to accept encroaching death would influence uptake. Appropriate timing to commence advance care planning may depend on case-based clinical and personal characteristics. Advance care planning can assist patients to achieve a sense of control and 'peace of mind' and facilitates important family discussion. However, the timing and style of its introduction needs to be approached sensitively. Tools and strategies for increasing the efficacy of advance care planning for motor neuron disease should be evaluated and implemented. © The Author(s) 2016.

  6. Increased TRPC5 glutathionylation contributes to striatal neuron loss in Huntington's disease.

    Science.gov (United States)

    Hong, Chansik; Seo, Hyemyung; Kwak, Misun; Jeon, Jeha; Jang, Jihoon; Jeong, Eui Man; Myeong, Jongyun; Hwang, Yu Jin; Ha, Kotdaji; Kang, Min Jueng; Lee, Kyu Pil; Yi, Eugene C; Kim, In-Gyu; Jeon, Ju-Hong; Ryu, Hoon; So, Insuk

    2015-10-01

    Aberrant glutathione or Ca(2+) homeostasis due to oxidative stress is associated with the pathogenesis of neurodegenerative disorders. The Ca(2+)-permeable transient receptor potential cation (TRPC) channel is predominantly expressed in the brain, which is sensitive to oxidative stress. However, the role of the TRPC channel in neurodegeneration is not known. Here, we report a mechanism of TRPC5 activation by oxidants and the effect of glutathionylated TRPC5 on striatal neurons in Huntington's disease. Intracellular oxidized glutathione leads to TRPC5 activation via TRPC5 S-glutathionylation at Cys176/Cys178 residues. The oxidized glutathione-activated TRPC5-like current results in a sustained increase in cytosolic Ca(2+), activated calmodulin-dependent protein kinase and the calpain-caspase pathway, ultimately inducing striatal neuronal cell death. We observed an abnormal glutathione pool indicative of an oxidized state in the striatum of Huntington's disease transgenic (YAC128) mice. Increased levels of endogenous TRPC5 S-glutathionylation were observed in the striatum in both transgenic mice and patients with Huntington's disease. Both knockdown and inhibition of TRPC5 significantly attenuated oxidation-induced striatal neuronal cell death. Moreover, a TRPC5 blocker improved rearing behaviour in Huntington's disease transgenic mice and motor behavioural symptoms in littermate control mice by increasing striatal neuron survival. Notably, low levels of TRPC1 increased the formation of TRPC5 homotetramer, a highly Ca(2+)-permeable channel, and stimulated Ca(2+)-dependent apoptosis in Huntington's disease cells (STHdh(Q111/111)). Taken together, these novel findings indicate that increased TRPC5 S-glutathionylation by oxidative stress and decreased TRPC1 expression contribute to neuronal damage in the striatum and may underlie neurodegeneration in Huntington's disease. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain

  7. Increased TRPC5 glutathionylation contributes to striatal neuron loss in Huntington’s disease

    Science.gov (United States)

    Hong, Chansik; Seo, Hyemyung; Kwak, Misun; Jeon, Jeha; Jang, Jihoon; Jeong, Eui Man; Myeong, Jongyun; Hwang, Yu Jin; Ha, Kotdaji; Kang, Min Jueng; Lee, Kyu Pil; Yi, Eugene C.; Kim, In-Gyu; Jeon, Ju-Hong

    2015-01-01

    Aberrant glutathione or Ca2+ homeostasis due to oxidative stress is associated with the pathogenesis of neurodegenerative disorders. The Ca2+-permeable transient receptor potential cation (TRPC) channel is predominantly expressed in the brain, which is sensitive to oxidative stress. However, the role of the TRPC channel in neurodegeneration is not known. Here, we report a mechanism of TRPC5 activation by oxidants and the effect of glutathionylated TRPC5 on striatal neurons in Huntington’s disease. Intracellular oxidized glutathione leads to TRPC5 activation via TRPC5 S-glutathionylation at Cys176/Cys178 residues. The oxidized glutathione-activated TRPC5-like current results in a sustained increase in cytosolic Ca2+, activated calmodulin-dependent protein kinase and the calpain-caspase pathway, ultimately inducing striatal neuronal cell death. We observed an abnormal glutathione pool indicative of an oxidized state in the striatum of Huntington’s disease transgenic (YAC128) mice. Increased levels of endogenous TRPC5 S-glutathionylation were observed in the striatum in both transgenic mice and patients with Huntington’s disease. Both knockdown and inhibition of TRPC5 significantly attenuated oxidation-induced striatal neuronal cell death. Moreover, a TRPC5 blocker improved rearing behaviour in Huntington’s disease transgenic mice and motor behavioural symptoms in littermate control mice by increasing striatal neuron survival. Notably, low levels of TRPC1 increased the formation of TRPC5 homotetramer, a highly Ca2+-permeable channel, and stimulated Ca2+-dependent apoptosis in Huntington’s disease cells (STHdhQ111/111). Taken together, these novel findings indicate that increased TRPC5 S-glutathionylation by oxidative stress and decreased TRPC1 expression contribute to neuronal damage in the striatum and may underlie neurodegeneration in Huntington’s disease. PMID:26133660

  8. Spliceosome integrity is defective in the motor neuron diseases ALS and SMA

    Science.gov (United States)

    Tsuiji, Hitomi; Iguchi, Yohei; Furuya, Asako; Kataoka, Ayane; Hatsuta, Hiroyuki; Atsuta, Naoki; Tanaka, Fumiaki; Hashizume, Yoshio; Akatsu, Hiroyasu; Murayama, Shigeo; Sobue, Gen; Yamanaka, Koji

    2013-01-01

    Two motor neuron diseases, amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are caused by distinct genes involved in RNA metabolism, TDP-43 and FUS/TLS, and SMN, respectively. However, whether there is a shared defective mechanism in RNA metabolism common to these two diseases remains unclear. Here, we show that TDP-43 and FUS/TLS localize in nuclear Gems through an association with SMN, and that all three proteins function in spliceosome maintenance. We also show that in ALS, Gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in motor neuron nuclei, but not in the temporal lobe of FTLD with TDP-43 pathology. This aberrant accumulation of U snRNAs in ALS motor neurons is in direct contrast to SMA motor neurons, which show reduced amounts of U snRNAs, while both have defects in the spliceosome. These findings indicate that a profound loss of spliceosome integrity is a critical mechanism common to neurodegeneration in ALS and SMA, and may explain cell-type specific vulnerability of motor neurons. PMID:23255347

  9. Crohn's disease but not chronic ulcerative colitis induces the expression of PAI-1 in enteric neurons

    DEFF Research Database (Denmark)

    Laerum, O.D.; Illemann, M.; Skarstein, A.

    2008-01-01

    OBJECTIVES: Chronic inflammation of the intestinal wall is the common characteristic of Crohn's disease and ulcerative colitis; disorders, which in some cases can be difficult to distinguish. The inflammation also affects the local neuronal plexuses of the enteric nervous system. It is known...

  10. Inflammatory cells in the peripheral nervous system in motor neuron disease

    NARCIS (Netherlands)

    Kerkhoff, H.; Troost, D.; Louwerse, E. S.; van Dijk, M.; Veldman, H.; Jennekens, F. G.

    1993-01-01

    We examined post-mortem material of the peripheral nervous system of 26 cases of motor neuron disease (MND) for the presence of lymphocyte subsets and macrophages. Findings were quantified and compared with those in control nerves. Lymphocytes in chronic and acute axonal degeneration were studied in

  11. Determination of neuronal antibodies in suspected and definite Creutzfeldt-Jakob disease

    NARCIS (Netherlands)

    O. Grau-Rivera (Oriol); R. Sánchez-Valle (Raquel); A. Saiz (Albert Abe); J.L. Molinuevo (José Luis); R. Bernabé (Reyes); E. Munteis (Elvira); F. Pujadas (Francesc); A. Salvador (Antoni); J. Saura (Júlia); A. Ugarte (Antonio); M.J. Titulaer (Maarten); J. Dalmau (Josep); F. Graus (Francesc)

    2014-01-01

    textabstractIMPORTANCE: Creutzfeldt-Jakob disease (CJD) and autoimmune encephalitis with antibodies against neuronal surface antigens (NSA-abs) may present with similar clinical features. Establishing the correct diagnosis has practical implications in the management of care for these patients.

  12. Single photon emission computed tomography in motor neuron disease with dementia

    Energy Technology Data Exchange (ETDEWEB)

    Sawada, H.; Udaka, F.; Kishi, Y.; Seriu, N.; Ohtani, S.; Abe, K.; Mezaki, T.; Kameyama, M.; Honda, M.; Tomonobu, M.

    1988-12-01

    Single photon emission computed tomography with (123 I) isopropylamphetamine was carried out on a patient with motor neutron disease with dementia. (123 I) uptake was decreased in the frontal lobes. This would reflect the histopathological findings such as neuronal loss and gliosis in the frontal lobes.

  13. Motor neuron disease and frontotemporal dementia: One, two, or three diseases?

    Directory of Open Access Journals (Sweden)

    Bak Thomas

    2010-10-01

    Full Text Available The relationship between motor neurone disease (MND and frontotemporal dementia (FTD has been a topic of scientific exploration for over hundred years. A connection between both diseases was first postulated in 1932 and has been strengthened by a steady stream of case reports since then. By the late 20th century, the link between both diseases was firmly established, with the resulting condition often referred to as MND/FTD. Several strands of evidence support the notion of an MND/FTD overlap. First, a small but well-documented group of patients present with a full-blown FTD, associated with MND. Second, subtle but characteristic changes in frontal-executive functions and social cognition have been described in non-demented MND patients, often in association with frontal atrophy/hypoactivity on neuroimaging. Third, amyotrophic features have been documented in patients primarily diagnosed with FTD. Moreover, the same genetic defect can lead to FTD and MND phenotypes in different members of the same family. However, as the current research is moving toward a more fine-grained evaluation, an increasingly complex picture begins to emerge. Some features, such as psychotic symptoms or severe language deficits (particularly in comprehension and verb processing, seem to occur more often in MND/dementia than in the classical FTD. On the basis of the review of 100 years of literature as well as 10 years of clinical experience of longitudinal follow-up of MND/dementia patients, this review argues in favor of MND/dementia (or, more precisely, MND/dementia/aphasia as a separate clinical entity, not sufficiently explained by a combination of MND and FTD.

  14. Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease.

    Science.gov (United States)

    Chouhan, Amit K; Guo, Caiwei; Hsieh, Yi-Chen; Ye, Hui; Senturk, Mumine; Zuo, Zhongyuan; Li, Yarong; Chatterjee, Shreyasi; Botas, Juan; Jackson, George R; Bellen, Hugo J; Shulman, Joshua M

    2016-06-23

    Common neurodegenerative proteinopathies, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by the misfolding and aggregation of toxic protein species, including the amyloid beta (Aß) peptide, microtubule-associated protein Tau (Tau), and alpha-synuclein (αSyn) protein. These factors also show toxicity in Drosophila; however, potential limitations of prior studies include poor discrimination between effects on the adult versus developing nervous system and neuronal versus glial cell types. In addition, variable expression paradigms and outcomes hinder systematic comparison of toxicity profiles. Using standardized conditions and medium-throughput assays, we express human Tau, Aß or αSyn selectively in neurons of the adult Drosophila retina and monitor age-dependent changes in both structure and function, based on tissue histology and recordings of the electroretinogram (ERG), respectively. We find that each protein causes a unique profile of neurodegenerative pathology, demonstrating distinct and separable impacts on neuronal death and dysfunction. Strikingly, expression of Tau leads to progressive loss of ERG responses whereas retinal architecture and neuronal numbers are largely preserved. By contrast, Aß induces modest, age-dependent neuronal loss without degrading the retinal ERG. αSyn expression, using a codon-optimized transgene, is characterized by marked retinal vacuolar change, progressive photoreceptor cell death, and delayed-onset but modest ERG changes. Lastly, to address potential mechanisms, we perform transmission electron microscopy (TEM) to reveal potential degenerative changes at the ultrastructural level. Surprisingly, Tau and αSyn each cause prominent but distinct synaptotoxic profiles, including disorganization or enlargement of photoreceptor terminals, respectively. Our findings highlight variable and dynamic properties of neurodegeneration triggered by these disease-relevant proteins in vivo, and suggest

  15. Huntington's disease modeling and treatment: from primary neuronal cultures to rodents

    OpenAIRE

    Zala, Diana; Aebischer, Patrick; Déglon, Nicole

    2007-01-01

    Huntington's disease (HD) is a mid-life-onset neurodegenerative disorder characterized by involuntary movements, personality changes and dementia. It progresses to death within 10-20 years after onset. There is currently no cure to treat this fatal disease. In HD patients, the protein huntingtin contains an abnormal expansion of a polyglutamine tract, which leads to the selective death of striatal neurons. The functions of huntingtin, as well as the dysfunctions induced by the mutation are st...

  16. Cognitive Decline in Neuronal Aging and Alzheimer's Disease: Role of NMDA Receptors and Associated Proteins

    Directory of Open Access Journals (Sweden)

    Jesús Avila

    2017-11-01

    Full Text Available Molecular changes associated with neuronal aging lead to a decrease in cognitive capacity. Here we discuss these alterations at the level of brain regions, brain cells, and brain membrane and cytoskeletal proteins with an special focus in NMDA molecular changes through aging and its effect in cognitive decline and Alzheimer disease. Here, we propose that some neurodegenerative disorders, like Alzheimer's disease (AD, are characterized by an increase and acceleration of some of these changes.

  17. Trafficking in neurons: searching for new targets for Alzheimer's disease future therapies.

    Science.gov (United States)

    Musardo, Stefano; Saraceno, Claudia; Pelucchi, Silvia; Marcello, Elena

    2013-11-05

    Alzheimer's disease (AD) is the most common cause of dementia and no cure is available at the moment. As the disease progresses, patients become increasingly dependent, needing constant supervision and care. Prevention or delay of AD onset is among the most urgent moral, social, economic and scientific imperatives in industrialized countries. A better understanding of the pathogenic mechanisms leading to the disease and the consequent identification of new pharmacological targets are now a need. One of the most prominent molecular events occurring in AD patients' brains is the deposition of a peptide named amyloid-β (Aβ). Aβ derives from the concerted action of β-secretase, which mediates the amyloid precursor protein (APP) shedding at Aβ N-terminus, and γ-secretase, responsible for APP C-terminal stub cleavage. The production of Aβ can be prevented by the cleavage of ADAM10 on APP. In regard of AD pathogenesis, it is notable that neurons are the cell type affected in AD and that APP and the secretases are all integral transmembrane proteins, and so they are dynamically sorted in neurons. Therefore, neuronal sorting mechanisms responsible for APP and the secretases colocalization in the same membranous compartment play important roles in the regulation of Aβ production. In light of these considerations, this review provides an overview on the actual knowledge of the trafficking mechanisms involved in the regulation of APP and secretases localization, paying particular attention to the specific neuronal setting. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Tyrosinase-Expressing Neuronal Cell Line as in Vitro Model of Parkinson’s Disease

    Science.gov (United States)

    Hasegawa, Takafumi

    2010-01-01

    Oxidized metabolites of dopamine known as dopamine quinone derivatives are thought to play a pivotal role in the degeneration of nigrostriatal dopaminergic neurons in Parkinson’s disease. Although such quinone derivatives are usually produced via the autoxidation of catecholamines, tyrosinase, which is a key enzyme in melanin biosynthesis via the production of DOPA and subsequent molecules, can potentially accelerate the induction of catecholamine quinone derivatives by its oxidase activity. We have developed neuronal cell lines in which the expression of human tyrosinase was inducible. Overexpression of tyrosinase resulted in increased intracellular dopamine content in association with the formation of melanin pigments in neuronal somata, which eventually causes apoptotic cell death. This cellular model will provide a useful tool for detailed analyses of the neurotoxicity of oxidized catechol metabolites. PMID:20480001

  19. Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy.

    Science.gov (United States)

    Wang, Zhi-Bo; Zhang, Xiaoqing; Li, Xue-Jun

    2013-03-01

    Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-Δ7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA.

  20. Glial degeneration with oxidative damage drives neuronal demise in MPSII disease

    Science.gov (United States)

    Zalfa, Cristina; Verpelli, Chiara; D'Avanzo, Francesca; Tomanin, Rosella; Vicidomini, Cinzia; Cajola, Laura; Manara, Renzo; Sala, Carlo; Scarpa, Maurizio; Vescovi, Angelo Luigi; De Filippis, Lidia

    2016-01-01

    Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the iduronate 2-sulfatase (IDS) enzyme, causing progressive neurodegeneration in patients. Neural stem cells (NSCs) derived from the IDS-ko mouse can recapitulate MPSII pathogenesis in vitro. In differentiating IDS-ko NSCs and in the aging IDS-ko mouse brain, glial degeneration precedes neuronal degeneration. Here we show that pure IDS-ko NSC-derived astrocytes are selectively able to drive neuronal degeneration when cocultured with healthy neurons. This phenotype suggests concurrent oxidative damage with metabolic dysfunction. Similar patterns were observed in murine IDS-ko animals and in human MPSII brains. Most importantly, the mutant phenotype of IDS-ko astrocytes was reversed by low oxygen conditions and treatment with vitamin E, which also reversed the toxic effect on cocultured neurons. Moreover, at very early stages of disease we detected in vivo the development of a neuroinflammatory background that precedes astroglial degeneration, thus suggesting a novel model of MPSII pathogenesis, with neuroinflammation preceding glial degeneration, which is finally followed by neuronal death. This hypothesis is also consistent with the progression of white matter abnormalities in MPSII patients. Our study represents a novel breakthrough in the elucidation of MPSII brain pathogenesis and suggests the antioxidant molecules as potential therapeutic tools to delay MPSII onset and progression. PMID:27512952

  1. Caregiver bodywork: family members' experiences of caring for a person with motor neurone disease.

    Science.gov (United States)

    Ray, Robin A; Street, Annette F

    2006-10-01

    This paper reports a study of how family members caring for people living with motor neurone disease managed the deteriorating body, their own bodywork and the associated emotional labour. People living with the neurodegenerative condition of motor neurone disease face the prospect of dying in 3-5 years from progressive loss of voluntary muscle mass and function, culminating in respiratory failure. Theories concerning the body in illness have been used to illustrate patient perspectives; however, family caregivers' experiences of the body have been neglected. An ethnographic case study was undertaken with 18 primary family caregivers and six peripheral caregivers. Primary caregivers participated over 10 months in three face-to-face, semi-structured interviews which included mapping their support networks using ecomaps. Observational data were also recorded as field notes. Peripheral caregivers were interviewed once during the same time period. The data were generated between 2003 and 2004. Informal caregiving requires engagement in various aspects of bodywork. Three body concepts were identified: the visible body--how the disease affected the patient and caregivers; the dependent body--the resulting care requirements; and the social body--how living with motor neurone disease affected their social support networks. The visible body is a continual reminder of the ravages of the disease, while the dependent body demands physical and emotional care. Social interactions decline over time, depriving family caregivers of the much needed support for sustaining their commitment to the bodywork required in caregiving. The demands of bodywork for family caregivers are increased by the continual presence of emotional labour as they seek to implement the best way to support their relative with motor neurone disease. Nurses and allied healthcare workers need to assess each family situation, asking appropriate questions to establish the most appropriate interventions to

  2. The sigma-1 receptor: roles in neuronal plasticity and disease

    Science.gov (United States)

    Kourrich, Saïd; Su, Tsung-Ping; Fujimoto, Michiko; Bonci, Antonello

    2012-01-01

    Sigma-1 receptors (Sig-1Rs) have been implicated in many neurological and psychiatric conditions. The Sig-1R is an intracellular chaperone that resides specifically at the endoplasmic reticulum (ER)-mitochondrion interface referred to as the mitochondrion-associated ER membrane (MAM). Here, Sig-1Rs regulate ER-mitochondrion Ca2+ signaling. In this review, we discuss the current understanding of Sig-1R functions. Based on this, we suggest that the key cellular mechanism linking Sig-1Rs to neurological disorders involve the translocation of Sig-1Rs from the MAM to other parts of the cell, whereby Sig-1Rs bind and modulate the activities of various ion channels, receptors, or kinases. Thus, Sig-1Rs and their associated ligands may represent new avenues for treating some aspects of neurological and psychiatric diseases. PMID:23102998

  3. Using induced pluripotent stem cells derived neurons to model brain diseases

    Directory of Open Access Journals (Sweden)

    Cindy E McKinney

    2017-01-01

    Full Text Available The ability to use induced pluripotent stem cells (iPSC to model brain diseases is a powerful tool for unraveling mechanistic alterations in these disorders. Rodent models of brain diseases have spurred understanding of pathology but the concern arises that they may not recapitulate the full spectrum of neuron disruptions associated with human neuropathology. iPSC derived neurons, or other neural cell types, provide the ability to access pathology in cells derived directly from a patient's blood sample or skin biopsy where availability of brain tissue is limiting. Thus, utilization of iPSC to study brain diseases provides an unlimited resource for disease modelling but may also be used for drug screening for effective therapies and may potentially be used to regenerate aged or damaged cells in the future. Many brain diseases across the spectrum of neurodevelopment, neurodegenerative and neuropsychiatric are being approached by iPSC models. The goal of an iPSC based disease model is to identify a cellular phenotype that discriminates the disease-bearing cells from the control cells. In this mini-review, the importance of iPSC cell models validated for pluripotency, germline competency and function assessments is discussed. Selected examples for the variety of brain diseases that are being approached by iPSC technology to discover or establish the molecular basis of the neuropathology are discussed.

  4. Meal size and frequency affect neuronal plasticity and vulnerability to disease: cellular and molecular mechanisms.

    Science.gov (United States)

    Mattson, Mark P; Duan, Wenzhen; Guo, Zhihong

    2003-02-01

    Although all cells in the body require energy to survive and function properly, excessive calorie intake over long time periods can compromise cell function and promote disorders such as cardiovascular disease, type-2 diabetes and cancers. Accordingly, dietary restriction (DR; either caloric restriction or intermittent fasting, with maintained vitamin and mineral intake) can extend lifespan and can increase disease resistance. Recent studies have shown that DR can have profound effects on brain function and vulnerability to injury and disease. DR can protect neurons against degeneration in animal models of Alzheimer's, Parkinson's and Huntington's diseases and stroke. Moreover, DR can stimulate the production of new neurons from stem cells (neurogenesis) and can enhance synaptic plasticity, which may increase the ability of the brain to resist aging and restore function following injury. Interestingly, increasing the time interval between meals can have beneficial effects on the brain and overall health of mice that are independent of cumulative calorie intake. The beneficial effects of DR, particularly those of intermittent fasting, appear to be the result of a cellular stress response that stimulates the production of proteins that enhance neuronal plasticity and resistance to oxidative and metabolic insults; they include neurotrophic factors such as brain-derived neurotrophic factor (BDNF), protein chaperones such as heat-shock proteins, and mitochondrial uncoupling proteins. Some beneficial effects of DR can be achieved by administering hormones that suppress appetite (leptin and ciliary neurotrophic factor) or by supplementing the diet with 2-deoxy-d-glucose, which may act as a calorie restriction mimetic. The profound influences of the quantity and timing of food intake on neuronal function and vulnerability to disease have revealed novel molecular and cellular mechanisms whereby diet affects the nervous system, and are leading to novel preventative and

  5. DNA methylation alterations in iPSC- and hESC-derived neurons: potential implications for neurological disease modeling.

    Science.gov (United States)

    de Boni, Laura; Gasparoni, Gilles; Haubenreich, Carolin; Tierling, Sascha; Schmitt, Ina; Peitz, Michael; Koch, Philipp; Walter, Jörn; Wüllner, Ullrich; Brüstle, Oliver

    2018-01-01

    Genetic predisposition and epigenetic alterations are both considered to contribute to sporadic neurodegenerative diseases (NDDs) such as Parkinson's disease (PD). Since cell reprogramming and the generation of induced pluripotent stem cells (iPSCs) are themselves associated with major epigenetic remodeling, it remains unclear to what extent iPSC-derived neurons lend themselves to model epigenetic disease-associated changes. A key question to be addressed in this context is whether iPSC-derived neurons exhibit epigenetic signatures typically observed in neurons derived from non-reprogrammed human embryonic stem cells (hESCs). Here, we compare mature neurons derived from hESC and isogenic human iPSC generated from hESC-derived neural stem cells. Genome-wide 450 K-based DNA methylation and HT12v4 gene array expression analyses were complemented by a deep analysis of selected genes known to be involved in NDD. Our studies show that DNA methylation and gene expression patterns of isogenic hESC- and iPSC-derived neurons are markedly preserved on a genome-wide and single gene level. Overall, iPSC-derived neurons exhibit similar DNA methylation patterns compared to isogenic hESC-derived neurons. Further studies will be required to explore whether the epigenetic patterns observed in iPSC-derived neurons correspond to those detectable in native brain neurons.

  6. Cell-type Dependent Alzheimer's Disease Phenotypes: Probing the Biology of Selective Neuronal Vulnerability

    Directory of Open Access Journals (Sweden)

    Christina R. Muratore

    2017-12-01

    Full Text Available Summary: Alzheimer's disease (AD induces memory and cognitive impairment in the absence of motor and sensory deficits during its early and middle course. A major unresolved question is the basis for this selective neuronal vulnerability. Aβ, which plays a central role in AD pathogenesis, is generated throughout the brain, yet some regions outside of the limbic and cerebral cortices are relatively spared from Aβ plaque deposition and synapse loss. Here, we examine neurons derived from iPSCs of patients harboring an amyloid precursor protein mutation to quantify AD-relevant phenotypes following directed differentiation to rostral fates of the brain (vulnerable and caudal fates (relatively spared in AD. We find that both the generation of Aβ and the responsiveness of TAU to Aβ are affected by neuronal cell type, with rostral neurons being more sensitive than caudal neurons. Thus, cell-autonomous factors may in part dictate the pattern of selective regional vulnerability in human neurons in AD. : In this article, Muratore et al. examine differential vulnerability of neuronal subtypes in AD by directing iPSC lines from control and familial AD subjects to different regional neuronal fates. APP processing and TAU proteostasis are differentially affected between regional fates, such that neuronal cell type dictates generation of and responsiveness to Aβ. Keywords: Alzheimer's disease, disease modeling, iPSCs, neural stem cells, Abeta, Tau, selective vulnerability, amyloid, familial AD, differential susceptibility

  7. Differential regulation of amyloid-β-protein mRNA expression within hippocampal neuronal subpopulations in Alzheimer disease

    International Nuclear Information System (INIS)

    Higgins, G.A.; Lewis, D.A.; Bahmanyar, S.; Goldgaber, D.; Gajdusek, D.C.; Young, W.G.; Morrison, J.H.; Wilson, M.C.

    1988-01-01

    The authors have mapped the neuroanatomical distribution of amyloid-β-protein mRNA within neuronal subpopulations of the hippocampal formation in the cynomolgus monkey (Macaca fascicularis), normal aged human, and patients with Alzheimer disease. Amyloid-β-protein mRNA appears to be expressed in all hippocampal neurons, but at different levels of abundance. In the central nervous system of monkey and normal aged human, image analysis shows that neurons of the dentate gyrus and cornu Ammonis fields contain a 2.5-times-greater hybridization signal than is present in neurons of the subiculum and entorhinal cortex. In contrast, in the Alzheimer disease hippocampal formation, the levels of amyloid-β-protein mRNA in the cornu Ammonis field 3 and parasubiculum are equivalent. These findings suggest that within certain neuronal subpopulations cell type-specific regulation of amyloid-β-protein gene expression may be altered in Alzheimer disease

  8. Message banking: Perceptions of persons with motor neuron disease, significant others and clinicians.

    Science.gov (United States)

    Oosthuizen, Imke; Dada, Shakila; Bornman, Juan; Koul, Rajinder

    2017-07-31

    Message banking is an intervention strategy that has the potential to facilitate effective communication for people with motor neuron disease when their condition deteriorates to the extent that they cannot communicate using natural speech. The aim of the current study was to determine and compare the perceptions on message banking of three stakeholder groups, namely, persons with motor neuron disease, their significant others and speech-language pathologists. A comparative group survey design was used. Participants listened to a short presentation about message banking, after which they individually completed a questionnaire. Although most participants reported that they had never heard of message banking, all were interested in it. The survey results revealed statistically significant differences between the various groups of stakeholders regarding the relevance of message banking and types of messages to bank. The study concluded that there is limited awareness about message banking amongst all participant groups.

  9. Determination of neuronal antibodies in suspected and definite Creutzfeldt-Jakob disease

    OpenAIRE

    Grau-Rivera, O.; Sánchez del Valle Díaz, Raquel; Saiz Hinajeros, Albert; Molinuevo, José L.; Bernabé, Reyes; Munteis, Elvira; Pujadas, Francesc; Salvador, Antoni; Saura, Júlia; Ugarte, Antonio; Titulaer, Maarten; Dalmau Obrador, Josep; Graus Ribas, Francesc

    2014-01-01

    IMPORTANCE Creutzfeldt-Jakob disease (CJD) and autoimmune encephalitis with antibodies against neuronal surface antigens (NSA-abs) may present with similar clinical features. Establishing the correct diagnosis has practical implications in the management of care for these patients. OBJECTIVE To determine the frequency of NSA-abs in the cerebrospinal fluid of patients with suspected CJD and in patients with pathologically confirmed (ie, definite) CJD. DESIGN, SETTING, AND PARTICIPANTS A mixed ...

  10. MicroRNA Profiling Reveals Marker of Motor Neuron Disease in ALS Models.

    Science.gov (United States)

    Hoye, Mariah L; Koval, Erica D; Wegener, Amy J; Hyman, Theodore S; Yang, Chengran; O'Brien, David R; Miller, Rebecca L; Cole, Tracy; Schoch, Kathleen M; Shen, Tao; Kunikata, Tomonori; Richard, Jean-Philippe; Gutmann, David H; Maragakis, Nicholas J; Kordasiewicz, Holly B; Dougherty, Joseph D; Miller, Timothy M

    2017-05-31

    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type to elucidate underlying disease mechanisms and to identify novel targets that inform on MN health during ALS disease time course. microRNAs (miRNAs) are short, noncoding RNAs that can shape the expression profile of a cell and thus often exhibit cell-type-enriched expression. To determine MN-enriched miRNA expression, we used Cre recombinase-dependent miRNA tagging and affinity purification in mice. By defining the in vivo miRNA expression of MNs, all neurons, astrocytes, and microglia, we then focused on MN-enriched miRNAs via a comparative analysis and found that they may functionally distinguish MNs postnatally from other spinal neurons. Characterizing the levels of the MN-enriched miRNAs in CSF harvested from ALS models of MN disease demonstrated that one miRNA (miR-218) tracked with MN loss and was responsive to an ALS therapy in rodent models. Therefore, we have used cellular expression profiling tools to define the distinct miRNA expression of MNs, which is likely to enrich future studies of MN disease. This approach enabled the development of a novel, drug-responsive marker of MN disease in ALS rodents. SIGNIFICANCE STATEMENT Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons (MNs) in the brain and spinal cord are selectively lost. To develop tools to aid in our understanding of the distinct expression profiles of MNs and, ultimately, to monitor MN disease progression, we identified small regulatory microRNAs (miRNAs) that were highly enriched or exclusive in MNs. The signal for one of these MN-enriched miRNAs is detectable in spinal tap biofluid from an ALS rat model, where its levels change as disease

  11. Small GSK-3 Inhibitor Shows Efficacy in a Motor Neuron Disease Murine Model Modulating Autophagy.

    Directory of Open Access Journals (Sweden)

    Estefanía de Munck

    Full Text Available Amyotrophic lateral sclerosis (ALS is a progressive motor neuron degenerative disease that has no effective treatment up to date. Drug discovery tasks have been hampered due to the lack of knowledge in its molecular etiology together with the limited animal models for research. Recently, a motor neuron disease animal model has been developed using β-N-methylamino-L-alanine (L-BMAA, a neurotoxic amino acid related to the appearing of ALS. In the present work, the neuroprotective role of VP2.51, a small heterocyclic GSK-3 inhibitor, is analysed in this novel murine model together with the analysis of autophagy. VP2.51 daily administration for two weeks, starting the first day after L-BMAA treatment, leads to total recovery of neurological symptoms and prevents the activation of autophagic processes in rats. These results show that the L-BMAA murine model can be used to test the efficacy of new drugs. In addition, the results confirm the therapeutic potential of GSK-3 inhibitors, and specially VP2.51, for the disease-modifying future treatment of motor neuron disorders like ALS.

  12. Dysregulation of the Autophagy-Endolysosomal System in Amyotrophic Lateral Sclerosis and Related Motor Neuron Diseases

    Directory of Open Access Journals (Sweden)

    Asako Otomo

    2012-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a heterogeneous group of incurable motor neuron diseases (MNDs characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Most cases of ALS are sporadic, while approximately 5–10% cases are familial. More than 16 causative genes for ALS/MNDs have been identified and their underlying pathogenesis, including oxidative stress, endoplasmic reticulum stress, excitotoxicity, mitochondrial dysfunction, neural inflammation, protein misfolding and accumulation, dysfunctional intracellular trafficking, abnormal RNA processing, and noncell-autonomous damage, has begun to emerge. It is currently believed that a complex interplay of multiple toxicity pathways is implicated in disease onset and progression. Among such mechanisms, ones that are associated with disturbances of protein homeostasis, the ubiquitin-proteasome system and autophagy, have recently been highlighted. Although it remains to be determined whether disease-associated protein aggregates have a toxic or protective role in the pathogenesis, the formation of them results from the imbalance between generation and degradation of misfolded proteins within neuronal cells. In this paper, we focus on the autophagy-lysosomal and endocytic degradation systems and implication of their dysfunction to the pathogenesis of ALS/MNDs. The autophagy-endolysosomal pathway could be a major target for the development of therapeutic agents for ALS/MNDs.

  13. Brain MR Imaging in Patients with Lower Motor Neuron-Predominant Disease.

    Science.gov (United States)

    Spinelli, Edoardo G; Agosta, Federica; Ferraro, Pilar M; Riva, Nilo; Lunetta, Christian; Falzone, Yuri M; Comi, Giancarlo; Falini, Andrea; Filippi, Massimo

    2016-08-01

    Purpose To investigate the patterns of cortical thinning and white matter tract damage in patients with lower motor neuron (LMN)-predominant disease compared with healthy control subjects and those with classic amyotrophic lateral sclerosis (ALS) and to evaluate the relationship between brain structural changes and clinical and cognitive features in these patients. Materials and Methods This study was approved by the local ethical committee, and written informed consent was obtained from all subjects before enrollment. Twenty-eight patients with LMN-predominant disease were compared with 55 patients with ALS and 56 healthy control subjects. Patients underwent a clinical and neuropsychological assessment and T1-weighted and diffusion-tensor magnetic resonance (MR) imaging. Surface-based morphometry was used to assess cortical thickness. Tract-based spatial statistics and tractography were used to study white matter tract damage. Results Patients with LMN-predominant disease did not show differences compared with healthy control subjects in cortical thickness and diffusion-tensor MR imaging metrics. Patients with ALS showed cortical thinning of the motor-related cortices and a distributed involvement of the prefrontal, temporal, and parietal gyri (P motor and extramotor tracts compared with control subjects and patients with LMN-predominant disease (tract-based spatial statistics: P disease, cognitive deficits correlated with alterations in diffusivity in the left cingulum (r = -0.66, P = .01) and superior longitudinal fasciculus (r = -0.65, P = .05). Conclusion Motor and extramotor cortical thinning and diffusion-tensor MR imaging alterations were specific for motor neuron disease phenotypes, with clinically overt upper motor neuron involvement. However, the lack of significant differences in cortical thickness between subjects with LMN-predominant disease and those with ALS and cognitive deficits associated with alterations in diffusivity in patients with LMN

  14. Inhibiting sphingosine kinase 2 mitigates mutant Huntingtin-induced neurodegeneration in neuron models of Huntington disease.

    Science.gov (United States)

    Moruno-Manchon, Jose F; Uzor, Ndidi-Ese; Blasco-Conesa, Maria P; Mannuru, Sishira; Putluri, Nagireddy; Furr-Stimming, Erin E; Tsvetkov, Andrey S

    2017-04-01

    Huntington disease (HD) is the most common inherited neurodegenerative disorder. It has no cure. The protein huntingtin causes HD, and mutations to it confer toxic functions to the protein that lead to neurodegeneration. Thus, identifying modifiers of mutant huntingtin-mediated neurotoxicity might be a therapeutic strategy for HD. Sphingosine kinases 1 (SK1) and 2 (SK2) synthesize sphingosine-1-phosphate (S1P), a bioactive lipid messenger critically involved in many vital cellular processes, such as cell survival. In the nucleus, SK2 binds to and inhibits histone deacetylases 1 and 2 (HDAC1/2). Inhibiting both HDACs has been suggested as a potential therapy in HD. Here, we found that SK2 is nuclear in primary neurons and, unexpectedly, overexpressed SK2 is neurotoxic in a dose-dependent manner. SK2 promotes DNA double-strand breaks in cultured primary neurons. We also found that SK2 is hyperphosphorylated in the brain samples from a model of HD, the BACHD mice. These data suggest that the SK2 pathway may be a part of a pathogenic pathway in HD. ABC294640, an inhibitor of SK2, reduces DNA damage in neurons and increases survival in two neuron models of HD. Our results identify a novel regulator of mutant huntingtin-mediated neurotoxicity and provide a new target for developing therapies for HD. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  15. Human iPS cell-derived dopaminergic neurons function in a primate Parkinson's disease model.

    Science.gov (United States)

    Kikuchi, Tetsuhiro; Morizane, Asuka; Doi, Daisuke; Magotani, Hiroaki; Onoe, Hirotaka; Hayashi, Takuya; Mizuma, Hiroshi; Takara, Sayuki; Takahashi, Ryosuke; Inoue, Haruhisa; Morita, Satoshi; Yamamoto, Michio; Okita, Keisuke; Nakagawa, Masato; Parmar, Malin; Takahashi, Jun

    2017-08-30

    Induced pluripotent stem cells (iPS cells) are a promising source for a cell-based therapy to treat Parkinson's disease (PD), in which midbrain dopaminergic neurons progressively degenerate. However, long-term analysis of human iPS cell-derived dopaminergic neurons in primate PD models has never been performed to our knowledge. Here we show that human iPS cell-derived dopaminergic progenitor cells survived and functioned as midbrain dopaminergic neurons in a primate model of PD (Macaca fascicularis) treated with the neurotoxin MPTP. Score-based and video-recording analyses revealed an increase in spontaneous movement of the monkeys after transplantation. Histological studies showed that the mature dopaminergic neurons extended dense neurites into the host striatum; this effect was consistent regardless of whether the cells were derived from patients with PD or from healthy individuals. Cells sorted by the floor plate marker CORIN did not form any tumours in the brains for at least two years. Finally, magnetic resonance imaging and positron emission tomography were used to monitor the survival, expansion and function of the grafted cells as well as the immune response in the host brain. Thus, this preclinical study using a primate model indicates that human iPS cell-derived dopaminergic progenitors are clinically applicable for the treatment of patients with PD.

  16. Mitochondrial mislocalization underlies Abeta42-induced neuronal dysfunction in a Drosophila model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Kanae Iijima-Ando

    2009-12-01

    Full Text Available The amyloid-beta 42 (Abeta42 is thought to play a central role in the pathogenesis of Alzheimer's disease (AD. However, the molecular mechanisms by which Abeta42 induces neuronal dysfunction and degeneration remain elusive. Mitochondrial dysfunctions are implicated in AD brains. Whether mitochondrial dysfunctions are merely a consequence of AD pathology, or are early seminal events in AD pathogenesis remains to be determined. Here, we show that Abeta42 induces mitochondrial mislocalization, which contributes to Abeta42-induced neuronal dysfunction in a transgenic Drosophila model. In the Abeta42 fly brain, mitochondria were reduced in axons and dendrites, and accumulated in the somata without severe mitochondrial damage or neurodegeneration. In contrast, organization of microtubule or global axonal transport was not significantly altered at this stage. Abeta42-induced behavioral defects were exacerbated by genetic reductions in mitochondrial transport, and were modulated by cAMP levels and PKA activity. Levels of putative PKA substrate phosphoproteins were reduced in the Abeta42 fly brains. Importantly, perturbations in mitochondrial transport in neurons were sufficient to disrupt PKA signaling and induce late-onset behavioral deficits, suggesting a mechanism whereby mitochondrial mislocalization contributes to Abeta42-induced neuronal dysfunction. These results demonstrate that mislocalization of mitochondria underlies the pathogenic effects of Abeta42 in vivo.

  17. Therapeutic opportunities and challenges of induced pluripotent stem cells-derived motor neurons for treatment of amyotrophic lateral sclerosis and motor neuron disease.

    Science.gov (United States)

    Jaiswal, Manoj Kumar

    2017-05-01

    Amyotrophic lateral sclerosis (ALS) and motor neuron diseases (MNDs) are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons (UMNs/LMNs), brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons (MNs), muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3-5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for the first time to obtain substantial amounts of human cells to recapitulate in vitro " disease in dish " and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs.

  18. Therapeutic opportunities and challenges of induced pluripotent stem cells-derived motor neurons for treatment of amyotrophic lateral sclerosis and motor neuron disease

    Directory of Open Access Journals (Sweden)

    Manoj Kumar Jaiswal

    2017-01-01

    Full Text Available Amyotrophic lateral sclerosis (ALS and motor neuron diseases (MNDs are progressive neurodegenerative diseases that affect nerve cells in the brain affecting upper and lower motor neurons (UMNs/LMNs, brain stem and spinal cord. The clinical phenotype is characterized by loss of motor neurons (MNs, muscular weakness and atrophy eventually leading to paralysis and death due to respiratory failure within 3–5 years after disease onset. No effective treatment or cure is currently available that halts or reverses ALS and MND except FDA approved drug riluzole that only modestly slows the progression of ALS in some patients. Recent advances in human derived induced pluripotent stem cells have made it possible for thefirst time to obtain substantial amounts of human cells to recapitulate in vitro “disease in dish” and test some of the underlying pathogenetic mechanisms involved in ALS and MNDs. In this review, I discussed the opportunities and challenges of induced pluropotent stem cells-derived motor neurons for treatment of ALS and MND patients with special emphasis on their implications in finding a cure for ALS and MNDs.

  19. An investigation into the inter-relationships of sulphur xeno-biotransformation pathways in Parkinson's and motor neurone diseases.

    Science.gov (United States)

    Steventon, Glyn B; Waring, Rosemary H; Williams, Adrian C

    2003-01-01

    The role of defective 'sulphur xenobiotic' biotransformations in the aetiology of Parkinson's and motor neurone diseases has been in the literature for over a decade. Problems in the S-oxidation of aliphatic thioethers, sulphation of phenolic compounds and the S-methylation of aliphatic sulphydryl groups have all been reported. These reports have also been consistent in observing that only a 'significant minority' of patients express these problems in sulphur biotransformation pathways. However, no investigation has yet reported on the incidence of these three defective pathways in control invididuals and in patients with Parkinson's and motor neurone disease. This investigation has found that: 1. Forty percent of patients with Parkinson's and motor neurone disease have a defect in the S-oxidation of S-carboxymethyl-L-cysteine compared to 4% of controls. 2. 35-40% of patients with Parkinson's and motor neurone disease have a defect in the sulphation of paracetamol compared to 4% of controls. 3. 60% of patients with motor neurone disease have a high capacity for the S-methylation of 2-mercaptoethanol compared to 4% of controls. 4. 38% of patients with Parkinson's disease have a low capacity for the S-methylation of 2-mercaptoethanol compared to 4% of controls. 5. There is no correlation between the S-oxidation phenotype, low paracetamol sulphation phenotype and low or high S-methylation phenotype in controls or patients with Parkinson's or motor neurone disease. 6. The number of controls that expressed one of the aberrant phenotypes was 4% compared to 38% of the patients with Parkinson's disease and 47% of the patients with motor neurone disease. 7. The number of controls that expressed two of the aberrant phenotypes was 0% compared to 18% of the patients with Parkinson's disease and 19% of those with motor neurone disease. 8. No controls or patients with Parkinson's disease or motor neurone disease expressed all three of the aberrant phenotypes. The results

  20. Adult Hippocampal Neurogenesis in Parkinson’s Disease: Impact on Neuronal Survival and Plasticity

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    Martin Regensburger

    2014-01-01

    Full Text Available In Parkinson’s disease (PD and other synucleinopathies, chronic neurodegeneration occurs within different areas of the central nervous system leading to progressive motor and nonmotor symptoms. The symptomatic treatment options that are currently available do not slow or halt disease progression. This highlights the need of a better understanding of disease mechanisms and disease models. The generation of newborn neurons in the adult hippocampus and in the subventricular zone/olfactory bulb system is affected by many different regulators and possibly involved in memory processing, depression, and olfaction, symptoms which commonly occur in PD. The pathology of the adult neurogenic niches in human PD patients is still mostly elusive, but different preclinical models have shown profound alterations of adult neurogenesis. Alterations in stem cell proliferation, differentiation, and survival as well as neurite outgrowth and spine formation have been related to different aspects in PD pathogenesis. Therefore, neurogenesis in the adult brain provides an ideal model to study disease mechanisms and compounds. In addition, adult newborn neurons have been proposed as a source of endogenous repair. Herein, we review current knowledge about the adult neurogenic niches in PD and highlight areas of future research.

  1. Adaptive Responses of Neuronal Mitochondria to Bioenergetic Challenges: Roles in Neuroplasticity and Disease Resistance

    Science.gov (United States)

    Raefsky, Sophia M.; Mattson, Mark P.

    2016-01-01

    An important concept in neurobiology is “neurons that fire together, wire together” which means that the formation and maintenance of synapses is promoted by activation of those synapses. Very similar to the effects of the stress of exercise on muscle cells, emerging findings suggest that neurons respond to activity by activating signaling pathways (e.g., Ca2+, CREB, PGC-1α, NF-κB) that stimulate mitochondrial biogenesis and cellular stress resistance. These pathways are also activated by aerobic exercise and food deprivation, two bioenergetic challenges of fundamental importance in the evolution of the brains of all mammals, including humans. The metabolic ‘switch’ in fuel source from liver glycogen store-derived glucose to adipose cell-derived fatty acids and their ketone metabolites during fasting and sustained exercise, appears to be a pivotal trigger of both brain-intrinsic and peripheral organ-derived signals that enhance learning and memory and underlying synaptic plasticity and neurogenesis. Brain-intrinsic extracellular signals include the excitatory neurotransmitter glutamate and the neurotrophic factor BDNF, and peripheral signals may include the liver-derived ketone 3-hydroxybutyrate and the muscle cell-derived protein irisin. Emerging findings suggest that fasting, exercise and an intellectually challenging lifestyle can protect neurons against the dysfunction and degeneration that they would otherwise suffer in acute brain injuries (stroke and head trauma) and neurodegenerative disorders including Alzheimer’s, Parkinson’s and Huntington’s disease. Among the prominent intracellular responses of neurons to these bioenergetic challenges are up-regulation of antioxidant defenses, autophagy/mitophagy and DNA repair. A better understanding of such fundamental hormesis-based adaptive neuronal response mechanisms is expected to result in the development and implementation of novel interventions to promote optimal brain function and healthy

  2. Alpha7 neuronal nicotinic receptor: a pluripotent target for diseases of the central nervous system.

    Science.gov (United States)

    Bencherif, Merouane; Narla, Sridhar T; Stachowiak, Michal S

    2014-01-01

    Twenty years ago the alpha7 nicotinic acetylcholine receptor (nAChR) was thought to be vestigial with little biological relevance, but in recent years it has emerged as a functional target with ubiquitous localization and biological roles. In the last decade more than two thousand manuscripts have been published unraveling the multi-dimensional complexity of this target, the heterogeneity of its genetic variants, the spectrum of transducing signals, and the critical roles it plays in pivotal biological functions in the protection and maturation of neurons and stems cells, immune and inflammatory responses, sensory gating, mnemonic and attentional processes. In addition research and development of novel drugs has also promoted an intense debate on the role of activation, desensitization, β -amyloid oligomers, glutamate, and alpha7 nAChR, in cognition, neuronal survival, and neurodegeneration. The initial alpha7 nAChRs transducing enzyme, aptly named after Janus the two-faced roman deity for crossroads and gateways, reflects the dichotomy of reports on alpha7 nAChRs in promoting neuronal survival and cognitive processes, or as the target of β- amyloid oligomers to destabilize neuronal homeostasis leading to an irreversible neurochemical demise and dementia. It is therefore important to understand the functional neural bases of alpha7 nAChRs-mediated improvement of biological functions. The promise of alpha7 nAChR-directed drugs has already recently translated into proof-of-concept in controlled clinical trials but the full promise of this target(s) will be fully unraveled when its impact on neuronal health and survival is tested in controlled long-term clinical trials of disease progression.

  3. An Inflammation-Centric View of Neurological Disease: Beyond the Neuron

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    Stephen D. Skaper

    2018-03-01

    Full Text Available Inflammation is a complex biological response fundamental to how the body deals with injury and infection to eliminate the initial cause of cell injury and effect repair. Unlike a normally beneficial acute inflammatory response, chronic inflammation can lead to tissue damage and ultimately its destruction, and often results from an inappropriate immune response. Inflammation in the nervous system (“neuroinflammation”, especially when prolonged, can be particularly injurious. While inflammation per se may not cause disease, it contributes importantly to disease pathogenesis across both the peripheral (neuropathic pain, fibromyalgia and central [e.g., Alzheimer disease, Parkinson disease, multiple sclerosis, motor neuron disease, ischemia and traumatic brain injury, depression, and autism spectrum disorder] nervous systems. The existence of extensive lines of communication between the nervous system and immune system represents a fundamental principle underlying neuroinflammation. Immune cell-derived inflammatory molecules are critical for regulation of host responses to inflammation. Although these mediators can originate from various non-neuronal cells, important sources in the above neuropathologies appear to be microglia and mast cells, together with astrocytes and possibly also oligodendrocytes. Understanding neuroinflammation also requires an appreciation that non-neuronal cell—cell interactions, between both glia and mast cells and glia themselves, are an integral part of the inflammation process. Within this context the mast cell occupies a key niche in orchestrating the inflammatory process, from initiation to prolongation. This review will describe the current state of knowledge concerning the biology of neuroinflammation, emphasizing mast cell-glia and glia-glia interactions, then conclude with a consideration of how a cell's endogenous mechanisms might be leveraged to provide a therapeutic strategy to target neuroinflammation.

  4. The Neuropsychiatric Disease-Associated Gene cacna1c Mediates Survival of Young Hippocampal Neurons123

    Science.gov (United States)

    Lee, Anni S.; Kabir, Zeeba D.; Knobbe, Whitney; Orr, Madeline; Burgdorf, Caitlin; Huntington, Paula; McDaniel, Latisha; Britt, Jeremiah K.; Hoffmann, Franz; Brat, Daniel J.; Rajadhyaksha, Anjali M.

    2016-01-01

    Genetic variations in CACNA1C, which encodes the Cav1.2 subunit of L-type calcium channels (LTCCs), are associated with multiple forms of neuropsychiatric disease that manifest high anxiety in patients. In parallel, mice harboring forebrain-specific conditional knockout of cacna1c (forebrain-Cav1.2 cKO) display unusually high anxiety-like behavior. LTCCs in general, including the Cav1.3 subunit, have been shown to mediate differentiation of neural precursor cells (NPCs). However, it has not previously been determined whether Cav1.2 affects postnatal hippocampal neurogenesis in vivo. Here, we show that forebrain-Cav1.2 cKO mice exhibit enhanced cell death of young hippocampal neurons, with no change in NPC proliferation, hippocampal size, dentate gyrus thickness, or corticosterone levels compared with wild-type littermates. These mice also exhibit deficits in brain levels of brain-derived neurotrophic factor (BDNF), and Cre recombinase-mediated knockdown of adult hippocampal Cav1.2 recapitulates the deficit in young hippocampal neurons survival. Treatment of forebrain-Cav1.2 cKO mice with the neuroprotective agent P7C3-A20 restored the net magnitude of postnatal hippocampal neurogenesis to wild-type levels without ameliorating their deficit in BDNF expression. The role of Cav1.2 in young hippocampal neurons survival may provide new approaches for understanding and treating neuropsychiatric disease associated with aberrations in CACNA1C. Visual Abstract PMID:27066530

  5. Selective alterations of neurons and circuits related to early memory loss in Alzheimer's disease

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    María eLlorens-Martín

    2014-05-01

    Full Text Available A progressive loss of episodic memory is a well-known clinical symptom that characterizes Alzheimer’s disease (AD. The beginning of this loss of memory has been associated with the very early, pathological accumulation of tau and neuronal degeneration observed in the entorhinal cortex (EC. Tau-related pathology is thought to then spread progressively to the hippocampal formation and other brain areas as the disease progresses. The major cortical afferent source of the hippocampus and dentate gyrus is the EC through the perforant pathway. At least two main circuits participate in the connection between EC and the hippocampus; one originating in layer II and the other in layer III of the EC giving rise to the classical trisynaptic (ECII→dentate gyrus→CA3→CA1 and monosynaptic (ECIII→CA1 circuits. Thus, the study of the early pathological changes in these circuits is of great interest. In this review, we will discuss mainly the alterations of the granule cell neurons of the dentate gyrus and the atrophy of CA1 pyramidal neurons that occur in AD in relation to the possible differential alterations of these two main circuits.

  6. Neuroprotective effects of sulforaphane on cholinergic neurons in mice with Alzheimer's disease-like lesions.

    Science.gov (United States)

    Zhang, Rui; Zhang, Jingzhu; Fang, Lingduo; Li, Xi; Zhao, Yue; Shi, Wanying; An, Li

    2014-08-18

    Alzheimer's disease (AD) is a common neurodegenerative disease in elderly individuals, and effective therapies are unavailable. This study was designed to investigate the neuroprotective effects of sulforaphane (an activator of NF-E2-related factor 2) on mice with AD-like lesions induced by combined administration of aluminum and D-galactose. Step-down-type passive avoidance tests showed sulforaphane ameliorated cognitive impairment in AD-like mice. Immunohistochemistry results indicated sulforaphane attenuated cholinergic neuron loss in the medial septal and hippocampal CA1 regions in AD-like mice. However, spectrophotometry revealed no significant difference in acetylcholine level or the activity of choline acetyltransferase or acetylcholinesterase in the cerebral cortex among groups of control and AD-like mice with and without sulforaphane treatment. Sulforaphane significantly increased the numbers of 5-bromo-2'-deoxyuridine-positive neurons in the subventricular and subgranular zones in AD-like mice which were significantly augmented compared with controls. Atomic absorption spectrometry revealed significantly lower aluminum levels in the brains of sulforaphane-treated AD-like mice than in those that did not receive sulforaphane treatment. In conclusion, sulforaphane ameliorates neurobehavioral deficits by reducing cholinergic neuron loss in the brains of AD-like mice, and the mechanism may be associated with neurogenesis and aluminum load reduction. These findings suggest that phytochemical sulforaphane has potential application in AD therapeutics.

  7. Neurobiology of axonal transport defects in motor neuron diseases: Opportunities for translational research?

    Science.gov (United States)

    De Vos, Kurt J; Hafezparast, Majid

    2017-09-01

    Intracellular trafficking of cargoes is an essential process to maintain the structure and function of all mammalian cell types, but especially of neurons because of their extreme axon/dendrite polarisation. Axonal transport mediates the movement of cargoes such as proteins, mRNA, lipids, membrane-bound vesicles and organelles that are mostly synthesised in the cell body and in doing so is responsible for their correct spatiotemporal distribution in the axon, for example at specialised sites such as nodes of Ranvier and synaptic terminals. In addition, axonal transport maintains the essential long-distance communication between the cell body and synaptic terminals that allows neurons to react to their surroundings via trafficking of for example signalling endosomes. Axonal transport defects are a common observation in a variety of neurodegenerative diseases, and mutations in components of the axonal transport machinery have unequivocally shown that impaired axonal transport can cause neurodegeneration (reviewed in El-Kadi et al., 2007, De Vos et al., 2008; Millecamps and Julien, 2013). Here we review our current understanding of axonal transport defects and the role they play in motor neuron diseases (MNDs) with a specific focus on the most common form of MND, amyotrophic lateral sclerosis (ALS). Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  8. Deficient Rab11 activity underlies glucose hypometabolism in primary neurons of Huntington's disease mice

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    Li, Xueyi, E-mail: xli12@partners.org [Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129 (United States); Valencia, Antonio; McClory, Hollis; Sapp, Ellen; Kegel, Kimberly B. [Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129 (United States); DiFiglia, Marian, E-mail: difiglia@helix.mgh.harvard.edu [Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129 (United States)

    2012-05-18

    Highlights: Black-Right-Pointing-Pointer Primary Huntington's disease neurons are impaired in taking up glucose. Black-Right-Pointing-Pointer Rab11 modulates glucose uptake in neurons. Black-Right-Pointing-Pointer Increasing Rab11 activity attenuates the glucose uptake defect in disease neurons. Black-Right-Pointing-Pointer We provide a novel mechanism for glucose hypometabolism in Huntington's disease. -- Abstract: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. Positron emission tomography studies have revealed a decline in glucose metabolism in the brain of patients with HD by a mechanism that has not been established. We examined glucose utilization in embryonic primary cortical neurons of wild-type (WT) and HD knock-in mice, which have 140 CAG repeats inserted in the endogenous mouse huntingtin gene (HD{sup 140Q/140Q}). Primary HD{sup 140Q/140Q} cortical neurons took up significantly less glucose than did WT neurons. Expression of permanently inactive and permanently active forms of Rab11 correspondingly altered glucose uptake in WT neurons, suggesting that normal activity of Rab11 is needed for neuronal uptake of glucose. It is known that Rab11 activity is diminished in HD{sup 140Q/140Q} neurons. Expression of dominant active Rab11 to enhance the activity of Rab11 normalized glucose uptake in HD{sup 140Q/140Q} neurons. These results suggest that deficient activity of Rab11 is a novel mechanism for glucose hypometabolism in HD.

  9. Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6.

    LENUS (Irish Health Repository)

    Arsov, Todor

    2011-05-13

    The molecular basis of Kufs disease is unknown, whereas a series of genes accounting for most of the childhood-onset forms of neuronal ceroid lipofuscinosis (NCL) have been identified. Diagnosis of Kufs disease is difficult because the characteristic lipopigment is largely confined to neurons and can require a brain biopsy or autopsy for final diagnosis. We mapped four families with Kufs disease for whom there was good evidence of autosomal-recessive inheritance and found two peaks on chromosome 15. Three of the families were affected by Kufs type A disease and presented with progressive myoclonus epilepsy, and one was affected by type B (presenting with dementia and motor system dysfunction). Sequencing of a candidate gene in one peak shared by all four families identified no mutations, but sequencing of CLN6, found in the second peak and shared by only the three families affected by Kufs type A disease, revealed pathogenic mutations in all three families. We subsequently sequenced CLN6 in eight other families, three of which were affected by recessive Kufs type A disease. Mutations in both CLN6 alleles were found in the three type A cases and in one family affected by unclassified Kufs disease. Mutations in CLN6 are the major cause of recessive Kufs type A disease. The phenotypic differences between variant late-infantile NCL, previously found to be caused by CLN6, and Kufs type A disease are striking; there is a much later age at onset and lack of visual involvement in the latter. Sequencing of CLN6 will provide a simple diagnostic strategy in this disorder, in which definitive identification usually requires invasive biopsy.

  10. Spread of neuronal degeneration in a dopaminergic, Lrrk-G2019S model of Parkinson disease

    Science.gov (United States)

    Hindle, Samantha J.; Elliott, Christopher J.H.

    2013-01-01

    Flies expressing the most common Parkinson disease (PD)-related mutation, LRRK2-G2019S, in their dopaminergic neurons show loss of visual function and degeneration of the retina, including mitochondrial abnormalities, apoptosis and autophagy. Since the photoreceptors that degenerate are not dopaminergic, this demonstrates nonautonomous degeneration, and a spread of pathology. This provides a model consistent with Braak’s hypothesis on progressive PD. The loss of visual function is specific for the G2019S mutation, implying the cause is its increased kinase activity, and is enhanced by increased neuronal activity. These data suggest novel explanations for the variability in animal models of PD. The specificity of visual loss to G2019S, coupled with the differences in neural firing rate, provide an explanation for the variability between people with PD in visual tests. PMID:23529190

  11. Locus coeruleus: A brain region exhibiting neuronal alterations in Parkinson’s disease rat model

    Directory of Open Access Journals (Sweden)

    Samah M. Fathy

    2015-05-01

    Full Text Available Toxic insults lead to increased α-synuclein expression in dopaminergic neurons. However, little information is known about α-synuclein alterations in relation to tyrosine hydroxylase (TH changes in locus coeruleus (LC of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP rat model for Parkinson’s disease (PD. Four injections (15 mg/kg each of the neurotoxicant MPTP to rats led to an upregulation of α-synuclein level and increased immunoreactivity with aggregated protein in the MPTP-treated group as revealed by Western blotting and immunohistochemical techniques. Meanwhile, MPTP reduced the level of and caused immunoreactivity toward TH antibody in LC and adjoining noradrenergic neurons. These data indicate that MPTP can induce α-synuclein alterations in other brain regions that have been implicated in the pathogenesis of PD. The findings are also consistent with a pattern that α-synuclein modification influences the TH level.

  12. Alzheimer's Proteins, Oxidative Stress, and Mitochondrial Dysfunction Interplay in a Neuronal Model of Alzheimer's Disease

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    Antonella Bobba

    2010-01-01

    Full Text Available In this paper, we discuss the interplay between beta-amyloid (A peptide, Tau fragments, oxidative stress, and mitochondria in the neuronal model of cerebellar granule neurons (CGNs in which the molecular events reminiscent of AD are activated. The identification of the death route and the cause/effect relationships between the events leading to death could be helpful to manage the progression of apoptosis in neurodegeneration and to define antiapoptotic treatments acting on precocious steps of the death process. Mitochondrial dysfunction is among the earliest events linked to AD and might play a causative role in disease onset and progression. Recent studies on CGNs have shown that adenine nucleotide translocator (ANT impairment, due to interaction with toxic N-ter Tau fragment, contributes in a significant manner to bioenergetic failure and mitochondrial dysfunction. These findings open a window for new therapeutic strategies aimed at preserving and/or improving mitochondrial function.

  13. Borna disease virus phosphoprotein modulates epigenetic signaling in neurons to control viral replication.

    Science.gov (United States)

    Bonnaud, Emilie M; Szelechowski, Marion; Bétourné, Alexandre; Foret, Charlotte; Thouard, Anne; Gonzalez-Dunia, Daniel; Malnou, Cécile E

    2015-06-01

    Understanding the modalities of interaction of neurotropic viruses with their target cells represents a major challenge that may improve our knowledge of many human neurological disorders for which viral origin is suspected. Borna disease virus (BDV) represents an ideal model to analyze the molecular mechanisms of viral persistence in neurons and its consequences for neuronal homeostasis. It is now established that BDV ensures its long-term maintenance in infected cells through a stable interaction of viral components with the host cell chromatin, in particular, with core histones. This has led to our hypothesis that such an interaction may trigger epigenetic changes in the host cell. Here, we focused on histone acetylation, which plays key roles in epigenetic regulation of gene expression, notably for neurons. We performed a comparative analysis of histone acetylation patterns of neurons infected or not infected by BDV, which revealed that infection decreases histone acetylation on selected lysine residues. We showed that the BDV phosphoprotein (P) is responsible for these perturbations, even when it is expressed alone independently of the viral context, and that this action depends on its phosphorylation by protein kinase C. We also demonstrated that BDV P inhibits cellular histone acetyltransferase activities. Finally, by pharmacologically manipulating cellular acetylation levels, we observed that inhibiting cellular acetyl transferases reduces viral replication in cell culture. Our findings reveal that manipulation of cellular epigenetics by BDV could be a means to modulate viral replication and thus illustrate a fascinating example of virus-host cell interaction. Persistent DNA viruses often subvert the mechanisms that regulate cellular chromatin dynamics, thereby benefitting from the resulting epigenetic changes to create a favorable milieu for their latent and persistent states. Here, we reasoned that Borna disease virus (BDV), the only RNA virus known to

  14. Reduced activity of AMP-activated protein kinase protects against genetic models of motor neuron disease.

    Science.gov (United States)

    Lim, M A; Selak, M A; Xiang, Z; Krainc, D; Neve, R L; Kraemer, B C; Watts, J L; Kalb, R G

    2012-01-18

    A growing body of research indicates that amyotrophic lateral sclerosis (ALS) patients and mouse models of ALS exhibit metabolic dysfunction. A subpopulation of ALS patients possesses higher levels of resting energy expenditure and lower fat-free mass compared to healthy controls. Similarly, two mutant copper zinc superoxide dismutase 1 (mSOD1) mouse models of familial ALS possess a hypermetabolic phenotype. The pathophysiological relevance of the bioenergetic defects observed in ALS remains largely elusive. AMP-activated protein kinase (AMPK) is a key sensor of cellular energy status and thus might be activated in various models of ALS. Here, we report that AMPK activity is increased in spinal cord cultures expressing mSOD1, as well as in spinal cord lysates from mSOD1 mice. Reducing AMPK activity either pharmacologically or genetically prevents mSOD1-induced motor neuron death in vitro. To investigate the role of AMPK in vivo, we used Caenorhabditis elegans models of motor neuron disease. C. elegans engineered to express human mSOD1 (G85R) in neurons develops locomotor dysfunction and severe fecundity defects when compared to transgenic worms expressing human wild-type SOD1. Genetic reduction of aak-2, the ortholog of the AMPK α2 catalytic subunit in nematodes, improved locomotor behavior and fecundity in G85R animals. Similar observations were made with nematodes engineered to express mutant tat-activating regulatory (TAR) DNA-binding protein of 43 kDa molecular weight. Altogether, these data suggest that bioenergetic abnormalities are likely to be pathophysiologically relevant to motor neuron disease.

  15. A new glucocerebrosidase-deficient neuronal cell model provides a tool to probe pathophysiology and therapeutics for Gaucher disease

    Directory of Open Access Journals (Sweden)

    Wendy Westbroek

    2016-07-01

    Full Text Available Glucocerebrosidase is a lysosomal hydrolase involved in the breakdown of glucosylceramide. Gaucher disease, a recessive lysosomal storage disorder, is caused by mutations in the gene GBA1. Dysfunctional glucocerebrosidase leads to accumulation of glucosylceramide and glycosylsphingosine in various cell types and organs. Mutations in GBA1 are also a common genetic risk factor for Parkinson disease and related synucleinopathies. In recent years, research on the pathophysiology of Gaucher disease, the molecular link between Gaucher and Parkinson disease, and novel therapeutics, have accelerated the need for relevant cell models with GBA1 mutations. Although induced pluripotent stem cells, primary rodent neurons, and transfected neuroblastoma cell lines have been used to study the effect of glucocerebrosidase deficiency on neuronal function, these models have limitations because of challenges in culturing and propagating the cells, low yield, and the introduction of exogenous mutant GBA1. To address some of these difficulties, we established a high yield, easy-to-culture mouse neuronal cell model with nearly complete glucocerebrosidase deficiency representative of Gaucher disease. We successfully immortalized cortical neurons from embryonic null allele gba−/− mice and the control littermate (gba+/+ by infecting differentiated primary cortical neurons in culture with an EF1α-SV40T lentivirus. Immortalized gba−/− neurons lack glucocerebrosidase protein and enzyme activity, and exhibit a dramatic increase in glucosylceramide and glucosylsphingosine accumulation, enlarged lysosomes, and an impaired ATP-dependent calcium-influx response; these phenotypical characteristics were absent in gba+/+ neurons. This null allele gba−/− mouse neuronal model provides a much-needed tool to study the pathophysiology of Gaucher disease and to evaluate new therapies.

  16. Neuronal complex I deficiency occurs throughout the Parkinson's disease brain, but is not associated with neurodegeneration or mitochondrial DNA damage.

    Science.gov (United States)

    Flønes, Irene H; Fernandez-Vizarra, Erika; Lykouri, Maria; Brakedal, Brage; Skeie, Geir Olve; Miletic, Hrvoje; Lilleng, Peer K; Alves, Guido; Tysnes, Ole-Bjørn; Haugarvoll, Kristoffer; Dölle, Christian; Zeviani, Massimo; Tzoulis, Charalampos

    2018-03-01

    Mitochondrial complex I deficiency occurs in the substantia nigra of individuals with Parkinson's disease. It is generally believed that this phenomenon is caused by accumulating mitochondrial DNA damage in neurons and that it contributes to the process of neurodegeneration. We hypothesized that if these theories are correct, complex I deficiency should extend beyond the substantia nigra to other affected brain regions in Parkinson's disease and correlate tightly with neuronal mitochondrial DNA damage. To test our hypothesis, we employed a combination of semiquantitative immunohistochemical analyses, Western blot and activity measurements, to assess complex I quantity and function in multiple brain regions from an extensively characterized population-based cohort of idiopathic Parkinson's disease (n = 18) and gender and age matched healthy controls (n = 11). Mitochondrial DNA was assessed in single neurons from the same areas by real-time PCR. Immunohistochemistry showed that neuronal complex I deficiency occurs throughout the Parkinson's disease brain, including areas spared by the neurodegenerative process such as the cerebellum. Activity measurements in brain homogenate confirmed a moderate decrease of complex I function, whereas Western blot was less sensitive, detecting only a mild reduction, which did not reach statistical significance at the group level. With the exception of the substantia nigra, neuronal complex I loss showed no correlation with the load of somatic mitochondrial DNA damage. Interestingly, α-synuclein aggregation was less common in complex I deficient neurons in the substantia nigra. We show that neuronal complex I deficiency is a widespread phenomenon in the Parkinson's disease brain which, contrary to mainstream theory, does not follow the anatomical distribution of neurodegeneration and is not associated with the neuronal load of mitochondrial DNA mutation. Our findings suggest that complex I deficiency in Parkinson's disease can

  17. Computational Analysis of Pharyngeal Swallowing Mechanics in Patients with Motor Neuron Disease: A Pilot Investigation.

    Science.gov (United States)

    Garand, K L; Schwertner, Ryan; Chen, Amy; Pearson, William G

    2018-04-01

    Swallowing impairment (dysphagia) is a common sequela in patients with motor neuron disease (MND). The purpose of this retrospective, observational pilot investigation was to characterize how pharyngeal swallowing mechanics are impacted in patients with MND using a comparison with healthy, non-dysphagic control group. Computational analysis of swallowing mechanics (CASM) was used to determine covariate biomechanics of pharyngeal swallowing from videofluoroscopic assessment in 15 patients with MND and 15 age- and sex-matched healthy controls. Canonical variant analysis with post hoc discriminate function analysis (DFA) was performed on coordinate data mapping functional muscle groups underlying pharyngeal swallowing. Differences in swallowing mechanics associated with group (MND; control), motor neuron predominance (upper; lower), onset (bulbar; spinal), and swallow task (thin, pudding) were evaluated and visualized. Pharyngeal swallowing mechanics differed significantly in patients with MND compared with healthy controls (D = 2.01, p mechanics by motor neuron predominance (D = 5.03, p mechanics of patients with MND differ from and are more heterogeneous than healthy controls. These findings suggest patients with MND may compensate reductions in pharyngeal shortening and tongue base retraction by extending the head and neck and increasing hyolaryngeal excursion. This work and further CASM investigations will lead to further insights into development and evaluation of targeted clinical treatments designed to prolong safe and efficient swallowing function in patients with MND.

  18. iPSC-Based Models to Unravel Key Pathogenetic Processes Underlying Motor Neuron Disease Development

    Directory of Open Access Journals (Sweden)

    Irene Faravelli

    2014-10-01

    Full Text Available Motor neuron diseases (MNDs are neuromuscular disorders affecting rather exclusively upper motor neurons (UMNs and/or lower motor neurons (LMNs. The clinical phenotype is characterized by muscular weakness and atrophy leading to paralysis and almost invariably death due to respiratory failure. Adult MNDs include sporadic and familial amyotrophic lateral sclerosis (sALS-fALS, while the most common infantile MND is represented by spinal muscular atrophy (SMA. No effective treatment is ccurrently available for MNDs, as for the vast majority of neurodegenerative disorders, and cures are limited to supportive care and symptom relief. The lack of a deep understanding of MND pathogenesis accounts for the difficulties in finding a cure, together with the scarcity of reliable in vitro models. Recent progresses in stem cell field, in particular in the generation of induced Pluripotent Stem Cells (iPSCs has made possible for the first time obtaining substantial amounts of human cells to recapitulate in vitro some of the key pathogenetic processes underlying MNDs. In the present review, recently published studies involving the use of iPSCs to unravel aspects of ALS and SMA pathogenesis are discussed with an overview of their implications in the process of finding a cure for these still orphan disorders.

  19. The development of neurology palliative care service for motor neuron disease (MND) patients: Hong Kong experience.

    Science.gov (United States)

    Cheng, Hon Wai Benjamin; Chen, Wai Tsan Tracy; Chu, Chun Kwok Angus; Lee, Savio; Lee, Joo Shium; Hong, Yeuk Fai; Chung, Yuen Kwan Judy

    2017-09-15

    Motor neuron disease (MND) is a neurodegenerative disease characterized by loss of motor neurons in the spinal cord, brainstem and motor cortex. Clinically it is manifested as progressive decline in physical, respiratory, swallowing and communication function and ultimately death. Traditional model of care was fragmented and did not match with patients and carers multi-facet needs. A special workgroup for MND patients that includes neurologist, respiratory physician, rehabilitation specialist and palliative care (PC) physician was formed in Hong Kong since year 2013. In various disease phase, each specialty team play a leading role in coordinated care of MND patients. From Apr 2013 to Mar 2015, 41 patients newly diagnosed with MND were cared in our model. 96.4% agreed to participate in the ACP discussion. Seventy-five percent of them opted for do-not-attempt cardiopulmonary resuscitation (DNACPR) and no intubation/mechanical ventilation. There were 16 (51.6%) of patients passed away within the review period. All of them succumbed with no CPR performed which was honoring their wish. The average duration under PC was 118 days. Strategies toward standardizing care delivery for MND patients and carers may help to address the physical, psychosocial and spiritual needs of MND patients. The experience shared from this article conceptualizes the roles of various multi-disciplinary team members, with emphasis paid on PC team position in taking care of advanced MND patients.

  20. SMN control of RNP assembly: from post-transcriptional gene regulation to motor neuron disease.

    Science.gov (United States)

    Li, Darrick K; Tisdale, Sarah; Lotti, Francesco; Pellizzoni, Livio

    2014-08-01

    At the post-transcriptional level, expression of protein-coding genes is controlled by a series of RNA regulatory events including nuclear processing of primary transcripts, transport of mature mRNAs to specific cellular compartments, translation and ultimately, turnover. These processes are orchestrated through the dynamic association of mRNAs with RNA binding proteins and ribonucleoprotein (RNP) complexes. Accurate formation of RNPs in vivo is fundamentally important to cellular development and function, and its impairment often leads to human disease. The survival motor neuron (SMN) protein is key to this biological paradigm: SMN is essential for the biogenesis of various RNPs that function in mRNA processing, and genetic mutations leading to SMN deficiency cause the neurodegenerative disease spinal muscular atrophy. Here we review the expanding role of SMN in the regulation of gene expression through its multiple functions in RNP assembly. We discuss advances in our understanding of SMN activity as a chaperone of RNPs and how disruption of SMN-dependent RNA pathways can cause motor neuron disease. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Motor neurone disease: can we do better? A study of 42 patients.

    OpenAIRE

    Newrick, P G; Langton-Hewer, R

    1984-01-01

    A feeling that patients with motor neurone disease were not always well managed prompted a study of the symptoms, functional levels, and use of aids in a group of 42 patients. Pain, falls, constipation, and swelling of the legs emerged as the major symptomatic problems. At the time of assessment two thirds of the patients appeared to be in need of aids which had not been provided. Disturbance of sleep secondary to positional nocturnal discomfort caused much distress to both the patient and sp...

  2. Interleukin-6 Deficiency Does Not Affect Motor Neuron Disease Caused by Superoxide Dismutase 1 Mutation.

    Science.gov (United States)

    Han, Yongmei; Ripley, Barry; Serada, Satoshi; Naka, Tetsuji; Fujimoto, Minoru

    2016-01-01

    Amyotrophic Lateral Sclerosis (ALS) is an adult-onset, progressive, motor neuron degenerative disease. Recent evidence indicates that inflammation is associated with many neurodegenerative diseases including ALS. Previously, abnormal levels of inflammatory cytokines including IL-1β, IL-6 and TNF-α were described in ALS patients and/or in mouse ALS models. In addition, one study showed that blocking IL-1β could slow down progression of ALS-like symptoms in mice. In this study, we examined a role for IL-6 in ALS, using an animal model for familial ALS. Mice with mutant SOD1 (G93A) transgene, a model for familial ALS, were used in this study. The expression of the major inflammatory cytokines, IL-6, IL-1β and TNF-α, in spinal cords of these SOD1 transgenic (TG) mice were assessed by real time PCR. Mice were then crossed with IL-6(-/-) mice to generate SOD1TG/IL-6(-/-) mice. SOD1 TG/IL-6(-/-) mice (n = 17) were compared with SOD1 TG/IL-6(+/-) mice (n = 18), SOD1 TG/IL-6(+/+) mice (n = 11), WT mice (n = 15), IL-6(+/-) mice (n = 5) and IL-6(-/-) mice (n = 8), with respect to neurological disease severity score, body weight and the survival. We also histologically compared the motor neuron loss in lumber spinal cords and the atrophy of hamstring muscles between these mouse groups. Levels of IL-6, IL-1β and TNF-α in spinal cords of SOD1 TG mice was increased compared to WT mice. However, SOD1 TG/IL-6(-/-) mice exhibited weight loss, deterioration in motor function and shortened lifespan (167.55 ± 11.52 days), similarly to SOD1 TG /IL-6(+/+) mice (164.31±12.16 days). Motor neuron numbers and IL-1β and TNF-α levels in spinal cords were not significantly different in SOD1 TG /IL-6(-/-) mice and SOD1 TG /IL-6 (+/+) mice. These results provide compelling preclinical evidence indicating that IL-6 does not directly contribute to motor neuron disease caused by SOD1 mutations.

  3. Age and Parkinson's disease-related neuronal death in the substantia nigra pars compacta

    DEFF Research Database (Denmark)

    Eriksen, Nina; Stark, Anette Kirstine; Pakkenberg, Bente

    2009-01-01

    of this system, Parkinson's disease, is characterized by a selective, progressive loss of dopaminergic neurons in the substantia nigra pars compacta. This review includes studies quantifying age and Parkinson's-related changes of the substantia nigra, with emphasis on stereological studies performed......During aging, decline in memory and cognitive abilities as well as motor weakening is of great concern. The dopaminergic system mediates some aspects of manual dexterity, in addition to cognition and emotion, and may be especially vulnerable to aging. A common neurodegenerative disorder...

  4. Interleukin-6 Deficiency Does Not Affect Motor Neuron Disease Caused by Superoxide Dismutase 1 Mutation.

    Directory of Open Access Journals (Sweden)

    Yongmei Han

    Full Text Available Amyotrophic Lateral Sclerosis (ALS is an adult-onset, progressive, motor neuron degenerative disease. Recent evidence indicates that inflammation is associated with many neurodegenerative diseases including ALS. Previously, abnormal levels of inflammatory cytokines including IL-1β, IL-6 and TNF-α were described in ALS patients and/or in mouse ALS models. In addition, one study showed that blocking IL-1β could slow down progression of ALS-like symptoms in mice. In this study, we examined a role for IL-6 in ALS, using an animal model for familial ALS.Mice with mutant SOD1 (G93A transgene, a model for familial ALS, were used in this study. The expression of the major inflammatory cytokines, IL-6, IL-1β and TNF-α, in spinal cords of these SOD1 transgenic (TG mice were assessed by real time PCR. Mice were then crossed with IL-6(-/- mice to generate SOD1TG/IL-6(-/- mice. SOD1 TG/IL-6(-/- mice (n = 17 were compared with SOD1 TG/IL-6(+/- mice (n = 18, SOD1 TG/IL-6(+/+ mice (n = 11, WT mice (n = 15, IL-6(+/- mice (n = 5 and IL-6(-/- mice (n = 8, with respect to neurological disease severity score, body weight and the survival. We also histologically compared the motor neuron loss in lumber spinal cords and the atrophy of hamstring muscles between these mouse groups.Levels of IL-6, IL-1β and TNF-α in spinal cords of SOD1 TG mice was increased compared to WT mice. However, SOD1 TG/IL-6(-/- mice exhibited weight loss, deterioration in motor function and shortened lifespan (167.55 ± 11.52 days, similarly to SOD1 TG /IL-6(+/+ mice (164.31±12.16 days. Motor neuron numbers and IL-1β and TNF-α levels in spinal cords were not significantly different in SOD1 TG /IL-6(-/- mice and SOD1 TG /IL-6 (+/+ mice.These results provide compelling preclinical evidence indicating that IL-6 does not directly contribute to motor neuron disease caused by SOD1 mutations.

  5. Neuronal plasticity and astrocytic reaction in Down syndrome and Alzheimer disease

    DEFF Research Database (Denmark)

    Jørgensen, Ole Steen; Brooksbank, B W; Balázs, R

    1990-01-01

    Proteins relatively enriched in neurons (neural cell adhesion molecule (NCAM) and D3-protein) or in glia (glutamine synthetase, glial fibrillary acidic protein (GFAP) and S100) were measured by quantitative immunochemical methods in autopsy samples of the cerebral cortex of subjects with Alzheimer...... disease (AD) and adults with Down syndrome (DS), the latter also presenting manifest signs of Alzheimer type of neuropathology. The trend of changes was similar in AD and DS, but more marked in the latter. The biochemical make-up of astrocytes was differentially affected: in both the frontal and DS...

  6. Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms.

    Science.gov (United States)

    Gautam, Mukesh; Jara, Javier H; Sekerkova, Gabriella; Yasvoina, Marina V; Martina, Marco; Özdinler, P Hande

    2016-03-15

    Mutations in the ALS2 gene result in early-onset amyotrophic lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia and juvenile primary lateral sclerosis, suggesting prominent upper motor neuron involvement. However, the importance of alsin function for corticospinal motor neuron (CSMN) health and stability remains unknown. To date, four separate alsin knockout (Alsin(KO)) mouse models have been generated, and despite hopes of mimicking human pathology, none displayed profound motor function defects. This, however, does not rule out the possibility of neuronal defects within CSMN, which is not easy to detect in these mice. Detailed cellular analysis of CSMN has been hampered due to their limited numbers and the complex and heterogeneous structure of the cerebral cortex. In an effort to visualize CSMN in vivo and to investigate precise aspects of neuronal abnormalities in the absence of alsin function, we generated Alsin(KO)-UeGFP mice, by crossing Alsin(KO) and UCHL1-eGFP mice, a CSMN reporter line. We find that CSMN display vacuolated apical dendrites with increased autophagy, shrinkage of soma size and axonal pathology even in the pons region. Immunocytochemistry coupled with electron microscopy reveal that alsin is important for maintaining cellular cytoarchitecture and integrity of cellular organelles. In its absence, CSMN displays selective defects both in mitochondria and Golgi apparatus. UCHL1-eGFP mice help understand the underlying cellular factors that lead to CSMN vulnerability in diseases, and our findings reveal unique importance of alsin function for CSMN health and stability. © The Author 2016. Published by Oxford University Press.

  7. Native valve endocarditis caused by an organism resembling Corynebacterium striatum.

    OpenAIRE

    Markowitz, S M; Coudron, P E

    1990-01-01

    An organism resembling Corynebacterium striatum was isolated from the blood of a patient with acute aortic valvular insufficiency and no history of valvular heart disease. At autopsy, histopathologic examination of the aortic valve revealed pleomorphic gram-positive bacilli and destruction of valvular tissue. Our isolate differed from other nondiphtherial corynebacteria, including the type strain of C. striatum (ATCC 6940), in its ability to reduce nitrite. Nitrite reduction may be useful for...

  8. AAV Vector-Mediated Gene Delivery to Substantia Nigra Dopamine Neurons: Implications for Gene Therapy and Disease Models

    Directory of Open Access Journals (Sweden)

    Katrina Albert

    2017-02-01

    Full Text Available Gene delivery using adeno-associated virus (AAV vectors is a widely used method to transduce neurons in the brain, especially due to its safety, efficacy, and long-lasting expression. In addition, by varying AAV serotype, promotor, and titer, it is possible to affect the cell specificity of expression or the expression levels of the protein of interest. Dopamine neurons in the substantia nigra projecting to the striatum, comprising the nigrostriatal pathway, are involved in movement control and degenerate in Parkinson′s disease. AAV-based gene targeting to the projection area of these neurons in the striatum has been studied extensively to induce the production of neurotrophic factors for disease-modifying therapies for Parkinson′s disease. Much less emphasis has been put on AAV-based gene therapy targeting dopamine neurons in substantia nigra. We will review the literature related to targeting striatum and/or substantia nigra dopamine neurons using AAVs in order to express neuroprotective and neurorestorative molecules, as well as produce animal disease models of Parkinson′s disease. We discuss difficulties in targeting substantia nigra dopamine neurons and their vulnerability to stress in general. Therefore, choosing a proper control for experimental work is not trivial. Since the axons along the nigrostriatal tract are the first to degenerate in Parkinson′s disease, the location to deliver the therapy must be carefully considered. We also review studies using AAV-a-synuclein (a-syn to target substantia nigra dopamine neurons to produce an α-syn overexpression disease model in rats. Though these studies are able to produce mild dopamine system degeneration in the striatum and substantia nigra and some behavioural effects, there are studies pointing to the toxicity of AAV-carrying green fluorescent protein (GFP, which is often used as a control. Therefore, we discuss the potential difficulties in overexpressing proteins in general in

  9. Supportive care needs of patients with amyotrophic lateral sclerosis/motor neuron disease and their caregivers: A scoping review.

    Science.gov (United States)

    Oh, Juyeon; Kim, Jung A

    2017-12-01

    To identify the supportive care needs of amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers, categorise and summarise them into a Supportive Care Needs Framework and identify gaps in literature. Little is known about the supportive care needs of amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers, and this subject has not previously been systemically reviewed. Scoping review. We conducted a scoping review from the MEDLINE, EMBASE, CINAHL and Cochrane databases for the period January 2000-July 2016, using the following inclusion criteria: (i) written in English only, (ii) published in peer-reviewed journals, (iii) at least part of the research considered the supportive care needs perspective of amyotrophic lateral sclerosis/motor neuron disease patients or their caregivers and (iv) the population sample included patients of amyotrophic lateral sclerosis/motor neuron disease or their caregivers. Thirty-seven articles were included. Our review shows that amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers' supportive care needs were mentioned across all seven domains of the Supportive Care Needs Framework. Most common were practical needs (n = 24), followed by Informational needs (n = 19), Social needs (n = 18), Psychological needs (n = 16), Physical needs (n = 15), Emotional needs (n = 13) and Spiritual needs (n = 8). From the perspectives of amyotrophic lateral sclerosis/motor neuron disease patients and their caregivers, there is a significant need for more practical, social, informational, psychological, physical, emotional and spiritual support. The Supportive Care Needs Framework has potential utility in the development of patient-centred support services or healthcare policies and serves as an important base for further studies; especially, specific examples of each supportive care needs domain can guide in clinical settings when healthcare professionals

  10. Resemblances in the Wedding and Natal Customs

    OpenAIRE

    Reneta Zlateva; Zlatozhivka Zdravkova

    2011-01-01

    The present article describes the natal rites and customs of the Azerbaijan and Bulgarian nations. Special attention is paid to the resemblances in the practicing and understanding of the traditions. Despite the fact that the two nations live in regions remote from each other, they have common beliefs and strive to provide prosperity for the home, family and children.

  11. Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations.

    Science.gov (United States)

    Le, Nhat T T; Chang, Lydia; Kovlyagina, Irina; Georgiou, Polymnia; Safren, Nathaniel; Braunstein, Kerstin E; Kvarta, Mark D; Van Dyke, Adam M; LeGates, Tara A; Philips, Thomas; Morrison, Brett M; Thompson, Scott M; Puche, Adam C; Gould, Todd D; Rothstein, Jeffrey D; Wong, Philip C; Monteiro, Mervyn J

    2016-11-22

    Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS-FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying UBQLN2 mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS-FTD-linked P497S or P506T UBQLN2 mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease. Neuropathologic analysis of the mice with end-stage disease revealed the accumulation of ubiquitinated inclusions in the brain and spinal cord, astrocytosis, a reduction in the number of hippocampal neurons, and reduced staining of TAR-DNA binding protein 43 in the nucleus, with concomitant formation of ubiquitin + inclusions in the cytoplasm of spinal motor neurons. Moreover, both lines displayed denervation muscle atrophy and age-dependent loss of motor neurons that correlated with a reduction in the number of large-caliber axons. By contrast, two mouse lines expressing WT UBQLN2 were mostly devoid of clinical and pathological signs of disease. These UBQLN2 mouse models provide valuable tools for identifying the mechanisms underlying ALS-FTD pathogenesis and for investigating therapeutic strategies to halt disease.

  12. Healthy and diseased corticospinal motor neurons are selectively transduced upon direct AAV2-2 injection into the motor cortex.

    Science.gov (United States)

    Jara, J H; Stanford, M J; Zhu, Y; Tu, M; Hauswirth, W W; Bohn, M C; DeVries, S H; Özdinler, P H

    2016-03-01

    Direct gene delivery to the neurons of interest, without affecting other neuron populations in the cerebral cortex, represent a challenge owing to the heterogeneity and cellular complexity of the brain. Genetic modulation of corticospinal motor neurons (CSMN) is required for developing effective and long-term treatment strategies for motor neuron diseases, in which voluntary movement is impaired. Adeno-associated viruses (AAV) have been widely used for neuronal transduction studies owing to long-term and stable gene expression as well as low immunoreactivity in humans. Here we report that AAV2-2 transduces CSMN with high efficiency upon direct cortex injection and that transduction efficiencies are similar during presymptomatic and symptomatic stages in hSOD1(G93A) transgenic amyotrophic lateral sclerosis (ALS) mice. Our findings reveal that choice of promoter improves selectivity as AAV2-2 chicken β-actin promoter injection results in about 70% CSMN transduction, the highest percentage reported to date. CSMN transduction in both wild-type and transgenic ALS mice allows detailed analysis of single axon fibers within the corticospinal tract in both cervical and lumbar spinal cord and reveals circuitry defects, which mainly occur between CSMN and spinal motor neurons in hSOD1(G93A) transgenic ALS mice. Our findings set the stage for CSMN gene therapy in ALS and related motor neuron diseases.

  13. Treatment for cramps in amyotrophic lateral sclerosis/motor neuron disease.

    Science.gov (United States)

    Baldinger, Reto; Katzberg, Hans Dieter; Weber, Markus

    2012-04-18

    Cramps are painful, involuntary muscle contractions. They commonly affect people with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) at all stages of the disease. To date, the treatment of muscle cramps in ALS has been largely empirical without any evidence from randomised controlled trials. To systematically assess the effect of interventions on muscle cramps as a primary or secondary endpoint or adverse event in people with ALS/MND. We searched the Cochrane Neuromuscular Disease Group Specialized Register (14 February 2011), the Cochrane Central Register of Controlled Trials (Issue 1, 2011 in The Cochrane Library), MEDLINE (January 1966 to January 2011) and EMBASE (January 1980 to January 2011) and reference lists of articles searched using the terms motor neuron disease, motor neurone disease, motoneuron disease or amyotrophic lateral sclerosis. We contacted authors of trials for further information. We included all randomised and quasi-randomised trials of oral medications in people with ALS which assessed cramps as a primary or secondary outcome measure or as an adverse event. We also included trials using subcutaneous or intravenous medications or physical therapy. All authors applied the selection criteria and assessed study quality independently, and all authors performed independent data extraction. Twenty studies including 4789 participants were identified. Only one trial, of tetrahydrocannabinol (THC), assessed cramps as the primary endpoint. Thirteen studies assessed cramps as a secondary endpoint. The medications comprised vitamin E, baclofen, riluzole, L-threonine, xaliproden, indinavir, and memantine. Six studies assessed cramps as an adverse event. The medications comprised creatine, gabapentin, dextromethorphan, quinidine, and lithium. In all 20 studies no favourable effect for the treatment of cramps in ALS/MND could be demonstrated, but many studies were underpowered to draw a definite conclusion. A meta-analysis of two small

  14. Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease.

    Science.gov (United States)

    Poesen, Koen; De Schaepdryver, Maxim; Stubendorff, Beatrice; Gille, Benjamin; Muckova, Petra; Wendler, Sindy; Prell, Tino; Ringer, Thomas M; Rhode, Heidrun; Stevens, Olivier; Claeys, Kristl G; Couwelier, Goedele; D'Hondt, Ann; Lamaire, Nikita; Tilkin, Petra; Van Reijen, Dimphna; Gourmaud, Sarah; Fedtke, Nadin; Heiling, Bianka; Rumpel, Matthias; Rödiger, Annekathrin; Gunkel, Anne; Witte, Otto W; Paquet, Claire; Vandenberghe, Rik; Grosskreutz, Julian; Van Damme, Philip

    2017-06-13

    To determine the diagnostic performance and prognostic value of phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) in CSF as possible biomarkers for amyotrophic lateral sclerosis (ALS) at the diagnostic phase. We measured CSF pNfH and NfL concentrations in 220 patients with ALS, 316 neurologic disease controls (DC), and 50 genuine disease mimics (DM) to determine and assess the accuracy of the diagnostic cutoff value for pNfH and NfL and to correlate with other clinical parameters. pNfH was most specific for motor neuron disease (specificity 88.2% [confidence interval (CI) 83.0%-92.3%]). pNfH had the best performance to differentially diagnose patients with ALS from DM with a sensitivity of 90.7% (CI 84.9%-94.8%), a specificity of 88.0% (CI 75.7%-95.5%) and a likelihood ratio of 7.6 (CI 3.6-16.0) at a cutoff of 768 pg/mL. CSF pNfH and NfL levels were significantly lower in slow disease progressors, however, with a poor prognostic performance with respect to the disease progression rate. CSF pNfH and NfL levels increased significantly as function of the number of regions with both upper and lower motor involvement. In particular, CSF pNfH concentrations show an added value as diagnostic biomarkers for ALS, whereas the prognostic value of pNfH and NfL warrants further investigation. Both pNfH and NfL correlated with the extent of motor neuron degeneration. This study provides Class II evidence that elevated concentrations of CSF pNfH and NfL can accurately identify patients with ALS. © 2017 American Academy of Neurology.

  15. Adaptive equipment use by people with motor neuron disease in Australia: a prospective, observational consecutive cohort study.

    Science.gov (United States)

    Connors, Karol A; Mahony, Lisa M; Morgan, Prue

    2017-10-28

    People with motor neuron sisease require adaptive equipment to enhance life quality. This study aimed to examine total and concurrent equipment items prescribed with phenotype consideration. A prospective, observational consecutive cohort study was undertaken. Data regarding Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, phenotype, symptom onset and Functional Independence Measure (inpatients only) was recorded. Equipment utilized was coded by therapist as: speech devices; transfer devices; mobility devices (including power wheelchairs); orthoses; activities of daily living equipment; assisted technology and home modification equipment. Two hundred and seventy-three people with motor neuron disease participated, mean age 67 years, mean amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score 32, a moderate level of disability. Equipment items per participant ranged from 0 to 20, median 5. The electric lift recliner chair was the most commonly used equipment item, used by 51.2% of the cohort. There was a statistically significant difference in equipment use between flail leg and bulbar (Md 11, 3 items, respectively; p = .005), and flail leg and cervical phenotypes (Md 11, 3.5 items respectively; p = .009). People with motor neuron disease have high equipment needs to optimize quality of life. Information regarding phenotype relative to equipment requirement, and most frequently prescribed equipment items can assist health-care providers anticipate equipment needs, burden and intensity for those with motor neuron disease. Implications for rehabilitation People with motor neuron disease have high concurrent equipment needs. Electric recliner lift chairs are the most frequently prescribed equipment item by those with motor neuron disease. There is variation in concurrent equipment needs relative to motor neuron disease phenotype.

  16. Monoamine oxidase B is elevated in Alzheimer disease neurons, is associated with γ-secretase and regulates neuronal amyloid β-peptide levels.

    Science.gov (United States)

    Schedin-Weiss, Sophia; Inoue, Mitsuhiro; Hromadkova, Lenka; Teranishi, Yasuhiro; Yamamoto, Natsuko Goto; Wiehager, Birgitta; Bogdanovic, Nenad; Winblad, Bengt; Sandebring-Matton, Anna; Frykman, Susanne; Tjernberg, Lars O

    2017-08-01

    Increased levels of the pathogenic amyloid β-peptide (Aβ), released from its precursor by the transmembrane protease γ-secretase, are found in Alzheimer disease (AD) brains. Interestingly, monoamine oxidase B (MAO-B) activity is also increased in AD brain, but its role in AD pathogenesis is not known. Recent neuroimaging studies have shown that the increased MAO-B expression in AD brain starts several years before the onset of the disease. Here, we show a potential connection between MAO-B, γ-secretase and Aβ in neurons. MAO-B immunohistochemistry was performed on postmortem human brain. Affinity purification of γ-secretase followed by mass spectrometry was used for unbiased identification of γ-secretase-associated proteins. The association of MAO-B with γ-secretase was studied by coimmunoprecipitation from brain homogenate, and by in-situ proximity ligation assay (PLA) in neurons as well as mouse and human brain sections. The effect of MAO-B on Aβ production and Notch processing in cell cultures was analyzed by siRNA silencing or overexpression experiments followed by ELISA, western blot or FRET analysis. Methodology for measuring relative intraneuronal MAO-B and Aβ42 levels in single cells was developed by combining immunocytochemistry and confocal microscopy with quantitative image analysis. Immunohistochemistry revealed MAO-B staining in neurons in the frontal cortex, hippocampus CA1 and entorhinal cortex in postmortem human brain. Interestingly, the neuronal staining intensity was higher in AD brain than in control brain in these regions. Mass spectrometric data from affinity purified γ-secretase suggested that MAO-B is a γ-secretase-associated protein, which was confirmed by immunoprecipitation and PLA, and a neuronal location of the interaction was shown. Strikingly, intraneuronal Aβ42 levels correlated with MAO-B levels, and siRNA silencing of MAO-B resulted in significantly reduced levels of intraneuronal Aβ42. Furthermore, overexpression of

  17. The Chihuahua dog: A new animal model for neuronal ceroid lipofuscinosis CLN7 disease?

    Science.gov (United States)

    Faller, Kiterie M E; Bras, Jose; Sharpe, Samuel J; Anderson, Glenn W; Darwent, Lee; Kun-Rodrigues, Celia; Alroy, Joseph; Penderis, Jacques; Mole, Sara E; Gutierrez-Quintana, Rodrigo; Guerreiro, Rita J

    2016-04-01

    Neuronal ceroid lipofuscinoses (NCLs) are a group of incurable lysosomal storage disorders characterized by neurodegeneration and accumulation of lipopigments mainly within the neurons. We studied two littermate Chihuahua dogs presenting with progressive signs of blindness, ataxia, pacing, and cognitive impairment from 1 year of age. Because of worsening of clinical signs, both dogs were euthanized at about 2 years of age. Postmortem examination revealed marked accumulation of autofluorescent intracellular inclusions within the brain, characteristic of NCL. Whole-genome sequencing was performed on one of the affected dogs. After sequence alignment and variant calling against the canine reference genome, variants were identified in the coding region or splicing regions of four previously known NCL genes (CLN6, ARSG, CLN2 [=TPP1], and CLN7 [=MFSD8]). Subsequent segregation analysis within the family (two affected dogs, both parents, and three relatives) identified MFSD8:p.Phe282Leufs13*, which had previously been identified in one Chinese crested dog with no available ancestries, as the causal mutation. Because of the similarities of the clinical signs and histopathological changes with the human form of the disease, we propose that the Chihuahua dog could be a good animal model of CLN7 disease. © 2016 Wiley Periodicals, Inc.

  18. Glia-neuron interactions in neurological diseases: Testing non-cell autonomy in a dish.

    Science.gov (United States)

    Meyer, Kathrin; Kaspar, Brian K

    2017-02-01

    For the past century, research on neurological disorders has largely focused on the most prominently affected cell types - the neurons. However, with increasing knowledge of the diverse physiological functions of glial cells, their impact on these diseases has become more evident. Thus, many conditions appear to have more complex origins than initially thought. Since neurological pathologies are often sporadic with unknown etiology, animal models are difficult to create and might only reflect a small portion of patients in which a mutation in a gene has been identified. Therefore, reliable in vitro systems to studying these disorders are urgently needed. They might be a pre-requisite for improving our understanding of the disease mechanisms as well as for the development of potential new therapies. In this review, we will briefly summarize the function of different glial cell types in the healthy central nervous system (CNS) and outline their implication in the development or progression of neurological conditions. We will then describe different types of culture systems to model non-cell autonomous interactions in vitro and evaluate advantages and disadvantages. This article is part of a Special Issue entitled SI: Exploiting human neurons. Copyright © 2016 Elsevier B.V. All rights reserved.

  19. Neuropeptide changes and neuroactive amino acids in CSF from humans and sheep with neuronal ceroid lipofuscinoses (NCLs, Batten disease).

    NARCIS (Netherlands)

    Kay, G.W.; Verbeek, M.M.; Furlong, J.M.; Willemsen, M.A.A.P.; Palmer, D.N.

    2009-01-01

    Anomalies in neuropeptides and neuroactive amino acids have been postulated to play a role in neurodegeneration in a variety of diseases including the inherited neuronal ceroid lipofuscinoses (NCLs, Batten disease). These are often indicated by concentration changes in cerebrospinal fluid (CSF).

  20. Activation of neuronal defense mechanisms in response to pathogenic factors triggering induction of amyloidosis in Alzheimer's disease.

    Science.gov (United States)

    Maltsev, Alexander V; Santockyte, Rasa; Bystryak, Simon; Galzitskaya, Oxana V

    2014-01-01

    We present a new model for etiology of Alzheimer's disease (AD) which postulates early involvement of specialized neuroprotective mechanisms in the pathology of AD. These neuroprotective mechanisms work in concert to regulate metabolic homeostasis in healthy neuronal cells, but contribute to the distinctive cytopathic phenotype of neuronal degeneration in AD. According to this model, two molecular/genetic hallmarks of AD, amyloid-β (Aβ) deposition and tau hyperphosphorylation, are associated with neuronal mechanisms for dissipating thermal energy associated with high levels of protein synthesis in highly temperature-sensitive neuronal cells. Development of effective methods of AD treatment will require a better understanding of how this neuronal defense system is activated in response to cytopathological triggers in sporadic AD. The cause and effect link between synthesis and processing of amyloid-β protein precursor (AβPP) and the AD terminal phenotype of neurofibrillary tangles and neuron loss involve the formation of Aβ peptides that accumulate as oligomers, cannot be controlled by neurons, and are toxic to the surrounding neuronal membranes. We analyze experimental and clinical studies that have investigated the correlation between phosphorylation of some transport proteins and increased synthesis of proteins in neurons. We also review the evidence related to the possibility that protein hyperphosphorylation may be a byproduct of energetic imbalances in AD cells associated with high levels of protein synthesis, and that activation of defense systems, through which energy-rich molecules are eliminated from the site of protein synthesis and are sequestered to the peripheral neuronal areas, may bring about some of the distinctive morphological features of AD.

  1. Familial frontotemporal dementia with neuronal intranuclear inclusions is not a polyglutamine expansion disease

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    Neal Scott J

    2006-08-01

    Full Text Available Abstract Background Many cases of frontotemporal dementia (FTD are familial, often with an autosomal dominant pattern of inheritance. Some are due to a mutation in the tau- encoding gene, on chromosome 17, and show an accumulation of abnormal tau in brain tissue (FTDP-17T. Most of the remaining familial cases do not exhibit tau pathology, but display neuropathology similar to patients with dementia and motor neuron disease, characterized by the presence of ubiquitin-immunoreactive (ub-ir, dystrophic neurites and neuronal cytoplasmic inclusions in the neocortex and hippocampus (FTLD-U. Recently, we described a subset of patients with familial FTD with autopsy-proven FTLD-U pathology and with the additional finding of ub-ir neuronal intranuclear inclusions (NII. NII are a characteristic feature of several other neurodegenerative conditions for which the genetic basis is abnormal expansion of a polyglutamine-encoding trinucleotide repeat region. The genetic basis of familial FTLD-U is currently not known, however the presence of NII suggests that a subset of cases may represent a polyglutamine expansion disease. Methods We studied DNA and post mortem brain tissue from 5 affected members of 4 different families with NII and one affected individual with familial FTLD-U without NII. Patient DNA was screened for CAA/CAG trinucleotide expansion in a set of candidate genes identified using a genome-wide computational approach. Genes containing CAA/CAG trinucleotide repeats encoding at least five glutamines were examined (n = 63, including the nine genes currently known to be associated with human disease. CAA/CAG tract sizes were compared with published normal values (where available and with those of healthy controls (n = 94. High-resolution agarose gel electrophoresis was used to measure allele size (number of CAA/CAG repeats. For any alleles estimated to be equal to or larger than the maximum measured in the control population, the CAA/CAG tract

  2. Structural and functional brain signatures of C9orf72 in motor neuron disease.

    Science.gov (United States)

    Agosta, Federica; Ferraro, Pilar M; Riva, Nilo; Spinelli, Edoardo Gioele; Domi, Teuta; Carrera, Paola; Copetti, Massimiliano; Falzone, Yuri; Ferrari, Maurizio; Lunetta, Christian; Comi, Giancarlo; Falini, Andrea; Quattrini, Angelo; Filippi, Massimo

    2017-09-01

    This study investigated structural and functional magnetic resonance imaging abnormalities in hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) motor neuron disease (MND) relative to disease severity-matched sporadic MND cases. We enrolled 19 C9orf72 and 67 disease severity-matched sporadic MND patients, and 22 controls. Sporadic cases were grouped in patients with: no cognitive/behavioral deficits (sporadic-motor); same patterns of cognitive/behavioral impairment as C9orf72 cases (sporadic-cognitive); shorter disease duration versus other sporadic groups (sporadic-early). C9orf72 patients showed cerebellar and thalamic atrophy versus all sporadic cases. All MND patients showed motor, frontal, and temporoparietal cortical thinning and motor and extramotor white matter damage versus controls, independent of genotype and presence of cognitive impairment. Compared with sporadic-early, C9orf72 patients revealed an occipital cortical thinning. C9orf72 patients had enhanced visual network functional connectivity versus sporadic-motor and sporadic-early cases. Structural cerebellar and thalamic damage and posterior cortical alterations are the brain magnetic resonance imaging signatures of C9orf72 MND. Frontotemporal cortical and widespread white matter involvement are likely to be an effect of the disease evolution rather than a C9orf72 marker. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Social perception of facial resemblance in humans.

    Science.gov (United States)

    DeBruine, Lisa M; Jones, Benedict C; Little, Anthony C; Perrett, David I

    2008-02-01

    Two lines of reasoning predict that highly social species will have mechanisms to influence behavior toward individuals depending on their degree of relatedness. First, inclusive fitness theory leads to the prediction that organisms will preferentially help closely related kin over more distantly related individuals. Second, evaluation of the relative costs and potential benefits of inbreeding suggests that the degree of kinship should also be considered when choosing a mate. In order to behaviorally discriminate between individuals with different levels of relatedness, organisms must be able to discriminate cues of kinship. Facial resemblance is one such potential cue in humans. Computer-graphic manipulation of face images has made it possible to experimentally test hypotheses about human kin recognition by facial phenotype matching. We review recent experimental evidence that humans respond to facial resemblance in ways consistent with inclusive fitness theory and considerations of the costs of inbreeding, namely by increasing prosocial behavior and positive attributions toward self-resembling images and selectively tempering attributions of attractiveness to other-sex faces in the context of a sexual relationship.

  4. Mulberry fruit protects dopaminergic neurons in toxin-induced Parkinson's disease models.

    Science.gov (United States)

    Kim, Hyo Geun; Ju, Mi Sun; Shim, Jin Sup; Kim, Min Cheol; Lee, Sang-Hun; Huh, Youngbuhm; Kim, Sun Yeou; Oh, Myung Sook

    2010-07-01

    Parkinson's disease (PD), one of the most common neurodegenerative disorders, is characterised by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) to the striatum (ST), and involves oxidative stress. Mulberry fruit from Morus alba L. (Moraceae) is commonly eaten, and has long been used in traditional oriental medicine. It contains well-known antioxidant agents such as anthocyanins. The present study examined the protective effects of 70 % ethanol extract of mulberry fruit (ME) against neurotoxicity in in vitro and in vivo PD models. In SH-SY5Y cells stressed with 6-hydroxydopamine (6-OHDA), ME significantly protected the cells from neurotoxicity in a dose-dependent manner. Other assays demonstrated that the protective effect of ME was mediated by its antioxidant and anti-apoptotic effects, regulating reactive oxygen species and NO generation, Bcl-2 and Bax proteins, mitochondrial membrane depolarisation and caspase-3 activation. In mesencephalic primary cells stressed with 6-OHDA or 1-methyl-4-phenylpyridinium (MPP+), pre-treatment with ME also protected dopamine neurons, showing a wide range of effective concentrations in MPP+-induced toxicity. In the sub-acute mouse PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), ME showed a preventative effect against PD-like symptoms (bradykinesia) in the behavioural test and prevented MPTP-induced dopaminergic neuronal damage in an immunocytochemical analysis of the SNpc and ST. These results indicate that ME has neuroprotective effects in in vitro and in vivo PD models, and that it may be useful in preventing or treating PD.

  5. DNA damage and cell cycle events implicate cerebellar dentate nucleus neurons as targets of Alzheimer's disease

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    Yang Yan

    2010-12-01

    Full Text Available Abstract Background Although the cerebellum is considered to be predominantly involved in fine motor control, emerging evidence documents its participation in language, impulsive behavior and higher cognitive functions. While the specific connections of the cerebellar deep nuclei (CDN that are responsible for these functions are still being worked out, their deficiency has been termed "cerebellar cognitive affective syndrome" - a syndrome that bears a striking similarity to many of the symptoms of Alzheimer's disease (AD. Using ectopic cell cycle events and DNA damage markers as indexes of cellular distress, we have explored the neuropathological involvement of the CDN in human AD. Results We examined the human cerebellar dentate nucleus in 22 AD cases and 19 controls for the presence of neuronal cell cycle events and DNA damage using immunohistochemistry and fluorescence in situ hybridization. Both techniques revealed several instances of highly significant correlations. By contrast, neither amyloid plaque nor neurofibrillary tangle pathology was detected in this region, consistent with previous reports of human cerebellar pathology. Five cases of early stage AD were examined and while cell cycle and DNA damage markers were well advanced in the hippocampus of all five, few indicators of either cell cycle events (1 case or a DNA damage response (1 case were found in CDN. This implies that CDN neurons are most likely affected later in the course of AD. Clinical-pathological correlations revealed that cases with moderate to high levels of cell cycle activity in their CDN are highly likely to show deficits in unorthodox cerebellar functions including speech, language and motor planning. Conclusion Our results reveal that the CDN neurons are under cellular stress in AD and suggest that some of the non-motor symptoms found in patients with AD may be partly cerebellar in origin.

  6. Diagnostic accuracy of electrically elicited multiplet discharges in patients with motor neuron disease.

    Science.gov (United States)

    Sleutjes, Boudewijn T H M; Montfoort, Inger; van Doorn, Pieter A; Visser, Gerhard H; Blok, Joleen H

    2015-11-01

    To determine and compare the diagnostic accuracy of electrically elicited multiplet discharges (MDs) and fasciculation potentials (FPs) in motor neuron disease (MND). Patients were eligible when they had MND in their differential diagnosis and were referred for electromyogram (EMG). Stimulated high-density surface EMG of the thenar muscles was performed on the same day as standard EMG examination. High-density recordings were analysed for presence of MDs and needle EMG of any muscle investigated in the cervical region for presence of FPs. Of the 61 patients enrolled in this diagnostic study, 24 patients were clinically diagnosed with amyotrophic lateral sclerosis (ALS) and 11 patients with progressive muscular atrophy (PMA). Another diagnosis was made in 26 patients. Sixteen patients in whom MDs were detected were diagnosed with either ALS (n = 11) or PMA (n = 5; sensitivity = 47.1%, PPV = 94.1%). MDs were detected in only one patient initially diagnosed with PMA, but in whom later on, multifocal motor neuropathy could not be excluded (specificity = 96.2%). Electrically elicited MDs had a higher specificity than FPs (96.2% vs 53.9%, p motor neuron involvement of ≥ 1 EMG region increased from 50% to 73.5% (p = 0.008, n = 34). Electrically evoked MDs are highly specific for ALS and PMA and are an early sign of lower motor neuron dysfunction. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  7. Treadmill exercise represses neuronal cell death in an aged transgenic mouse model of Alzheimer's disease.

    Science.gov (United States)

    Um, Hyun-Sub; Kang, Eun-Bum; Koo, Jung-Hoon; Kim, Hyun-Tae; Jin-Lee; Kim, Eung-Joon; Yang, Chun-Ho; An, Gil-Young; Cho, In-Ho; Cho, Joon-Yong

    2011-02-01

    The present study was undertaken to further investigate the protective effect of treadmill exercise on the hippocampal proteins associated with neuronal cell death in an aged transgenic (Tg) mice with Alzheimer's disease (AD). To address this, Tg mouse model of AD, Tg-NSE/PS2m, which expresses human mutant PS2 in the brain, was chosen. Animals were subjected to treadmill exercise for 12 weeks from 24 months of age. The exercised mice were treadmill run at speed of 12 m/min, 60 min/day, 5 days/week on a 0% gradient for 3 months. Treadmill exercised mice improved cognitive function in water maze test. Treadmill exercised mice significantly reduced the expression of Aβ-42, Cox-2, and caspase-3 in the hippocampus. In parallel, treadmill exercised Tg mice decreased the phosphorylation levels of JNK, p38MAPK and tau (Ser404, Ser202, Thr231), and increased the phosphorylation levels of ERK, PI3K, Akt and GSK-3α/β. In addition, treadmill exercised Tg mice up-regulated the expressions of NGF, BDNF and phospho-CREB, and the expressions of SOD-1, SOD-2 and HSP-70. Treadmill exercised Tg mice up-regulated the expression of Bcl-2, and down-regulated the expressions of cytochrome c and Bax in the hippocampus. The number of TUNEL-positive cells in the hippocampus in mice was significantly decreased after treadmill exercise. Finally, serum TC, insulin, glucose, and corticosterone levels were significantly decreased in the Tg mice after treadmill exercise. As a consequence of such change, Aβ-dependent neuronal cell death in the hippocampus of Tg mice was markedly suppressed following treadmill exercise. These results strongly suggest that treadmill exercise provides a therapeutic potential to inhibit both Aβ-42 and neuronal death pathways. Therefore, treadmill exercise may be beneficial in prevention or treatment of AD. Copyright © 2010 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.

  8. Modulators of cytoskeletal reorganization in CA1 hippocampal neurons show increased expression in patients at mid-stage Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Patricia F Kao

    2010-10-01

    Full Text Available During the progression of Alzheimer's disease (AD, hippocampal neurons undergo cytoskeletal reorganization, resulting in degenerative as well as regenerative changes. As neurofibrillary tangles form and dystrophic neurites appear, sprouting neuronal processes with growth cones emerge. Actin and tubulin are indispensable for normal neurite development and regenerative responses to injury and neurodegenerative stimuli. We have previously shown that actin capping protein beta2 subunit, Capzb2, binds tubulin and, in the presence of tau, affects microtubule polymerization necessary for neurite outgrowth and normal growth cone morphology. Accordingly, Capzb2 silencing in hippocampal neurons resulted in short, dystrophic neurites, seen in neurodegenerative diseases including AD. Here we demonstrate the statistically significant increase in the Capzb2 expression in the postmortem hippocampi in persons at mid-stage, Braak and Braak stage (BB III-IV, non-familial AD in comparison to controls. The dynamics of Capzb2 expression in progressive AD stages cannot be attributed to reactive astrocytosis. Moreover, the increased expression of Capzb2 mRNA in CA1 pyramidal neurons in AD BB III-IV is accompanied by an increased mRNA expression of brain derived neurotrophic factor (BDNF receptor tyrosine kinase B (TrkB, mediator of synaptic plasticity in hippocampal neurons. Thus, the up-regulation of Capzb2 and TrkB may reflect cytoskeletal reorganization and/or regenerative response occurring in hippocampal CA1 neurons at a specific stage of AD progression.

  9. Motor neuron disease mortality rates in New Zealand 1992-2013.

    Science.gov (United States)

    Cao, Maize C; Chancellor, Andrew; Charleston, Alison; Dragunow, Mike; Scotter, Emma L

    2018-05-01

    We determined the mortality rates of motor neuron disease (MND) in New Zealand over 22 years from 1992 to 2013. Previous studies have found an unusually high and/or increasing incidence of MND in certain regions of New Zealand; however, no studies have examined MND rates nationwide to corroborate this. Death certificate data coded G12.2 by International Classification of Diseases (ICD)-10 coding, or 335.2 by ICD-9 coding were obtained. These codes specify amyotrophic lateral sclerosis, progressive bulbar palsy, or other motor neuron diseases as the underlying cause of death. Mortality rates for MND deaths in New Zealand were age-standardized to the European Standard Population and compared with rates from international studies that also examined death certificate data and were age-standardized to the same standard population. The age-standardized mortality from MND in New Zealand was 2.3 per 100,000 per year from 1992-2007 and 2.8 per 100,000 per year from 2008-2013. These rates were 3.3 and 4.0 per 100,000 per year, respectively, for the population 20 years and older. The increase in rate between these two time periods was likely due to changes in MND death coding from 2008. Contrary to a previous regional study of MND incidence, nationwide mortality rates did not increase steadily over this time period once aging was accounted for. However, New Zealand MND mortality rate was higher than comparable studies we examined internationally (mean 1.67 per 100,000 per year), suggesting that further analysis of MND burden in New Zealand is warranted.

  10. Bright light exposure reduces TH-positive dopamine neurons: implications of light pollution in Parkinson's disease epidemiology.

    Science.gov (United States)

    Romeo, Stefania; Viaggi, Cristina; Di Camillo, Daniela; Willis, Allison W; Lozzi, Luca; Rocchi, Cristina; Capannolo, Marta; Aloisi, Gabriella; Vaglini, Francesca; Maccarone, Rita; Caleo, Matteo; Missale, Cristina; Racette, Brad A; Corsini, Giovanni U; Maggio, Roberto

    2013-01-01

    This study explores the effect of continuous exposure to bright light on neuromelanin formation and dopamine neuron survival in the substantia nigra. Twenty-one days after birth, Sprague-Dawley albino rats were divided into groups and raised under different conditions of light exposure. At the end of the irradiation period, rats were sacrificed and assayed for neuromelanin formation and number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra. The rats exposed to bright light for 20 days or 90 days showed a relatively greater number of neuromelanin-positive neurons. Surprisingly, TH-positive neurons decreased progressively in the substantia nigra reaching a significant 29% reduction after 90 days of continuous bright light exposure. This decrease was paralleled by a diminution of dopamine and its metabolite in the striatum. Remarkably, in preliminary analysis that accounted for population density, the age and race adjusted Parkinson's disease prevalence significantly correlated with average satellite-observed sky light pollution.

  11. Pharmacological Inhibition of Necroptosis Protects from Dopaminergic Neuronal Cell Death in Parkinson’s Disease Models

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    Angelo Iannielli

    2018-02-01

    Full Text Available Dysfunctions in mitochondrial dynamics and metabolism are common pathological processes associated with Parkinson’s disease (PD. It was recently shown that an inherited form of PD and dementia is caused by mutations in the OPA1 gene, which encodes for a key player in mitochondrial fusion and structure. iPSC-derived neural cells from these patients exhibited severe mitochondrial fragmentation, respiration impairment, ATP deficits, and heightened oxidative stress. Reconstitution of normal levels of OPA1 in PD-derived neural cells normalized mitochondria morphology and function. OPA1-mutated neuronal cultures showed reduced survival in vitro. Intriguingly, selective inhibition of necroptosis effectively rescued this survival deficit. Additionally, dampening necroptosis in MPTP-treated mice protected from DA neuronal cell loss. This human iPSC-based model captures both early pathological events in OPA1 mutant neural cells and the beneficial effects of blocking necroptosis, highlighting this cell death process as a potential therapeutic target for PD.

  12. [The pathological TDP-43 protein expression in the central nervous system of motor neuron disease].

    Science.gov (United States)

    Zhu, Mingwei; Liu, Jia; Wang, Luning; Gui, Qiuping

    2015-01-01

    To understand pathological TDP-43 features in the central nervous systems of patients with clinically and autopsy confirmed motor neuron disease (MND). The clinical and histopathological features of 4 cases with MND confirmed by autopsy were summarized; anti-ubiquitin (Ub) and anti-TDP-43 immunohistochemical staining were carried out on tissue of brains and spinal cords from 4 cases with MND and 3 control cases without history of neurological disorders. These 4 cases presented with typical clinical and histologic features of MND. Ub-positive inclusions were observed in brain and spinal cord from 3 cases with the Ub-positive inclusions of skein- round- and lewy body- like structures. Strong TDP-43 pathological staining in brain and spinal cord was identified in 2 cases with MND presented as neuronal and glial cytoplasmic inclusions with various shapes. The TDP-43 positive inclusions were widely distributed in the motor cortex of brain and the anterior horn of spinal cord. TDP-43 weak staining in the spinal cord tissue was observed in 1 case with MND. No Ub- and TDP-43 positive inclusions were found in 3 control cases. There is widespread pathological TDP-43 expression in the central nervous system of MND. TDP-43 positive inclusions in MND have relatively high specificity. It is worth further study on their formation mechanism.

  13. Research on motor neuron diseases konzo and neurolathyrism: trends from 1990 to 2010.

    Directory of Open Access Journals (Sweden)

    Delphin Diasolua Ngudi

    Full Text Available Konzo (caused by consumption of improperly processed cassava, Manihot esculenta and neurolathyrism (caused by prolonged overconsumption of grass pea, Lathyrus sativus are two distinct non-infectious upper motor neurone diseases with identical clinical symptoms of spastic paraparesis of the legs. They affect many thousands of people among the poor in the remote rural areas in the central and southern parts of Africa afflicting them with konzo in Ethiopia and in the Indian sub-continent with neurolathyrism. Both diseases are toxico-nutritional problems due to monotonous consumption of starchy cassava roots or protein-rich grass pea seeds as a staple, especially during drought and famine periods. Both foods contain toxic metabolites (cyanogenic glycosides in cassava and the neuro-excitatory amino acid β-ODAP in grass pea that are blamed for theses diseases. The etiology is also linked to the deficiency in the essential sulfur amino acids that protect against oxidative stress. The two diseases are not considered reportable by the World Health Organization (WHO and only estimated numbers can be found. This paper analyzes research performance and determines scientific interest in konzo and neurolathyrism. A literature search of over 21 years (from 1990 to 2010 shows that in terms of scientific publications there is little interest in these neglected motorneurone diseases konzo and neurolathyrism that paralyze the legs. Comparison is made with HTLV-1/TSP, an infectious disease occurring mainly in Latin America of which the clinical manifestation is similar to konzo and neurolathyrism and requires a differential diagnosis. Our findings emphasize the multidisciplinary nature of studies on these neglected diseases, which however have not really captured the attention of decision makers and project planners, especially when compared with the infectious HTLV-1/TSP. Konzo and neurolathyrism can be prevented by a balanced diet.

  14. Concentrations of trace minerals in the spinal cord of horses with equine motor neuron disease.

    Science.gov (United States)

    Polack, E W; King, J M; Cummings, J F; Mohammed, H O; Birch, M; Cronin, T

    2000-06-01

    To compare concentrations of trace minerals in the spinal cord of horses with equine motor neuron disease (EMND) with those of horses without neurologic disease (control horses). 24 horses with EMND and 22 control horses. Spinal cord trace mineral concentrations in horses with EMND and control horses were analyzed by use of inductively coupled plasma atomic emission spectroscopy (calcium, phosphorus, sodium, potassium, magnesium, copper, iron, manganese, nickel, zinc, aluminum, cobalt, and chromium), atomic absorption spectrophotometry (lead and cadmium), flameless atomic absorption (mercury), and fluorometry (selenium). Copper concentration was significantly higher in the spinal cord of horses with EMND, compared with control horses; spinal cord concentrations of all other trace minerals were similar between groups. Among spinal cord trace minerals investigated in the study, only copper concentrations were significantly different between horses with EMND and horses without neurologic disease, which suggests that copper may be involved in the pathogenesis of EMND. An hypothesis of oxidative injury in this disease is supported by the finding of increased copper concentrations in the spinal cord and by low vitamin E concentrations reported by other researchers.

  15. Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression.

    Directory of Open Access Journals (Sweden)

    Cristin D Davidson

    2009-09-01

    Full Text Available Niemann-Pick type C (NPC disease is a fatal neurodegenerative disorder caused most commonly by a defect in the NPC1 protein and characterized by widespread intracellular accumulation of unesterified cholesterol and glycosphingolipids (GSLs. While current treatment therapies are limited, a few drugs tested in Npc1(-/- mice have shown partial benefit. During a combination treatment trial using two such compounds, N-butyldeoxynojirimycin (NB-DNJ and allopregnanolone, we noted increased lifespan for Npc1(-/- mice receiving only 2-hydroxypropyl-beta-cyclodextrin (CD, the vehicle for allopregnanolone. This finding suggested that administration of CD alone, but with greater frequency, might provide additional benefit.Administration of CD to Npc1(-/- mice beginning at either P7 or P21 and continuing every other day delayed clinical onset, reduced intraneuronal cholesterol and GSL storage as well as free sphingosine accumulation, reduced markers of neurodegeneration, and led to longer survival than any previous treatment regime. We reasoned that other lysosomal diseases characterized by cholesterol and GSL accumulation, including NPC disease due to NPC2 deficiency, GM1 gangliosidosis and mucopolysaccharidosis (MPS type IIIA, might likewise benefit from CD treatment. Treated Npc2(-/- mice showed benefits similar to NPC1 disease, however, mice with GM1 gangliosidosis or MPS IIIA failed to show reduction in storage.Treatment with CD delayed clinical disease onset, reduced intraneuronal storage and secondary markers of neurodegeneration, and significantly increased lifespan of both Npc1(-/- and Npc2(-/- mice. In contrast, CD failed to ameliorate cholesterol or glycosphingolipid storage in GM1 gangliosidosis and MPS IIIA disease. Understanding the mechanism(s by which CD leads to reduced neuronal storage may provide important new opportunities for treatment of NPC and related neurodegenerative diseases characterized by cholesterol dyshomeostasis.

  16. Effect of Estradiol on Neurotrophin Receptors in Basal Forebrain Cholinergic Neurons: Relevance for Alzheimer’s Disease

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    Andrea Kwakowsky

    2016-12-01

    Full Text Available The basal forebrain is home to the largest population of cholinergic neurons in the brain. These neurons are involved in a number of cognitive functions including attention, learning and memory. Basal forebrain cholinergic neurons (BFCNs are particularly vulnerable in a number of neurological diseases with the most notable being Alzheimer’s disease, with evidence for a link between decreasing cholinergic markers and the degree of cognitive impairment. The neurotrophin growth factor system is present on these BFCNs and has been shown to promote survival and differentiation on these neurons. Clinical and animal model studies have demonstrated the neuroprotective effects of 17β-estradiol (E2 on neurodegeneration in BFCNs. It is believed that E2 interacts with neurotrophin signaling on cholinergic neurons to mediate these beneficial effects. Evidence presented in our recent study confirms that altering the levels of circulating E2 levels via ovariectomy and E2 replacement significantly affects the expression of the neurotrophin receptors on BFCN. However, we also showed that E2 differentially regulates neurotrophin receptor expression on BFCNs with effects depending on neurotrophin receptor type and neuroanatomical location. In this review, we aim to survey the current literature to understand the influence of E2 on the neurotrophin system, and the receptors and signaling pathways it mediates on BFCN. In addition, we summarize the physiological and pathophysiological significance of E2 actions on the neurotrophin system in BFCN, especially focusing on changes related to Alzheimer’s disease.

  17. Lesion of the olfactory epithelium accelerates prion neuroinvasion and disease onset when prion replication is restricted to neurons.

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    Jenna Crowell

    Full Text Available Natural prion diseases of ruminants are moderately contagious and while the gastrointestinal tract is the primary site of prion agent entry, other mucosae may be entry sites in a subset of infections. In the current study we examined prion neuroinvasion and disease induction following disruption of the olfactory epithelium in the nasal mucosa since this site contains environmentally exposed olfactory sensory neurons that project directly into the central nervous system. Here we provide evidence for accelerated prion neuroinvasion and clinical onset from the olfactory mucosa after disruption and regeneration of the olfactory epithelium and when prion replication is restricted to neurons. In transgenic mice with neuron restricted replication of prions, there was a reduction in survival when the olfactory epithelium was disrupted prior to intranasal inoculation and there was >25% decrease in the prion incubation period. In a second model, the neurotropic DY strain of transmissible mink encephalopathy was not pathogenic in hamsters by the nasal route, but 50% of animals exhibited brain infection and/or disease when the olfactory epithelium was disrupted prior to intranasal inoculation. A time course analysis of prion deposition in the brain following loss of the olfactory epithelium in models of neuron-restricted prion replication suggests that neuroinvasion from the olfactory mucosa is via the olfactory nerve or brain stem associated cranial nerves. We propose that induction of neurogenesis after damage to the olfactory epithelium can lead to prion infection of immature olfactory sensory neurons and accelerate prion spread to the brain.

  18. Age and Parkinson's disease-related neuronal death in the substantia nigra pars compacta

    DEFF Research Database (Denmark)

    Eriksen, Nina; Stark, Anette Kirstine; Pakkenberg, Bente

    2009-01-01

    During aging, decline in memory and cognitive abilities as well as motor weakening is of great concern. The dopaminergic system mediates some aspects of manual dexterity, in addition to cognition and emotion, and may be especially vulnerable to aging. A common neurodegenerative disorder of this s......During aging, decline in memory and cognitive abilities as well as motor weakening is of great concern. The dopaminergic system mediates some aspects of manual dexterity, in addition to cognition and emotion, and may be especially vulnerable to aging. A common neurodegenerative disorder...... of this system, Parkinson's disease, is characterized by a selective, progressive loss of dopaminergic neurons in the substantia nigra pars compacta. This review includes studies quantifying age and Parkinson's-related changes of the substantia nigra, with emphasis on stereological studies performed...

  19. Neuronal plasticity and astrocytic reaction in Down syndrome and Alzheimer disease

    DEFF Research Database (Denmark)

    Jørgensen, Ole Steen; Brooksbank, B W; Balázs, R

    1990-01-01

    disease (AD) and adults with Down syndrome (DS), the latter also presenting manifest signs of Alzheimer type of neuropathology. The trend of changes was similar in AD and DS, but more marked in the latter. The biochemical make-up of astrocytes was differentially affected: in both the frontal and DS...... were about 180% and 230% of control. The observations (normal GS and elevated levels of the other markers) might suggest that the pathological changes involve a differentiated astrocytic reaction and that the astrocytic reaction is more marked in DS than in AD. In DS the increase in S100 could...... be explained, in part, by a gene dosage effect and in part by reactive gliosis. The neuronal markers were also differentially affected. In comparison with appropriate controls, the concentration of D3-protein in frontal cortex was decreased by 24% in DS and by 14% in AD, whereas NCAM levels were...

  20. Brain region specific mitophagy capacity could contribute to selective neuronal vulnerability in Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Zabel Claus

    2011-09-01

    Full Text Available Abstract Parkinson's disease (PD is histologically well defined by its characteristic degeneration of dopaminergic neurons in the substantia nigra pars compacta. Remarkably, divergent PD-related mutations can generate comparable brain region specific pathologies. This indicates that some intrinsic region-specificity respecting differential neuron vulnerability exists, which codetermines the disease progression. To gain insight into the pathomechanism of PD, we investigated protein expression and protein oxidation patterns of three different brain regions in a PD mouse model, the PINK1 knockout mice (PINK1-KO, in comparison to wild type control mice. The dysfunction of PINK1 presumably affects mitochondrial turnover by disturbing mitochondrial autophagic pathways. The three brain regions investigated are the midbrain, which is the location of substantia nigra; striatum, the major efferent region of substantia nigra; and cerebral cortex, which is more distal to PD pathology. In all three regions, mitochondrial proteins responsible for energy metabolism and membrane potential were significantly altered in the PINK1-KO mice, but with very different region specific accents in terms of up/down-regulations. This suggests that disturbed mitophagy presumably induced by PINK1 knockout has heterogeneous impacts on different brain regions. Specifically, the midbrain tissue seems to be most severely hit by defective mitochondrial turnover, whereas cortex and striatum could compensate for mitophagy nonfunction by feedback stimulation of other catabolic programs. In addition, cerebral cortex tissues showed the mildest level of protein oxidation in both PINK1-KO and wild type mice, indicating either a better oxidative protection or less reactive oxygen species (ROS pressure in this brain region. Ultra-structural histological examination in normal mouse brain revealed higher incidences of mitophagy vacuoles in cerebral cortex than in striatum and substantia

  1. Diagnostic contribution of magnetic resonance imaging in an atypical presentation of motor neuron disease.

    Science.gov (United States)

    Ugga, Lorenzo; Coppola, Cinzia; Cocozza, Sirio; Saracino, Dario; Caranci, Ferdinando; Tuccillo, Francesco; Signoriello, Elisabetta; Casertano, Sara; Di Iorio, Giuseppe; Tedeschi, Enrico

    2017-12-01

    Motor neuron disease (MND) is a neurodegenerative disease determining progressive and relentless motor deterioration involving both upper and lower motor neurons (UMN and LMN); several variants at onset are described. Here we describe a case of MND presenting as pure spastic monoparesis in which magnetic resonance imaging (MRI) gave a substantial contribution in confirming the diagnosis and assessing the severity of UMN involvement. An isolated pyramidal syndrome, with complete absence of LMN signs, is a rare phenotype in the context of MND (less than 4% of total cases), especially if restricted to only one limb. Several other elements made this case an unusual presentation of MND: the late age of onset (8 th decade), the subacute evolution of symptoms (raising the suspicion of an ischemic or inflammatory, rather than degenerative, etiology), the patient's past medical history (achalasia, erythema nodosum), the increase of inflammatory indices. Conventional MRI showed no focal lesions that could explain the clinical features; therefore, we used advanced MR sequences. Diffusion tensor imaging (DTI) evaluation evidenced bilateral impairment of corticospinal tract (CST) diffusion metrics, with clear right-left asymmetry, pointing to a neurodegenerative etiology, which clinically appeared less likely at that time. Magnetic resonance spectroscopy (MRS) showed a significant reduction of NAA/Cho + Cr ratio in the motor cortex (MC), further supporting the hypothesis of UMN degeneration. In conclusion, in this particular case of MND, whose nosographic framing has not been fully defined, advanced MRI techniques with DTI and MRS proved to be of great usefulness in confirming a diffuse UMN involvement, possibly at a more advanced stage than its clinical expression.

  2. Cardiac sympathetic neuronal damage precedes myocardial fibrosis in patients with Anderson-Fabry disease

    Energy Technology Data Exchange (ETDEWEB)

    Imbriaco, Massimo; Piscopo, Valentina; Ponsiglione, Andrea; Nappi, Carmela; Puglia, Marta; Dell' Aversana, Serena; Spinelli, Letizia; Cuocolo, Alberto [University Federico II, Department of Advanced Biomedical Sciences, Naples (Italy); Pellegrino, Teresa [National Council of Research, Institute of Biostructure and Bioimaging, Naples (Italy); Petretta, Mario [University Federico II, Department of Translational Medical Sciences, Naples (Italy); Riccio, Eleonora; Pisani, Antonio [University of Naples Federico II, Department of Public Health, Naples (Italy)

    2017-12-15

    Cardiac sympathetic denervation may be detectable in patients with Anderson-Fabry disease (AFD), suggesting its usefulness for early detection of the disease. However, the relationship between sympathetic neuronal damage measured by {sup 123}I-metaiodobenzylguanidine (MIBG) imaging with myocardial fibrosis on cardiac magnetic resonance (CMR) is still unclear. Cardiac sympathetic innervation was assessed by {sup 123}I-MIBG single-photon emission computed tomography (SPECT) in 25 patients with genetically proved AFD. Within one month from MIBG imaging, all patients underwent contrast-enhanced CMR. MIBG defect size and fibrosis size on CMR were measured for the left ventricle (LV) and expressed as %LV. Patients were divided into three groups according to MIBG and CMR findings: (1) matched normal, without MIBG defects and without fibrosis on CMR (n = 10); (2) unmatched, with MIBG defect but without fibrosis (n = 5); and (3) matched abnormal, with MIBG defect and fibrosis (n = 10). The three groups did not differ with respect to age, gender, α-galactosidase, proteinuria, glomerular filtration rate, and troponin I, while New York Heart Association class (p = 0.008), LV hypertrophy (p = 0.05), and enzyme replacement therapy (p = 0.02) were different among groups. Although in patients with matched abnormal findings, there was a significant correlation between MIBG defect size and area of fibrosis at CMR (r{sup 2} = 0.98, p < 0.001), MIBG defect size was larger than fibrosis size (26 ± 23 vs. 18 ± 13%LV, p = 0.02). Sympathetic neuronal damage is frequent in AFD patients, and it may precede myocardial damage, such as fibrosis. Thus, {sup 123}I-MIBG imaging can be considered a challenging technique for early detection of cardiac involvement in AFD. (orig.)

  3. Multiple ureterolithiasis resembling steinstrasse: An unusual presentation

    Directory of Open Access Journals (Sweden)

    Praveen Kumar Pandey

    2014-12-01

    Full Text Available Steinstrasse or “stone street” is an expected complication after extracorporeal shock wave lithotripsy in patients with high stone burden. However, there are published reports of multiple ureterolithiasis resembling steinstrasse in patients with distal renal tubular acidosis. Here we report an uncommon case of a 60-year-old woman who presented with right renal calculi. Her right ureter was studded with multiple calculi up to the vesicoureteric junction. The affected right kidney was nonfunctional and was managed by nephroureterectomy.

  4. Lychee Seed Saponins Improve Cognitive Function and Prevent Neuronal Injury via Inhibiting Neuronal Apoptosis in a Rat Model of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Xiuling Wang

    2017-02-01

    Full Text Available Lychee seed is a traditional Chinese medicine and possesses many activities, including hypoglycemia, liver protection, antioxidation, antivirus, and antitumor. However, its effect on neuroprotection is still unclear. The present study investigated the effects of lychee seed saponins (LSS on neuroprotection and associated mechanisms. We established a rat model of Alzheimer’s disease (AD by injecting Aβ25–35 into the lateral ventricle of rats and evaluated the effect of LSS on spatial learning and memory ability via the Morris water maze. Neuronal apoptosis was analyzed by hematoxylin and eosin stain and terminal deoxynucleotidyl transferase (Tdt-mediated dUTP nick-end labeling analysis, and mRNA expression of caspase-3 and protein expressions of Bax and Bcl-2 by reverse transcription-polymerase chain reaction (RT-PCR and Western blotting, respectively. The results showed that LSS remarkably improved cognitive function and alleviated neuronal injury by inhibiting apoptosis in the hippocampus of AD rats. Furthermore, the mRNA expression of caspase-3 and the protein expression of Bax were downregulated, while the protein expression of Bcl-2 and the ratio of Bcl-2/Bax were increased by LSS. We demonstrate that LSS significantly improves cognitive function and prevent neuronal injury in the AD rats via regulation of the apoptosis pathway. Therefore, LSS may be developed as a nutritional supplement and sold as a drug for AD prevention and/or treatment.

  5. The meaning of living with uncertainty for people with motor neurone disease.

    Science.gov (United States)

    Harris, Denise Andrea; Jack, Kirsten; Wibberley, Christopher

    2018-03-08

    The aim of this study was to explore the meaning of living with uncertainty for people diagnosed with motor neurone disease (MND). MND is a progressive neurodegenerative condition resulting in multiple needs, arising from the complex nature of the disease trajectory. People with MND are often required to make decisions for symptom management and end-of-life care. Research into the lived experience of MND has previously highlighted: the shock of receiving such a diagnosis and prognosis; subsequent concerns relating to the future and loss; and the existential suffering for a person with MND. The lived experiences of MND accentuate the devastating nature of the disease and this can impact upon how people respond to care. Hermeneutic (interpretive) phenomenology: suitable for studying lifeworld experiences. Life story interviews were conducted with four participants and subjected to interpretive analysis. Three phases of the MND illness trajectory emerged: 'body failing prematurely and searching for answers', 'body deterioration and responses to care', and 'body nearing its end and needing to talk'. These phases highlight the phenomenon under study, all relating to uncertainty for people living with MND. This study showed that people with MND are living with uncertainty and other concerns throughout their illness trajectory. People are having to turn to palliative care professionals who are more able to meet their concerns than those caring for other aspects of their disease. MND is a complex disease and it is important that professionals continue to provide holistic care throughout the illness trajectory. The identification of three distinct phases of the MND illness trajectory will help nurses and other professionals to better understand the meaning of uncertainty and other concerns for people with MND. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  6. The Docosanoid Neuroprotectin D1 Induces TH-Positive Neuronal Survival in a Cellular Model of Parkinson's Disease.

    Science.gov (United States)

    Calandria, Jorgelina M; Sharp, Michelle W; Bazan, Nicolas G

    2015-11-01

    Parkinson's disease (PD) does not manifest clinically until 80 % of striatal dopamine is reduced, thus most neuronal damage takes place before the patient presents clinical symptoms. Therefore, it is important to develop preventive strategies for this disease. In the experimental models of PD, 1-methyl-4-phenylpyridinium ion (MPP+) and rotenone induce toxicity in dopaminergic neurons. Neuroprotectin D1 (NPD1) displays neuroprotection in cells undergoing proteotoxic and oxidative stress. In the present report, we established an in vitro model using a primary neuronal culture from mesencephalic embryonic mouse tissue in which 17-20 % of neurons were TH-positive when differentiated in vitro. NPD1 (100 nM) rescued cells from apoptosis induced by MPP+ and rotenone, and the dendritic arbor of surviving neurons was examined using Sholl analysis. Rotenone, as well as MPP+ and its precursor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), severely promoted retraction of dendritic arbor distal segments, thus decreasing the maximum branch order reached. On average, NPD1 counteracted the effects of MPP+ on the dendritic arborization, but failed to do so in the rotenone-treated neurons. However, rotenone did decrease the Sholl intersection number from radii 25 to 125 µm, and NPD1 did restore the pattern to control levels. Similarly, NPD1 partially reverted the dendrite retraction caused by MPP+ and MPTP. These results suggest that the apoptosis occurring in mesencephalic TH-positive neurons is not a direct consequence of mitochondrial dysfunction alone and that NPD1 signaling may be counteracting this damage. These findings lay the groundwork for the use of the in vitro model developed for future studies and for the search of specific molecular events that NPD1 targets to prevent early neurodegeneration in PD.

  7. Osthole promotes neuronal differentiation and inhibits apoptosis via Wnt/β-catenin signaling in an Alzheimer's disease model

    International Nuclear Information System (INIS)

    Yao, Yingjia; Gao, Zhong; Liang, Wenbo; Kong, Liang; Jiao, Yanan; Li, Shaoheng; Tao, Zhenyu; Yan, Yuhui; Yang, Jingxian

    2015-01-01

    Neurogenesis is the process by which neural stem cells (NSCs) proliferate and differentiate into neurons. This is diminished in several neurodegenerative disorders such as Alzheimer's disease (AD), which is characterized by the deposition of amyloid (A)β peptides and neuronal loss. Stimulating NSCs to replace lost neurons is therefore a promising approach for AD treatment. Our previous study demonstrated that osthole modulates NSC proliferation and differentiation, and may reduce Aβ protein expression in nerve cells. Here we investigated the mechanism underlying the effects of osthole on NSCs. We found that osthole enhances NSC proliferation and neuronal differentiation while suppressing apoptosis, effects that were exerted via activation of Wnt/β-catenin signaling. These results provide evidence that osthole can potentially be used as a therapeutic agent in the treatment of AD and other neurodegenerative disorders. - Highlights: • An Alzheimer's disease model was successfully established by transfecting APP gene into neural stem cells in vitro. • Roles of osthole in experimental AD cells were studied. • Osthole promotes proliferation and differentiation into neurons and inhibits accumulation of Aβ 1–42 peptide and apoptosis. • Osthole exerts protection via Wnt/β-catenin signaling pathway.

  8. Aberrant Levels of Hematopoietic/Neuronal Growth and Differentiation Factors in Euthyroid Women at Risk for Autoimmune Thyroid Disease

    NARCIS (Netherlands)

    Massolt, Elske T.; Effraimidis, Grigoris; Korevaar, Tim I. M.; Wiersinga, Wilmar M.; Visser, W. Edward; Peeters, Robin P.; Drexhage, Hemmo A.

    2016-01-01

    Subjects at risk for major mood disorders have a higher risk to develop autoimmune thyroid disease (AITD) and vice-versa, implying a shared pathogenesis. In mood disorder patients, an abnormal profile of hematopoietic/neuronal growth factors is observed, suggesting that growth/differentiation

  9. Functional Rescue of Dopaminergic Neuron Loss in Parkinson's Disease Mice After Transplantation of Hematopoietic Stem and Progenitor Cells.

    Science.gov (United States)

    Altarche-Xifro, Wassim; di Vicino, Umberto; Muñoz-Martin, Maria Isabel; Bortolozzi, Analía; Bové, Jordi; Vila, Miquel; Cosma, Maria Pia

    2016-06-01

    Parkinson's disease is a common neurodegenerative disorder, which is due to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and for which no definitive cure is currently available. Cellular functions in mouse and human tissues can be restored after fusion of bone marrow (BM)-derived cells with a variety of somatic cells. Here, after transplantation of hematopoietic stem and progenitor cells (HSPCs) in the SNpc of two different mouse models of Parkinson's disease, we significantly ameliorated the dopaminergic neuron loss and function. We show fusion of transplanted HSPCs with neurons and with glial cells in the ventral midbrain of Parkinson's disease mice. Interestingly, the hybrids can undergo reprogramming in vivo and survived up to 4weeks after transplantation, while acquiring features of mature astroglia. These newly generated astroglia produced Wnt1 and were essential for functional rescue of the dopaminergic neurons. Our data suggest that glial-derived hybrids produced upon fusion of transplanted HSPCs in the SNpc can rescue the Parkinson's disease phenotype via a niche-mediated effect, and can be exploited as an efficient cell-therapy approach. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  10. Co-localization of high-affinity neurotrophin receptors in nucleus basalis of Meynert neurons and their differential reduction in Alzheimer's disease

    NARCIS (Netherlands)

    Salehi, A.; Verhaagen, J.; Dijkhuizen, P. A.; Swaab, D. F.

    1996-01-01

    It has been suggested that degeneration of neurons in Alzheimer's disease is the result of diminished trophic support. However, so far no evidence has been forwarded that neuronal degeneration in Alzheimer's disease is causally related to insufficient production of neurotrophins. The present study

  11. Direct Reprogramming of Spiral Ganglion Non-neuronal Cells into Neurons: Toward Ameliorating Sensorineural Hearing Loss by Gene Therapy

    Directory of Open Access Journals (Sweden)

    Teppei Noda

    2018-02-01

    Full Text Available Primary auditory neurons (PANs play a critical role in hearing by transmitting sound information from the inner ear to the brain. Their progressive degeneration is associated with excessive noise, disease and aging. The loss of PANs leads to permanent hearing impairment since they are incapable of regenerating. Spiral ganglion non-neuronal cells (SGNNCs, comprised mainly of glia, are resident within the modiolus and continue to survive after PAN loss. These attributes make SGNNCs an excellent target for replacing damaged PANs through cellular reprogramming. We used the neurogenic pioneer transcription factor Ascl1 and the auditory neuron differentiation factor NeuroD1 to reprogram SGNNCs into induced neurons (iNs. The overexpression of both Ascl1 and NeuroD1 in vitro generated iNs at high efficiency. Transcriptome analyses revealed that iNs displayed a transcriptome profile resembling that of endogenous PANs, including expression of several key markers of neuronal identity: Tubb3, Map2, Prph, Snap25, and Prox1. Pathway analyses indicated that essential pathways in neuronal growth and maturation were activated in cells upon neuronal induction. Furthermore, iNs extended projections toward cochlear hair cells and cochlear nucleus neurons when cultured with each respective tissue. Taken together, our study demonstrates that PAN-like neurons can be generated from endogenous SGNNCs. This work suggests that gene therapy can be a viable strategy to treat sensorineural hearing loss caused by degeneration of PANs.

  12. Direct Reprogramming of Spiral Ganglion Non-neuronal Cells into Neurons: Toward Ameliorating Sensorineural Hearing Loss by Gene Therapy.

    Science.gov (United States)

    Noda, Teppei; Meas, Steven J; Nogami, Jumpei; Amemiya, Yutaka; Uchi, Ryutaro; Ohkawa, Yasuyuki; Nishimura, Koji; Dabdoub, Alain

    2018-01-01

    Primary auditory neurons (PANs) play a critical role in hearing by transmitting sound information from the inner ear to the brain. Their progressive degeneration is associated with excessive noise, disease and aging. The loss of PANs leads to permanent hearing impairment since they are incapable of regenerating. Spiral ganglion non-neuronal cells (SGNNCs), comprised mainly of glia, are resident within the modiolus and continue to survive after PAN loss. These attributes make SGNNCs an excellent target for replacing damaged PANs through cellular reprogramming. We used the neurogenic pioneer transcription factor Ascl1 and the auditory neuron differentiation factor NeuroD1 to reprogram SGNNCs into induced neurons (iNs). The overexpression of both Ascl1 and NeuroD1 in vitro generated iNs at high efficiency. Transcriptome analyses revealed that iNs displayed a transcriptome profile resembling that of endogenous PANs, including expression of several key markers of neuronal identity: Tubb3, Map2, Prph, Snap25, and Prox1. Pathway analyses indicated that essential pathways in neuronal growth and maturation were activated in cells upon neuronal induction. Furthermore, iNs extended projections toward cochlear hair cells and cochlear nucleus neurons when cultured with each respective tissue. Taken together, our study demonstrates that PAN-like neurons can be generated from endogenous SGNNCs. This work suggests that gene therapy can be a viable strategy to treat sensorineural hearing loss caused by degeneration of PANs.

  13. Amygdala TDP-43 Pathology in Frontotemporal Lobar Degeneration and Motor Neuron Disease.

    Science.gov (United States)

    Takeda, Takahiro; Seilhean, Danielle; Le Ber, Isabelle; Millecamps, Stéphanie; Sazdovitch, Véronique; Kitagawa, Kazuo; Uchihara, Toshiki; Duyckaerts, Charles

    2017-09-01

    TDP-43-positive inclusions are present in the amygdala in frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND) including amyotrophic lateral sclerosis. Behavioral abnormalities, one of the chief symptoms of FTLD, could be, at least partly, related to amygdala pathology. We examined TDP-43 inclusions in the amygdala of patients with sporadic FTLD/MND (sFTLD/MND), FTLD/MND with mutation of the C9ORF72 (FTLD/MND-C9) and FTLD with mutation of the progranulin (FTLD-GRN). TDP-43 inclusions were common in each one of these subtypes, which can otherwise be distinguished on topographical and genetic grounds. Conventional and immunological stainings were performed and we quantified the numerical density of inclusions on a regional basis. TDP-43 inclusions in amygdala could be seen in 10 out of 26 sFTLD/MND cases, 5 out of 9 FTLD/MND-C9 cases, and all 4 FTLD-GRN cases. Their numerical density was lower in FTLD/MND-C9 than in sFTLD/MND and FTLD-GRN. TDP-43 inclusions were more numerous in the ventral region of the basolateral nucleus group in all subtypes. This contrast was apparent in sporadic and C9-mutated FTLD/MND, while it was less evident in FTLD-GRN. Such differences in subregional involvement of amygdala may be related to the region-specific neuronal connections that are differentially affected in FTLD/MND and FTLD-GRN. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

  14. [Experimental approach to the gene therapy of motor neuron disease with the use of genes hypoxia-inducible factors].

    Science.gov (United States)

    Ismailov, Sh M; Barykova, Iu A; Shmarov, M M; Tarantul, V Z; Barskov, I V; Kucherianu, V G; Brylev, L V; Logunov, D Iu; Tutykhina, I L; Bocharov, E V; Zakharova, M N; Naroditskiĭ, B S; Illarioshkin, S N

    2014-05-01

    Motor neuron disease (MND), or amyotrophic lateral sclerosis, is a fatal neurodegenerative disorder characterized by a progressive loss of motor neurons in the spinal cord and the brain. Several angiogenic and neurogenic growth factors, such as the vascular endothelial growth factor (VEGF), angiogenin (ANG), insulin-like growth factor (IGF) and others, have been shown to promote survival of the spinal motor neurons during ischemia. We constructed recombinant vectors using human adenovirus 5 (Ad5) carrying the VEGF, ANG or IGF genes under the control of the cytomegalovirus promoter. As a model for MND, we employed a transgenic mice strain, B6SJL-Tg (SOD1*G93A)d11 Gur/J that develops a progressive degeneration of the spinal motor neurons caused by the expression of a mutated Cu/Zn superoxide dismutase gene SOD1. Delivery of the therapeutic genes to the spinal motor neurons was done using the effect of the retrograde axonal transport after multiple injections of the Ad5-VEGF, Ad5-ANG and Ad5-IGF vectors and their combinations into the limbs and back muscles of the SOD1(G93A) mice. Viral transgene expression in the spinal cord motor neurons was confirmed by immunocytochemistry and RT-RCR. We assessed the neurological status, motor activity and lifespan of experimental and control animal groups. We discovered that SOD1(G93A) mice injected with the Ad5-VEGF + Ad5-ANG combination showed a 2-3 week delay in manifestation of the disease, higher motor activity at the advanced stages of the disease, and at least a 10% increase in the lifespan compared to the control and other experimental groups. These results support the safety and therapeutic efficacy of the tested recombinant treatment. We propose that the developed experimental MND treatment based on viral delivery of VEGF + ANG can be used as a basis for gene therapy drug development and testing in the preclinical and clinical trials of the MND.

  15. Clinical profile of motor neuron disease patients with lower urinary tract symptoms and neurogenic bladder.

    Science.gov (United States)

    Vázquez-Costa, Juan Francisco; Arlandis, Salvador; Hervas, David; Martínez-Cuenca, Esther; Cardona, Fernando; Pérez-Tur, Jordi; Broseta, Enrique; Sevilla, Teresa

    2017-07-15

    Lower urinary tract symptoms (LUTS) are frequent in motor neuron disease (MND) patients, but clinical factors related to them are unknown. We describe differences in LUTS among MND phenotypes and their relationship with other clinical characteristics, including prognosis. For this study, we collected clinical data of a previously published cohort of patients diagnosed with classical amyotrophic lateral sclerosis (cALS), progressive muscular atrophy (PMA) or primary lateral sclerosis (PLS) with and without LUTS. Familial history was recorded and the C9ORF72 expansion was analysed in the entire cohort. Patients were followed-up for survival until August 2016. Fifty-five ALS patients (37 cALS, 10 PMA and 8 PLS) were recruited. Twenty-four reported LUTS and neurogenic bladder (NB) could be demonstrated in nine of them. LUTS were not influenced by age, phenotype, disability, cognitive or behavioural impairment, or disease progression, but female sex appeared to be a protective factor (OR=0.39, p=0.06). Neither family history nor the C9ORF72 expansion was linked to LUTS or NB. In the multivariate analysis, patients reporting LUTS early in the disease course tended to show poorer survival. In this study, LUTS appear to be more frequent in male MND patients, but are not related to age, clinical or genetic characteristics. When reported early, LUTS could be a sign of rapid disease spread and poor prognosis. Further prospective longitudinal and neuroimaging studies are warranted to confirm this hypothesis. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Contrasting effects of cerebrospinal fluid from motor neuron disease patients on the survival of primary motor neurons cultured with or without glia.

    Science.gov (United States)

    Barber, Siân C; Wood-Allum, Clare A; Sargsyan, Siranush A; Walsh, Theresa; Cox, Laura E; Monk, Peter N; Shaw, Pamela J

    2011-07-01

    Motor neuronal (MN) degeneration in motor neuron disease (MND) often starts focally before spreading to neighbouring MN populations, suggesting soluble factors may contribute to disease propagation. Whether cerebrospinal fluid (CSF) from MND patients contains such factors has been difficult to prove. We aimed to determine the effect of glia on the response of MNs to CSF from MND patients. Primary rat spinal MNs grown in mono-culture or cocultured with glia were exposed to CSF from patients (MND-CSF) or controls (Con-CSF) and survival measured by cell counting. In mono-culture both MND-CSF and Con-CSF reduced MN survival with MND-CSF reducing MN survival by less than Con-CSF. In coculture MN survival was unchanged by exposure to MND-CSF while exposure to Con-CSF improved MN survival. In separate experiments, murine MNs grown in mono-culture and stressed by growth factor withdrawal were partially rescued by the application of monocyte chemoattractant protein-1 (MCP-1), a trophic factor previously found to be elevated in MND-CSF. Our results suggest that MND-CSF may contain factors harmful to MNs as well as factors protective of MNs, the interplay of which is altered by the presence of glial cells. These preliminary results further emphasize the importance of MN environment to MN health.

  17. Sialorrhoea: How to Manage a Frequent Complication of Motor Neuron Disease

    Directory of Open Access Journals (Sweden)

    Andrea Pellegrini

    2015-08-01

    Full Text Available Sialorrhoea, the unintentional loss of saliva through the mouth, is the frequent complication of neurological disorders affecting strength or coordination of oropharyngeal muscles, such as motor neuron disease/amyotrophic lateral sclerosis (MND/ALS or Parkinson’s disease. Sialorrhoea might affect up to 42% of ALS patients, with almost half of them having poorly managed symptoms. Sialorrhoea can impair patients’ social life, while dermatological complications, such as skin rashes, may arise due to constant exposure to moisture. Moreover, the excess mouth-retained saliva in ALS patients may lead to serious complications, such as choking, which causes anxiety, and aspiration with the consequent pneumonia. The inclusion of a sialorrhoea-related item in the ALS functional rating scale testifies both the incidence and importance of sialorrhoea during the ALS clinical course. Because of the progressive nature of ALS, presence and severity of sialorrhoea should be assessed at every visit and, when present, active treatment pursued. Available treatments include behavioural therapy, i.e. techniques to enhance periodic swallowing of saliva, systemic or local anticholinergic medications, botulinum toxin injection, electron beam irradiation, and surgical techniques. This review paper briefly describes the available options with related side-effects and current guideline recommendations for managing sialorrhoea in ALS patients.

  18. [Effect of Shouwu Shudi Yin on dopaminegic neurons in MPTP induced Parkinson's disease mouse model].

    Science.gov (United States)

    Tunje, Reginachizi; Ye, Yang-Lie; Sonauddin, Ahmed; Hansraj, Bhugun; Ngawang, Sangye; Shivani, Sharma; Zhang, Xiong; Zhu, Jian-Hong; Liu, Rong-Pei

    2016-09-01

    In order to investigate the effect of Shouwu Shudi Yin on dopaminegic neurons in MPTP induced Parkinson's disease mouse model and the possible mechamism, the experimental mice were randomly divided into 4 groups: control, Shouwu Shudi Yin, MPTP and the treatment (MPTP+Shouwu Shudi Yin) groups. The number of tyrosine hydroxylase (TH) positive cells in the substantia nigra was measured by immunohistochemistry, and mRNA expression of TH and glutathione peroxidase (GPX) were detected by PCR. The results showed that the number of TH positive cells and mRNA expression of TH were significantly reduced in MPTP group compared with the control (PYin didn't show protective effect. Compared to MPTP group, the mRNA expression of four subtypes of GPX were increased in various degrees in the treatment group pretreated with Shouwu Shudi Yin, although the difference was not statistically significant. These indicated that the preventive medication of Shouwu Shudi Yin don't have protective effect on the mice with Parkinson' s disease induced by MPTP, but it may enhance the antioxidant capacity through increasing the expression of GPX. Copyright© by the Chinese Pharmaceutical Association.

  19. The preferred priorities for care document in motor neurone disease: views of bereaved relatives and carers.

    Science.gov (United States)

    Preston, Harriet; Fineberg, Iris Cohen; Callagher, Pauline; Mitchell, Douglas J

    2012-03-01

    Increasing emphasis is being placed on the need for advanced care planning (ACP) at the end of life. The Preferred Priorities for Care (PPC) document is a patient-held record promoted by the End of Life Care Strategy as an ACP tool to promote discussion and communication amongst patients, family and health care providers. However, little research exists into evaluating its effectiveness or exploring patient and carer views, particularly in non-malignant disease. Because the majority of patients with Motor Neurone Disease (MND) lose verbal communication, early discussion of patients' wishes and preferences, a central aspect of ACP, is vital. This study examined MND patients' bereaved relatives' experiences of using the PPC document and their perceptions about its impact on end-of-life care using qualitative methods. Key findings adding to existing literature were that the PPC document was felt to have little impact on end-of-life care amongst this patient group and that there was a perceived lack of awareness of the document amongst health care professionals (HCPs), in particular hospital staff. This was felt to limit the effectiveness of the document. This has obvious implications for practice, looking at awareness amongst HCPs and ways to improve this situation, particularly in light of the current pressures to meet patient preferences at the end of life.

  20. Dying with motor neurone disease, what can we learn from family caregivers?

    Science.gov (United States)

    Ray, Robin A; Brown, Janice; Street, Annette F

    2014-08-01

    Increasingly, people with neurodegenerative illness are cared for at home until close to death. Yet, discussing the reality of dying remains a social taboo. To examine the ways, family caregivers of people living with motor neurone disease (MND) experienced the dying of their relative and to identify how health practitioners can better prepare families for end-of-life care. Secondary analysis was undertaken on data sets generated from two longitudinal qualitative studies employing similar data collection and analysis methods. Combining data sets increased participant numbers in a low incidence disease group. Primary studies were undertaken with family caregivers in England and Australia. Interview and observational data were collected mostly in home. Participants who discussed dying and death formed the sample for secondary analysis. Combined data revealed four major themes: planning for end of life, unexpected dying, dignity in the dying body and positive end to MND. Despite short survival predictions, discussions among family members about dying were often sporadic and linked to loss of hope. Effective planning for death assisted caregivers to manage the final degenerative processes of dying. When plans were not effectively communicated or enacted, capacity to preserve personhood was reduced. Returning death and dying to social discourse will raise the level of community awareness and normalize conversations about end-of-life care. Strategies for on-going, effective communication that facilitates advance care planning among patients, their families and practitioners are essential to improve dying and death for people with MND and their family caregivers. © 2012 John Wiley & Sons Ltd.

  1. Comparison of a Mirror Neuron System among Elders with Mild Cognitive Impairment, Alzheimer's Disease, and No Disease

    International Nuclear Information System (INIS)

    Rattanachayoto, P.; Tritanon, O.; Laothamatas, J.; Sungkarat, W.

    2012-01-01

    Alzheimer's disease (AD) is the most common cause of dementia. There are lots of old people suffering from the disease. Mild cognitive impairment (MCI) is a transitional state between normal aging and dementia. An individual with MCI has an increased risk of developing AD. The mirror neuron system (MNS), activated during the observation and execution of actions, has been linked with cognitive processes.The objective of this study is to examine the MNS abnormalities in elders with MCI and AD. Ninety-two subjects (5 MCI,7 mild AD, and 80 cognitively normal) were studied by using functional magnetic resonance imaging (fMRI). In the fMRI experiment, subjects were asked to observe a video showing hand movement (tearing a piece of paper) and a control condition (observing a fixation point).The image data were analyzed using SPM2 (Statistical Parametric Mapping).There were significant activations of bilateral inferior frontal lobule and inferior parietal lobule due to the observation of hand movement.The brain activations of the normal group were statistical significant greater than those in the MCI and mild AD groups.There was no significant difference between the MCI and mild AD groups. Elders with MCI and mild AD had fewer MNS activations than the normal controls, suggesting that the dysfunction of MNS may underlie cognitive impairments in MCI and AD patients.These findings imply that fMRI is sufficiently sensitive to detect MNS changes occurring in MCI and AD.

  2. Electromagnetized gold nanoparticles mediate direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson's disease therapy

    Science.gov (United States)

    Yoo, Junsang; Lee, Euiyeon; Kim, Hee Young; Youn, Dong-Ho; Jung, Junghyun; Kim, Hongwon; Chang, Yujung; Lee, Wonwoong; Shin, Jaein; Baek, Soonbong; Jang, Wonhee; Jun, Won; Kim, Soochan; Hong, Jongki; Park, Hi-Joon; Lengner, Christopher J.; Moh, Sang Hyun; Kwon, Youngeun; Kim, Jongpil

    2017-10-01

    Electromagnetic fields (EMF) are physical energy fields generated by electrically charged objects, and specific ranges of EMF can influence numerous biological processes, which include the control of cell fate and plasticity. In this study, we show that electromagnetized gold nanoparticles (AuNPs) in the presence of specific EMF conditions facilitate an efficient direct lineage reprogramming to induced dopamine neurons in vitro and in vivo. Remarkably, electromagnetic stimulation leads to a specific activation of the histone acetyltransferase Brd2, which results in histone H3K27 acetylation and a robust activation of neuron-specific genes. In vivo dopaminergic neuron reprogramming by EMF stimulation of AuNPs efficiently and non-invasively alleviated symptoms in mouse Parkinson's disease models. This study provides a proof of principle for EMF-based in vivo lineage conversion as a potentially viable and safe therapeutic strategy for the treatment of neurodegenerative disorders.

  3. Spontaneous activity in electromyography may differentiate certain benign lower motor neuron disease forms from amyotrophic lateral sclerosis.

    Science.gov (United States)

    Jokela, Manu E; Jääskeläinen, Satu K; Sandell, Satu; Palmio, Johanna; Penttilä, Sini; Saukkonen, Annamaija; Soikkeli, Raija; Udd, Bjarne

    2015-08-15

    There is limited data on electromyography (EMG) findings in other motor neuron disorders than amyotrophic lateral sclerosis (ALS). We assessed whether the distribution of active denervation detected by EMG, i.e. fibrillations and fasciculations, differs between ALS and slowly progressive motor neuron disorders. We compared the initial EMG findings of 43 clinically confirmed, consecutive ALS patients with those of 41 genetically confirmed Late-onset Spinal Motor Neuronopathy and 14 Spinal and Bulbar Muscular Atrophy patients. Spontaneous activity was more frequently detected in the first dorsal interosseus and deltoid muscles of ALS patients than in patients with the slowly progressive motor neuron diseases. The most important observation was that absent fibrillations in the first dorsal interosseus muscle identified the benign forms with sensitivities of 66%-77% and a specificity of 93%. The distribution of active denervation may help to separate ALS from mimicking disorders at an early stage. Copyright © 2015 Elsevier B.V. All rights reserved.

  4. Intracellular accumulation of amyloid-beta - a predictor for synaptic dysfunction and neuron loss in Alzheimer's disease

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    Thomas A Bayer

    2010-03-01

    Full Text Available Despite of long-standing evidence that beta-amyloid (Aβ peptides have detrimental effects on synaptic function, the relationship between Aβ, synaptic and neuron loss is largely unclear. During the last years there is growing evidence that early intraneuronal accumulation of Aβ peptides is one of the key events leading to synaptic and neuronal dysfunction. Many studies have been carried out using transgenic mouse models of Alzheimer’s disease (AD which have been proven to be valuable model system in modern AD research. The present review discusses the impact of intraneuronal Aβ accumulation on synaptic impairment and neuron loss and provides an overview of currently available AD mouse models showing these pathological alterations.

  5. The Mirror Neurons Network in Aging, Mild Cognitive Impairment, and Alzheimer Disease: A functional MRI Study.

    Science.gov (United States)

    Farina, Elisabetta; Baglio, Francesca; Pomati, Simone; D'Amico, Alessandra; Campini, Isabella C; Di Tella, Sonia; Belloni, Giulia; Pozzo, Thierry

    2017-01-01

    The aim of the current study is to investigate the integrity of the Mirror Neurons (MN) network in normal aging, Mild Cognitive Impairment (MCI), and Alzheimer disease (AD). Although AD and MCI are considered "cognitive" diseases, there has been increasing recognition of a link between motor function and AD. More recently the embodied cognition hypothesis has also been developed: it postulates that a part of cognition results from the coupling between action and perception representations. MN represent a neuronal population which links perception, action, and cognition, therefore we decided to characterize MN functioning in neurodegenerative cognitive decline. Three matched groups of 16 subjects (normal elderly-NE, amnesic MCI with hippocampal atrophy and AD) were evaluated with a focused neuropsychological battery and an fMRI task specifically created to test MN: that comprised of an observation run, where subjects were shown movies of a right hand grasping different objects, and of a motor run, where subjects observed visual pictures of objects oriented to be grasped with the right hand. In NE subjects, the conjunction analysis (comparing fMRI activation during observation and execution), showed the activation of a bilateral fronto-parietal network in "classical" MN areas, and of the superior temporal gyrus (STG). The MCI group showed the activation of areas belonging to the same network, however, parietal areas were activated to a lesser extent and the STG was not activated, while the opposite was true for the right Broca's area. We did not observe any activation of the fronto-parietal network in AD participants. They did not perform as well as the NE subjects in all the neuropsychological tests (including tests of functions attributed to MN) whereas the MCI subjects were significantly different from the NE subjects only in episodic memory and semantic fluency. Here we show that the MN network is largely preserved in aging, while it appears involved following an

  6. The Mirror Neurons Network in Aging, Mild Cognitive Impairment, and Alzheimer Disease: A functional MRI Study

    Directory of Open Access Journals (Sweden)

    Elisabetta Farina

    2017-11-01

    Full Text Available The aim of the current study is to investigate the integrity of the Mirror Neurons (MN network in normal aging, Mild Cognitive Impairment (MCI, and Alzheimer disease (AD. Although AD and MCI are considered “cognitive” diseases, there has been increasing recognition of a link between motor function and AD. More recently the embodied cognition hypothesis has also been developed: it postulates that a part of cognition results from the coupling between action and perception representations. MN represent a neuronal population which links perception, action, and cognition, therefore we decided to characterize MN functioning in neurodegenerative cognitive decline. Three matched groups of 16 subjects (normal elderly-NE, amnesic MCI with hippocampal atrophy and AD were evaluated with a focused neuropsychological battery and an fMRI task specifically created to test MN: that comprised of an observation run, where subjects were shown movies of a right hand grasping different objects, and of a motor run, where subjects observed visual pictures of objects oriented to be grasped with the right hand. In NE subjects, the conjunction analysis (comparing fMRI activation during observation and execution, showed the activation of a bilateral fronto-parietal network in “classical” MN areas, and of the superior temporal gyrus (STG. The MCI group showed the activation of areas belonging to the same network, however, parietal areas were activated to a lesser extent and the STG was not activated, while the opposite was true for the right Broca's area. We did not observe any activation of the fronto-parietal network in AD participants. They did not perform as well as the NE subjects in all the neuropsychological tests (including tests of functions attributed to MN whereas the MCI subjects were significantly different from the NE subjects only in episodic memory and semantic fluency. Here we show that the MN network is largely preserved in aging, while it appears

  7. Globular Glial Mixed Four Repeat Tau and TDP-43 Proteinopathy with Motor Neuron Disease and Frontotemporal Dementia.

    Science.gov (United States)

    Takeuchi, Ryoko; Toyoshima, Yasuko; Tada, Mari; Tanaka, Hidetomo; Shimizu, Hiroshi; Shiga, Atsushi; Miura, Takeshi; Aoki, Kenju; Aikawa, Akane; Ishizawa, Shin; Ikeuchi, Takeshi; Nishizawa, Masatoyo; Kakita, Akiyoshi; Takahashi, Hitoshi

    2016-01-01

    Amyotrophic lateral sclerosis (ALS) may be accompanied by frontotemporal dementia (FTD). We report a case of glial mixed tau and TDP-43 proteinopathies in a Japanese patient diagnosed clinically as having ALS-D. Autopsy revealed loss of lower motor neurons and degeneration of the pyramidal tracts in the spinal cord and brain stem. The brain showed frontotemporal lobar degeneration (FTLD), the most severe neuronal loss and gliosis being evident in the precentral gyrus. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. AT8 immunostaining revealed that predominant occurrence of astrocytic tau lesions termed globular astrocytic inclusions (GAIs) was a feature of the affected regions. These GAIs were Gallyas-Braak negative. Neuronal and oligodendrocytic tau lesions were comparatively scarce. pS409/410 immunostaining also revealed similar neuronal and glial TDP-43 lesions. Interestingly, occasional co-localization of tau and TDP-43 was evident in the GAIs. Immunoblot analyses revealed band patterns characteristic of a 4-repeat (4R) tauopathy, corticobasal degeneration and a TDP-43 proteinopathy, ALS/FTLD-TDP Type B. No mutations were found in the MAPT or TDP-43 genes. We consider that this patient harbored a distinct, sporadic globular glial mixed 4R tau and TDP-43 proteinopathy associated with motor neuron disease and FTD. © 2015 International Society of Neuropathology.

  8. Mitophagy Failure in Fibroblasts and iPSC-Derived Neurons of Alzheimer’s Disease-Associated Presenilin 1 Mutation

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    Patricia Martín-Maestro

    2017-09-01

    Full Text Available Familial Alzheimer’s disease (FAD is clearly related with the accumulation of amyloid-beta (Aβ and its deleterious effect on mitochondrial function is well established. Anomalies in autophagy have also been described in these patients. In the present work, functional analyses have been performed to study mitochondrial recycling process in patient-derived fibroblasts and neurons from induced pluripotent stem cells harboring the presenilin 1 mutation A246E. Mitophagy impairment was observed due to a diminished autophagy degradation phase associated with lysosomal anomalies, thus causing the accumulation of dysfunctional mitochondria labeled by Parkin RBR E3 ubiquitin protein ligase (PARK2. The failure of mitochondrial recycling by autophagy was enhanced in the patient-derived neuronal model. Our previous studies have demonstrated similar mitophagy impairment in sporadic Alzheimer’s disease (AD; therefore, our data indicate that mitophagy deficiency should be considered a common nexus between familial and sporadic cases of the disease.

  9. The Importance of Non-neuronal Cell Types in hiPSC-Based Disease Modeling and Drug Screening

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    David M. Gonzalez

    2017-12-01

    Full Text Available Current applications of human induced pluripotent stem cell (hiPSC technologies in patient-specific models of neurodegenerative and neuropsychiatric disorders tend to focus on neuronal phenotypes. Here, we review recent efforts toward advancing hiPSCs toward non-neuronal cell types of the central nervous system (CNS and highlight their potential use for the development of more complex in vitro models of neurodevelopment and disease. We present evidence from previous works in both rodents and humans of the importance of these cell types (oligodendrocytes, microglia, astrocytes in neurological disease and highlight new hiPSC-based models that have sought to explore these relationships in vitro. Lastly, we summarize efforts toward conducting high-throughput screening experiments with hiPSCs and propose methods by which new screening platforms could be designed to better capture complex relationships between neural cell populations in health and disease.

  10. iPSC-derived Insights into Motor Neuron Disease and Inflammatory Neuropathies

    NARCIS (Netherlands)

    Härschnitz, O.

    2017-01-01

    The proper function of the motor circuit is essential for normal interaction as a human being with external cues. While the motor circuit consists of a variety of cell types, one of its core components is the motor neuron itself. Dysfunction of motor neurons is a hallmark of many neuromuscular

  11. A systematic review and meta-analysis of the funtional MRI investigation of motor neuron disease

    Directory of Open Access Journals (Sweden)

    Dongchao eShen

    2015-11-01

    Full Text Available Background: To assess the use of functional magnetic resonance imaging (fMRI in motor neuron disease (MND, a systematic review and voxelwise meta-analysis of studies comparing brain activity in patients with MND and in healthy controls (HCs was conducted to identify common findings across studies.Methods: A search for related papers published in English and Chinese was performed in Ovid Medline, Pubmed and Embase database. Voxelwise meta-analysis was performed using signed differential mapping.Results: The findings from 55 fMRI studies on MND were tabulated, and some common findings were discussed in further details. Conclusions: These findings are preliminary, sometimes even contradictory, and do not allow a complete understanding of the functional alterations in MND. However, we documented reliable findings that MND is not confined to the motor system, but is a multisystem disorder involving extra-motor cortex areas, causing cognitive dysfunction and deficits in socioemotional and sensory processing pathways.

  12. Human striatal recordings reveal abnormal discharge of projection neurons in Parkinson's disease.

    Science.gov (United States)

    Singh, Arun; Mewes, Klaus; Gross, Robert E; DeLong, Mahlon R; Obeso, José A; Papa, Stella M

    2016-08-23

    Circuitry models of Parkinson's disease (PD) are based on striatal dopamine loss and aberrant striatal inputs into the basal ganglia network. However, extrastriatal mechanisms have increasingly been the focus of attention, whereas the status of striatal discharges in the parkinsonian human brain remains conjectural. We now report the activity pattern of striatal projection neurons (SPNs) in patients with PD undergoing deep brain stimulation surgery, compared with patients with essential tremor (ET) and isolated dystonia (ID). The SPN activity in ET was very low (2.1 ± 0.1 Hz) and reminiscent of that found in normal animals. In contrast, SPNs in PD fired at much higher frequency (30.2 ± 1.2 Hz) and with abundant spike bursts. The difference between PD and ET was reproduced between 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated and normal nonhuman primates. The SPN activity was also increased in ID, but to a lower level compared with the hyperactivity observed in PD. These results provide direct evidence that the striatum contributes significantly altered signals to the network in patients with PD.

  13. Mutation of RET proto-oncogene in Hirschsprung’s disease and intestinal neuronal dysplasia

    Science.gov (United States)

    Tou, Jin-Fa; Li, Min-Ju; Guan, Tao; Li, Ji-Cheng; Zhu, Xiong-Kai; Feng, Zhi-Gang

    2006-01-01

    AIM: To investigate the genetic relationship between Hirschsprung’s disease (HD) and intestinal neuronal dysplasia (IND) in Chinese population. METHODS: Peripheral blood samples were obtained from 30 HD patients, 20 IND patients, 18 HD/IND combined patients and 20 normal individuals as control. Genomic DNA was extracted according to standard procedure. Exons 11,13,15,17 of RET proto-oncogene were amplified by polymerase chain reaction (PCR). The mutations of RET proto-oncogene were analyzed by single strand conformational polymorphism (SSCP) and sequencing of the positive amplified products was performed. RESULTS: Eight germline sequence variants were detected. In HD patients, 2 missense mutations in exon 11 at nucleotide 15165 G→A (G667S), 2 frameshift mutations in exon 13 at nucleotide 18974 (18974insG), 1 missense mutation in exon 13 at nucleotide 18919 A→G (K756E) and 1 silent mutation in exon 15 at nucleotide 20692 G→A(Q916Q) were detected. In HD/IND combined patients, 1 missense mutation in exon 11 at nucleotide 15165 G→A and 1 silent mutation in exon 13 at nucleotide 18888 T→G (L745L) were detected. No mutation was found in IND patients and controls. CONCLUSION: Mutation of RET proto-oncogene is involved in the etiopathogenesis of HD. The frequency of RET proto-oncogene mutation is quite different between IND and HD in Chinese population. IND is a distinct clinical entity genetically different from HD. PMID:16534860

  14. Touching moments: phenomenological sociology and the haptic dimension in the lived experience of motor neurone disease.

    Science.gov (United States)

    Allen-Collinson, Jacquelyn; Pavey, Amanda

    2014-07-01

    Currently, there is a relative research lacuna in phenomenological research into the lived experience of motor neurone disease. Based on a sociological research project in the UK, involving 42 participants diagnosed with MND, this article explores the potential of a phenomenological sociology for analysing experiences of this drastically life-limiting neurological disorder. Calls have been made for sociological researchers to analyse more fully and deeply the sensory dimension of the lived body, and this article also contributes to this newly developing body of literature. While the social sciences have been accused of a high degree of ocularcentrism, here we take forward the literature by specifically focusing upon the haptic dimension, given that touch - and particularly the loss of key elements of the haptic dimension- emerged as salient in MND patients' accounts. To illustrate the potential of our phenomenologically inspired theoretical perspective, we consider two specific haptic themes: (i) being out of touch: the loss of certain forms of touch within MND and (ii) unwelcome touch by medical staff. © 2013 The Authors. Sociology of Health & Illness © 2013 Foundation for the Sociology of Health & Illness/John Wiley & Sons Ltd.

  15. Protective Effect of Antioxidants on Neuronal Dysfunction and Plasticity in Huntington’s Disease

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    Thirunavukkarasu Velusamy

    2017-01-01

    Full Text Available Huntington’s disease (HD is characterised by movement disorders, cognitive impairments, and psychiatric problems. The abnormal generation of reactive oxygen species and the resulting oxidative stress-induced mitochondrial damage in neurons upon CAG mutations in the HTT gene have been hypothesized as the contributing factors of neurodegeneration in HD. The potential use of antioxidants against free radical toxicity has been an emerging field in the management of ageing and many neurodegenerative disorders. Neural stem cells derived adult neurogenesis represents the regenerative capacity of the adult brain. The process of adult neurogenesis has been implicated in the cognitive functions of the brain and is highly modulated positively by different factors including antioxidants. The supportive role of antioxidants to reduce the severity of HD via promoting the functional neurogenesis and neuroprotection in the pathological adult brain has great promise. This review comprehends the recent studies describing the therapeutic roles of antioxidants in HD and other neurologic disorders and highlights the scope of using antioxidants to promote adult neurogenesis in HD. It also advocates a new line of research to delineate the mechanisms by which antioxidants promote adult neurogenesis in HD.

  16. Body elimination attitude family resemblance in Kuwait.

    Science.gov (United States)

    Al-Fayez, Ghenaim; Awadalla, Abdelwahid; Arikawa, Hiroko; Templer, Donald I; Hutton, Shane

    2009-12-01

    The purpose of the present study was to determine the family resemblance of attitude toward body elimination in Kuwaiti participants. This study was conceptualized in the context of the theories of moral development, importance of cleanliness in the Muslim religion, cross-cultural differences in personal hygiene practices, previous research reporting an association between family attitudes and body elimination attitude, and health implications. The 24-item Likert-type format Body Elimination Attitude Scale-Revised was administered to 277 Kuwaiti high school students and 437 of their parents. Females scored higher, indicating greater disgust, than the males. Moreover, sons' body elimination attitude correlated more strongly with fathers' attitude (r = .85) than with that of the mothers (r = .64). Daughters' attitude was similarly associated with the fathers' (r = .89) and the mothers' attitude (r = .86). The high correlations were discussed within the context of Kuwait having a collectivistic culture with authoritarian parenting style. The higher adolescent correlations, and in particular the boys' correlation with fathers than with mothers, was explained in terms of the more dominant role of the Muslim father in the family. Public health and future research implications were suggested. A theoretical formulation was advanced in which "ideal" body elimination attitude is relative rather than absolute, and is a function of one's life circumstances, one's occupation, one's culture and subculture, and the society that one lives in.

  17. Role of Serotonin Neurons in L-DOPA- and Graft-Induced Dyskinesia in a Rat Model of Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Eunju Shin

    2012-01-01

    Full Text Available L-DOPA, the most effective drug to treat motor symptoms of Parkinson's disease, causes abnormal involuntary movements, limiting its use in advanced stages of the disease. An increasing body of evidence points to the serotonin system as a key player in the appearance of L-DOPA-induced dyskinesia (LID. In fact, exogenously administered L-DOPA can be taken up by serotonin neurons, converted to dopamine and released as a false transmitter, contributing to pulsatile stimulation of striatal dopamine receptors. Accordingly, destruction of serotonin fibers or silencing serotonin neurons by serotonin agonists could counteract LID in animal models. Recent clinical work has also shown that serotonin neurons are present in the caudate/putamen of patients grafted with embryonic ventral mesencephalic cells, producing intense serotonin hyperinnervation. These patients experience graft-induced dyskinesia (GID, a type of dyskinesia phenotypically similar to the one induced by L-DOPA but independent from its administration. Interestingly, the 5-HT1A receptor agonist buspirone has been shown to suppress GID in these patients, suggesting that serotonin neurons might be involved in the etiology of GID as for LID. In this paper we will discuss the experimental and clinical evidence supporting the involvement of the serotonin system in both LID and GID.

  18. iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease.

    Directory of Open Access Journals (Sweden)

    Charles Arber

    Full Text Available Mutations in PANK2 lead to neurodegeneration with brain iron accumulation. PANK2 has a role in the biosynthesis of coenzyme A (CoA from dietary vitamin B5, but the neuropathological mechanism and reasons for iron accumulation remain unknown. In this study, atypical patient-derived fibroblasts were reprogrammed into induced pluripotent stem cells (iPSCs and subsequently differentiated into cortical neuronal cells for studying disease mechanisms in human neurons. We observed no changes in PANK2 expression between control and patient cells, but a reduction in protein levels was apparent in patient cells. CoA homeostasis and cellular iron handling were normal, mitochondrial function was affected; displaying activated NADH-related and inhibited FADH-related respiration, resulting in increased mitochondrial membrane potential. This led to increased reactive oxygen species generation and lipid peroxidation in patient-derived neurons. These data suggest that mitochondrial deficiency is an early feature of the disease process and can be explained by altered NADH/FADH substrate supply to oxidative phosphorylation. Intriguingly, iron chelation appeared to exacerbate the mitochondrial phenotype in both control and patient neuronal cells. This raises caution for the use iron chelation therapy in general when iron accumulation is absent.

  19. Microglial AGE-albumin is critical for neuronal death in Parkinson's disease: a possible implication for theranostics.

    Science.gov (United States)

    Bayarsaikhan, Enkhjargal; Bayarsaikhan, Delger; Lee, Jaesuk; Son, Myeongjoo; Oh, Seyeon; Moon, Jeongsik; Park, Hye-Jeong; Roshini, Arivazhagan; Kim, Seung U; Song, Byoung-Joon; Jo, Seung-Mook; Byun, Kyunghee; Lee, Bonghee

    2015-01-01

    Advanced glycation end products (AGEs) are known to play an important role in the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD), by inducing protein aggregation and cross-link, formation of Lewy body, and neuronal death. In this study, we observed that AGE-albumin, the most abundant AGE product in the human PD brain, is synthesized in activated microglial cells and accumulates in the extracellular space. AGE-albumin synthesis in human-activated microglial cells is distinctly inhibited by ascorbic acid and cytochalasin treatment. Accumulated AGE-albumin upregulates the receptor to AGE, leading to apoptosis of human primary dopamine (DA) neurons. In animal experiments, we observed reduced DA neuronal cell death by treatment with soluble receptor to AGE. Our study provides evidence that activated microglial cells are one of the main contributors in AGE-albumin accumulation, deleterious to DA neurons in human and animal PD brains. Finally, activated microglial AGE-albumin could be used as a diagnostic and therapeutic biomarker with high sensitivity for neurodegenerative disorders, including PD.

  20. The influence of phospho-tau on dendritic spines of cortical pyramidal neurons in patients with Alzheimer’s disease

    Science.gov (United States)

    Merino-Serrais, Paula; Benavides-Piccione, Ruth; Blazquez-Llorca, Lidia; Kastanauskaite, Asta; Rábano, Alberto; Avila, Jesús

    2013-01-01

    The dendritic spines on pyramidal cells represent the main postsynaptic elements of cortical excitatory synapses and they are fundamental structures in memory, learning and cognition. In the present study, we used intracellular injections of Lucifer yellow in fixed tissue to analyse over 19 500 dendritic spines that were completely reconstructed in three dimensions along the length of the basal dendrites of pyramidal neurons in the parahippocampal cortex and CA1 of patients with Alzheimer’s disease. Following intracellular injection, sections were immunostained for anti-Lucifer yellow and with tau monoclonal antibodies AT8 and PHF-1, which recognize tau phosphorylated at Ser202/Thr205 and at Ser396/404, respectively. We observed that the diffuse accumulation of phospho-tau in a putative pre-tangle state did not induce changes in the dendrites of pyramidal neurons, whereas the presence of tau aggregates forming intraneuronal neurofibrillary tangles was associated with progressive alteration of dendritic spines (loss of dendritic spines and changes in their morphology) and dendrite atrophy, depending on the degree of tangle development. Thus, the presence of phospho-tau in neurons does not necessarily mean that they suffer severe and irreversible effects as thought previously but rather, the characteristic cognitive impairment in Alzheimer’s disease is likely to depend on the relative number of neurons that have well developed tangles. PMID:23715095

  1. Prion-like propagation of mutant SOD1 misfolding and motor neuron disease spread along neuroanatomical pathways.

    Science.gov (United States)

    Ayers, Jacob I; Fromholt, Susan E; O'Neal, Veronica M; Diamond, Jeffrey H; Borchelt, David R

    2016-01-01

    A hallmark feature of amyotrophic lateral sclerosis (ALS) is that symptoms appear to spread along neuroanatomical pathways to engulf the motor nervous system, suggesting a propagative toxic entity could be involved in disease pathogenesis. Evidence for such a propagative entity emerged recently in studies using mice that express G85R-SOD1 mutant protein fused to YFP (G85R-SOD1:YFP). Heterozygous G85R-SOD1:YFP transgenic mice do not develop ALS symptoms out to 20 months of age. However, when newborns are injected with spinal homogenates from paralyzed mutant SOD1 mice, the G85R-SOD1:YFP mice develop paralysis as early as 6 months of age. We now demonstrate that injecting spinal homogenates from paralyzed mutant SOD1 mice into the sciatic nerves of adult G85R-SOD1:YFP mice produces a spreading motor neuron disease within 3.0 ± 0.2 months of injection. The formation of G85R-SOD1:YFP inclusion pathology spreads slowly in this model system; first appearing in the ipsilateral DRG, then lumbar spinal cord, before spreading rostrally up to the cervical cord by the time mice develop paralysis. Reactive astrogliosis mirrors the spread of inclusion pathology and motor neuron loss is most severe in lumbar cord. G85R-SOD1:YFP inclusion pathology quickly spreads to discrete neurons in the brainstem and midbrain that are synaptically connected to spinal neurons, suggesting a trans-synaptic propagation of misfolded protein. Taken together, the data presented here describe the first animal model that recapitulates the spreading phenotype observed in patients with ALS, and implicates the propagation of misfolded protein as a potential mechanism for the spreading of motor neuron disease.

  2. Successful function of autologous iPSC-derived dopamine neurons following transplantation in a non-human primate model of Parkinson's disease

    DEFF Research Database (Denmark)

    Hallett, Penelope J; Deleidi, Michela; Astradsson, Arnar

    2015-01-01

    Autologous transplantation of patient-specific induced pluripotent stem cell (iPSC)-derived neurons is a potential clinical approach for treatment of neurological disease. Preclinical demonstration of long-term efficacy, feasibility, and safety of iPSC-derived dopamine neurons in non-human primat...... neurons and extensive outgrowth into the transplanted putamen. Our proof of concept findings support further development of autologous iPSC-derived cell transplantation for treatment of PD....

  3. On the resemblance of synapse formation and CNS myelination.

    Science.gov (United States)

    Almeida, R G; Lyons, D A

    2014-09-12

    The myelination of axons in the central nervous system (CNS) is essential for nervous system formation, function and health. CNS myelination continues well into adulthood, but not all axons become myelinated. Unlike the peripheral nervous system, where we know of numerous axon-glial signals required for myelination, we have a poor understanding of the nature or identity of such molecules that regulate which axons are myelinated in the CNS. Recent studies have started to elucidate cell behavior during myelination in vivo and indicate that the choice of which axons are myelinated is made prior to myelin sheath generation. Here we propose that interactions between axons and the exploratory processes of oligodendrocyte precursor cells (OPCs) lead to myelination and may be similar to those between dendrites and axons that prefigure and lead to synapse formation. Indeed axons and OPCs form synapses with striking resemblance to those of neurons, suggesting a similar mode of formation. We discuss families of molecules with specific functions at different stages of synapse formation and address studies that implicate the same factors during axon-OPC synapse formation and myelination. We also address the possibility that the function of such synapses might directly regulate the myelinating behavior of oligodendrocyte processes in vivo. In the future it may be of benefit to consider these similarities when taking a candidate-based approach to dissect mechanisms of CNS myelination. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Neurogenesis in Aplysia californica resembles nervous system formation in vertebrates

    International Nuclear Information System (INIS)

    Jacob, M.H.

    1984-01-01

    The pattern of neurogenesis of the central nervous system of Aplysia californica was investigated by [ 3 H]thymidine autoradiography. Large numbers of animals at a series of early developmental stages were labeled with [ 3 H]thymidine for 24 or 48 hr and were subsequently sampled at specific intervals throughout the life cycle. I found that proliferative zones, consisting of columnar and placodal ectodermal cells, are established in regions of the body wall adjacent to underlying mesodermal cells. Mitosis in the proliferative zones generates a population of cells which leave the surface and migrate inward to join the nearby forming ganglia. Tracing specific [ 3 H]thymidine-labeled cells from the body wall to a particular ganglion and within the ganglion over time suggests that the final genomic replication of the neuronal precursors occurs before the cells join the ganglion while glial cell precursors and differentiating glial cells continue to divide within the ganglion for some time. Ultrastructural examination of the morphological features of the few mitosing cells observed within the Aplysia central nervous system supports this interpretation. The pattern of neurogenesis in the Aplysia central nervous system resembles the proliferation of cells in the neural tube and the migration of neural crest and ectodermal placode cells in the vertebrate nervous system but differs from the pattern described for other invertebrates

  5. Antibody transfection into neurons as a tool to study disease pathogenesis.

    Science.gov (United States)

    Douglas, Joshua N; Gardner, Lidia A; Lee, Sangmin; Shin, Yoojin; Groover, Chassidy J; Levin, Michael C

    2012-09-26

    Antibodies provide the ability to gain novel insight into various events taking place in living systems. The ability to produce highly specific antibodies to target proteins has allowed for very precise biological questions to be addressed. Importantly, antibodies have been implicated in the pathogenesis of a number of human diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), paraneoplastic syndromes, multiple sclerosis (MS) and human T-lymphotropic virus type 1 (HTLV-1) associated myelopathy/tropical spastic paraparesis (HAM/TSP). How antibodies cause disease is an area of ongoing investigation, and data suggests that interactions between antibodies and various intracellular molecules results in inflammation, altered cellular messaging, and apoptosis. It has been shown that patients with MS and HAM/TSP produce autoantibodies to the intracellular RNA binding protein heterogeneous ribonuclear protein A1 (hnRNP A1). Recent data indicate that antibodies to both intra-neuronal and surface antigens are pathogenic. Thus, a procedure that allows for the study of intracellular antibody:protein interactions would lend great insight into disease pathogenesis. Genes are commonly transfected into primary cells and cell lines in culture, however transfection of antibodies into cells has been hindered by alteration of antibody structure or poor transfection efficiency. Other methods of transfection include antibody transfection based on cationic liposomes (consisting of DOTAP/DOPE) and polyethylenimines (PEI); both of which resulted in a ten-fold decrease in antibody transfection compared to controls. The method performed in our study is similar to cationic lipid-mediated methods and uses a lipid-based mechanism to form non-covalent complexes with the antibodies through electrostatic and hydrophobic interactions. We utilized Ab-DeliverIN reagent, which is a lipid formulation capable of capturing antibodies through non-covalent electrostatic and

  6. Genetic background effects on disease onset and lifespan of the mutant dynactin p150Glued mouse model of motor neuron disease.

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    Heiman-Patterson, Terry D; Blankenhorn, Elizabeth P; Sher, Roger B; Jiang, Juliann; Welsh, Priscilla; Dixon, Meredith C; Jeffrey, Jeremy I; Wong, Philip; Cox, Gregory A; Alexander, Guillermo M

    2015-01-01

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease primarily affecting motor neurons in the central nervous system. Although most cases of ALS are sporadic, about 5-10% of cases are familial (FALS) with approximately 20% of FALS caused by mutations in the Cu/Zn superoxide dismutase (SOD1) gene. We have reported that hSOD1-G93A transgenic mice modeling this disease show a more severe phenotype when the transgene is bred on a pure SJL background and a milder phenotype when bred on a pure B6 background and that these phenotype differences link to a region on mouse Chromosome 17.To examine whether other models of motor neuron degeneration are affected by genetic background, we bred the mutant human dynactin p150Glued (G59S-hDCTN1) transgene onto inbred SJL and B6 congenic lines. This model is based on an autosomal dominant lower motor neuron disease in humans linked to a mutation in the p150Glued subunit of the dynactin complex. As seen in hSOD1-G93A mice, we observed a more severe phenotype with earlier disease onset (pdisease onset in hSOD1-G93A mice also showed delays onset in G59S-hDCTN1 mice suggesting that at least some genetic modifiers are shared. We have shown that genetic background influences phenotype in G59S-hDCTN1 mice, in part through a region of chromosome 17 similar to the G93-hSOD1 ALS mouse model. These results support the presence of genetic modifiers in both these models some of which may be shared. Identification of these modifiers will highlight intracellular pathways involved in motor neuron disease and provide new therapeutic targets that may be applicable to motor neuron degeneration.

  7. miR-302/367-induced neurons reduce behavioral impairment in an experimental model of Alzheimer's disease.

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    Ghasemi-Kasman, Maryam; Shojaei, Amir; Gol, Mohammad; Moghadamnia, Ali Akbar; Baharvand, Hossein; Javan, Mohammad

    2018-01-01

    In vivo reprogramming of reactive glial cells to neurons has opened a new horizon in regenerative medicine. Our previous study showed that astrocytes could be converted to neurons by the microRNA-302/367 (miR-302/367) cluster in adult brains. In this study, we investigated the possible contribution of miR-302/367-induced neurons in behavioral improvement and neural repair in an Alzheimer's disease (AD) animal model. The AD model was induced by an intracerebroventricular (i.c.v) injection of streptozotocin (STZ). GFP-only or miR-302/367+GFP expressing lentiviral particles were injected into the dentate gyrus of the hippocampus along with intraperitoneal (i.p) valproate (VPA) injection, 3weeks after the STZ administration. We assessed short-term and spatial memories by the Y-maze and Morris water maze (MWM) tasks, respectively. Electrophysiological activities of induced neuron-like cells were investigated using a whole-cell patch clamp technique, 6months after injection of miR-302/367. Behavioral analysis showed that the STZ injection significantly impaired short-term memory and increased escape latency parameter in the MWM task. Compared to STZ and STZ+VPA groups, miR-302/367 combined with VPA significantly improved the spontaneous alternation and spatial memory. Immunostaining against NeuN, as a mature neuronal marker, and its quantification indicated that co-labeled GFP and NeuN significantly increased in the miR-302/367+VPA group. Induced neurons were detected 6months after the miR-302/367 injection. The patch-clamp recording suggested that induced neurons could fire repetitive action potential like endogenous neurons. In conclusion, our results indicated that in vivo reprogramming of reactive astrocytes to neurons by the miR-302/367 cluster might be considered as a novel strategy to restore learning and memory in AD patients. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Accuracy of routinely-collected healthcare data for identifying motor neurone disease cases: A systematic review.

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    Sophie Horrocks

    Full Text Available Motor neurone disease (MND is a rare neurodegenerative condition, with poorly understood aetiology. Large, population-based, prospective cohorts will enable powerful studies of the determinants of MND, provided identification of disease cases is sufficiently accurate. Follow-up in many such studies relies on linkage to routinely-collected health datasets. We systematically evaluated the accuracy of such datasets in identifying MND cases.We performed an electronic search of MEDLINE, EMBASE, Cochrane Library and Web of Science for studies published between 01/01/1990-16/11/2015 that compared MND cases identified in routinely-collected, coded datasets to a reference standard. We recorded study characteristics and two key measures of diagnostic accuracy-positive predictive value (PPV and sensitivity. We conducted descriptive analyses and quality assessments of included studies.Thirteen eligible studies provided 13 estimates of PPV and five estimates of sensitivity. Twelve studies assessed hospital and/or death certificate-derived datasets; one evaluated a primary care dataset. All studies were from high income countries (UK, Europe, USA, Hong Kong. Study methods varied widely, but quality was generally good. PPV estimates ranged from 55-92% and sensitivities from 75-93%. The single (UK-based study of primary care data reported a PPV of 85%.Diagnostic accuracy of routinely-collected health datasets is likely to be sufficient for identifying cases of MND in large-scale prospective epidemiological studies in high income country settings. Primary care datasets, particularly from countries with a widely-accessible national healthcare system, are potentially valuable data sources warranting further investigation.

  9. Risk factors for respiratory failure of motor neuron disease in a multiracial Asian population.

    Science.gov (United States)

    Deng, Xiao; Hao, Ying; Xiao, Bin; Tan, Eng-King; Lo, Yew-Long

    2017-05-01

    Motor neuron disease (MND) is a devastating degenerative disorder. Amyotrophic Lateral Sclerosis (ALS) is the most common and severe form of MND. Respiratory failure arising from ventilator musculature atrophy is the most common cause of death for ALS patients. Exploring the factors correlated with respiratory failure can contribute to disease management. To characterize the clinical features of MND and determine the factors that may affect respiratory failure of MND patients. The case records of all MND patients seen in Singapore General Hospital (SGH) between January 2004 and December 2014 were examined. Demographic, clinical information were collected by reviewing case records. Mortality data, if not available from records, were obtained via phone call interview of family members. Demographic data and clinical treatments were compared between Respiratory support group and Non-respiratory support group. There were 73 patients included in our study. 49 (67.1%) patients died during follow-up. The mean age of onset was 58±11.1years. With regard to treatment, 63% needed feeding support, and 42.5% required ventilation aid. The median overall survival was 36months from symptom onset. Chi-square tests showed there was significantly higher percentage of respiratory support needed in Chinese than in other races (P=0.016). Compared with non-feeding support patients, patients with feeding support were more likely to require assisted ventilation (P=0.001). We report for the first time that the need of feeding support is significantly associated with assisted ventilation. Chinese MND patients may be more inclined to require respiratory support. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Determination of neuronal antibodies in suspected and definite Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Grau-Rivera, Oriol; Sánchez-Valle, Raquel; Saiz, Albert; Molinuevo, José Luis; Bernabé, Reyes; Munteis, Elvira; Pujadas, Francesc; Salvador, Antoni; Saura, Júlia; Ugarte, Antonio; Titulaer, Maarten; Dalmau, Josep; Graus, Francesc

    2014-01-01

    Creutzfeldt-Jakob disease (CJD) and autoimmune encephalitis with antibodies against neuronal surface antigens (NSA-abs) may present with similar clinical features. Establishing the correct diagnosis has practical implications in the management of care for these patients. To determine the frequency of NSA-abs in the cerebrospinal fluid of patients with suspected CJD and in patients with pathologically confirmed (ie, definite) CJD. A mixed prospective (suspected) and retrospective (definite) CJD cohort study was conducted in a reference center for detection of NSA-abs. The population included 346 patients with suspected CJD and 49 patients with definite CJD. Analysis of NSA-abs in cerebrospinal fluid with brain immunohistochemistry optimized for cell-surface antigens was performed. Positive cases in the suspected CJD group were further studied for antigen specificity using cell-based assays. All definite CJD cases were comprehensively tested for NSA-abs, with cell-based assays used for leucine-rich glioma-inactivated 1 (LGI1), contactin-associated protein-like 2 (CASPR2), N-methyl-d-aspartate (NMDA), and glycine (GlY) receptors. Neuronal surface antigens were detected in 6 of 346 patients (1.7%) with rapid neurologic deterioration suggestive of CJD. None of these 6 patients fulfilled the diagnostic criteria for probable or possible CJD. The target antigens included CASPR2, LGI1, NMDAR, aquaporin 4, Tr (DNER [δ/notch-like epidermal growth factor-related receptor]), and an unknown protein. Four of the patients developed rapidly progressive dementia, and the other 2 patients had cerebellar ataxia or seizures that were initially considered to be myoclonus without cognitive decline. The patient with Tr-abs had a positive 14-3-3 test result. Small cell lung carcinoma was diagnosed in the patient with antibodies against an unknown antigen. All patients improved or stabilized after appropriate treatment. None of the 49 patients with definite CJD had NSA-abs. A low, but

  11. Incidence of and risk factors for Motor Neurone Disease in UK women: a prospective study

    Directory of Open Access Journals (Sweden)

    Doyle Pat

    2012-05-01

    Full Text Available Abstract Background Motor neuron disease (MND is a severe neurodegenerative disease with largely unknown etiology. Most epidemiological studies are hampered by small sample sizes and/or the retrospective collection of information on behavioural and lifestyle factors. Methods 1.3 million women from the UK Million Women Study, aged 56 years on average at recruitment, were followed up for incident and/or fatal MND using NHS hospital admission and mortality data. Adjusted relative risks were calculated using Cox regression models. Findings During follow-up for an average of 9·2 years, 752 women had a new diagnosis of MND. Age-specific rates increased with age, from 1·9 (95% CI 1·3 – 2·7 to 12·5 (95% CI 10·2 – 15·3 per 100,000 women aged 50–54 to 70–74, respectively, giving a cumulative risk of diagnosis with the disease of 1·74 per 1000 women between the ages of 50 and 75 years. There was no significant variation in risk of MND with region of residence, socio-economic status, education, height, alcohol use, parity, use of oral contraceptives or hormone replacement therapy. Ever-smokers had about a 20% greater risk than never smokers (RR 1·19 95% CI 1·02 to 1·38, p = 0·03. There was a statistically significant reduction in risk of MND with increasing body mass index (pfor trend = 0·009: obese women (body mass index, 30 kg/m2 or more had a 20% lower risk than women of normal body mass index (20 to 2(RR 0·78 95% CI 0·65-0·94; p = 0·03. This effect persisted after exclusion of the first three years of follow-up. Interpretation MND incidence in UK women rises rapidly with age, and an estimated 1 in 575 women are likely to be affected between the ages of 50 and 75 years. Smoking slightly increases the risk of MND, and adiposity in middle age is associated with a lower risk of the disease.

  12. Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer's disease.

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    Simpkins, J W; Green, P S; Gridley, K E; Singh, M; de Fiebre, N C; Rajakumar, G

    1997-09-22

    Recent evidence supports a role for estrogens in both normal neural development and neuronal maintenance throughout life. Women spend 25-33% of their life in an estrogen-deprived state and retrospective studies have shown an inverse correlation between dose and duration of estrogen replacement therapy (ERT) and incidence of Alzheimer's disease (AD), suggesting a role for estrogen in the prevention and/or treatment of neurodegenerative diseases. To explore these observations further, an animal model was developed using ovariectomy (OVX) and ovariectomy with estradiol replacement (E2) in female Sprague-Dawley rats to mimic postmenopausal changes. Using an active-avoidance paradigm and a spatial memory task, the effects of estrogen deprivation were tested on memory-related behaviors. OVX caused a decline in avoidance behavior, and estrogen replacement normalized the response. In the Morris water task of spatial memory, OVX animals showed normal spatial learning but were deficient in spatial memory, an effect that was prevented by estrogen treatment. Together these data indicate that OVX in rats results in an estrogen-reversible impairment of learning/memory behavior. Because a plethora of information has been generated that links decline in memory-related behavior to dysfunction of cholinergic neurons, the effects of estrogens on cholinergic neurons were tested. We demonstrated that OVX causes a decrease in high affinity choline uptake and choline acetyltransferase activity in the hippocampus and frontal cortex; ERT reverses this effect. Further, we showed that estrogens promote the expression of mRNA for brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), 2 neurotrophic substances that have been shown to ameliorate the effects of age and injury on cholinergic neurons. Tissue culture models were used to evaluate whether estrogen treatment increases the survival of neurons when exposed to a variety of insults. 17-beta-Estradiol (beta-E2) protects

  13. Increased expression of the remodeling- and tumorigenic-associated factor osteopontin in pyramidal neurons of the Alzheimer's disease brain.

    Science.gov (United States)

    Wung, John K; Perry, George; Kowalski, Aaron; Harris, Peggy L R; Bishop, Glenda M; Trivedi, Mehul A; Johnson, Sterling C; Smith, Mark A; Denhardt, David T; Atwood, Craig S

    2007-02-01

    Osteopontin (OPN) is a glycophosphoprotein expressed by several cell types and has pro-adhesive, chemotactic, and cytokine-like properties. OPN is involved in a number of physiologic and pathologic events including angiogenesis, apoptosis, inflammation, oxidative stress, remyelination, wound healing, bone remodeling, cell migration and tumorigenesis. Since these functions of OPN, and the events that it regulates, are involved with neurodegeneration, we examined whether OPN was differentially expressed in the hippocampus of the Alzheimer's disease (AD) compared with age-matched (59-93 years) control brain. We report for the first time the immunocytochemical localization of OPN in the cytoplasm of pyramidal neurons. In AD brains, there was a significant 41 % increase in the expression of neuron OPN compared with age-matched control brain. No staining of other neuronal cell types was observed. Additionally, there was a significant positive correlation between OPN staining intensity and both amyloid-beta load (r(2) = 0.25; P < 0.05; n = 20) and aging (r(2) = 0.32; P < 0.01; n = 20) among all control and AD subjects. Controlling for age indicated that OPN expression was significantly influenced by amyloid-beta load, but not age. While the functional consequences of this amyloid-beta associated increase in OPN expression are unclear, it is notable that OPN is primarily localized to those neurons that are known to be vulnerable to AD-related neurite loss, degeneration and death. Given that the induction of OPN expression (and amyloid-beta generation) is associated with remodeling and tumorigenesis, our results suggest that OPN may play a role in the aberrant re-entry of neurons into the cell cycle and/or neuronal remyelination in AD.

  14. Treatment for spasticity in amyotrophic lateral sclerosis/motor neuron disease.

    Science.gov (United States)

    Ashworth, Nigel L; Satkunam, L E; Deforge, Dan

    2012-02-15

    Spasticity commonly affects patients with motor neuron disease. It is likely to contribute to worsening muscle dysfunction, increased difficulty with activities of daily living and deteriorating quality of life. This is an update of a review first published in 2003 and previously updated in 2005 and 2008. The objective of this review is to systematically review treatments for spasticity in amyotrophic lateral sclerosis, also known as motor neuron disease. We searched the Cochrane Neuromuscular Disease Group Specialized Register (4 July 2011), CENTRAL (2011, Issue 2), MEDLINE (January 1966 to July 2011), EMBASE (January 1980 to July 2011 ), CINAHL Plus (January 1937 to July 2011), AMED (January 1985 to July 2011) and LILACS (January 1982 to July 2011 ). We reviewed the bibliographies of the randomized controlled trials identified, and contacted authors and experts in the field. We included quasi-randomized or randomized controlled trials of participants with probable or definite amyotrophic lateral sclerosis according to the El Escorial diagnostic criteria (or a revised version) or the Airlie House revision. We would have included trials of physical therapy, modalities, prescription medications, non-prescription medications, chemical neurolysis, surgical interventions, and alternative therapies. Our primary outcome measure was reduction in spasticity at three months or greater as measured by the Ashworth (or modified Ashworth) spasticity scale. Our secondary outcome measures were: validated measures based on history, physical examination, physiological measures, measures of function, measures of quality of life, all adverse events, and measures of cost. Two authors independently screened the abstracts of potential trials retrieved from the searches. Two authors extracted the data. We also contacted the author of the paper and obtained information not available in the published article. All three authors assessed the methodological quality of all included trials

  15. Oxidative modifications, mitochondrial dysfunction, and impaired protein degradation in Parkinson's disease: how neurons are lost in the Bermuda triangle.

    Science.gov (United States)

    Malkus, Kristen A; Tsika, Elpida; Ischiropoulos, Harry

    2009-06-05

    While numerous hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of neurodegenerative diseases, the theory of oxidative stress has received considerable support. Although many correlations have been established and encouraging evidence has been obtained, conclusive proof of causation for the oxidative stress hypothesis is lacking and potential cures have not emerged. Therefore it is likely that other factors, possibly in coordination with oxidative stress, contribute to neuron death. Using Parkinson's disease (PD) as the paradigm, this review explores the hypothesis that oxidative modifications, mitochondrial functional disruption, and impairment of protein degradation constitute three interrelated molecular pathways that execute neuron death. These intertwined events are the consequence of environmental exposure, genetic factors, and endogenous risks and constitute a "Bermuda triangle" that may be considered the underlying cause of neurodegenerative pathogenesis.

  16. Oxidative modifications, mitochondrial dysfunction, and impaired protein degradation in Parkinson's disease: how neurons are lost in the Bermuda triangle

    Directory of Open Access Journals (Sweden)

    Malkus Kristen A

    2009-06-01

    Full Text Available Abstract While numerous hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of neurodegenerative diseases, the theory of oxidative stress has received considerable support. Although many correlations have been established and encouraging evidence has been obtained, conclusive proof of causation for the oxidative stress hypothesis is lacking and potential cures have not emerged. Therefore it is likely that other factors, possibly in coordination with oxidative stress, contribute to neuron death. Using Parkinson's disease (PD as the paradigm, this review explores the hypothesis that oxidative modifications, mitochondrial functional disruption, and impairment of protein degradation constitute three interrelated molecular pathways that execute neuron death. These intertwined events are the consequence of environmental exposure, genetic factors, and endogenous risks and constitute a "Bermuda triangle" that may be considered the underlying cause of neurodegenerative pathogenesis.

  17. Localization and expression of ciliary neurotrophic factor (CNTF) in postmortem sciatic nerve from patients with motor neuron disease and diabetic neuropathy

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    Lee, D.A. [Univ. Medical Center, New Orleans, LA (United States); Gross, L.; Wittrock, D.A.; Windebank, A.J. [Mayo Clinic, Rochester, MN (United States)

    1996-08-01

    Ciliary neurotrophic factor (CNTF) is thought to play an important role in the maintenance of the mature motor system. The factor is found most abundantly in myelinating Schwann cells in the adult sciatic nerve. Lack of neuronal growth factors has been proposed as one possible etiology of amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Growth factor replacement therapies are currently being evaluated as a treatment for motor neuron disease. In this report we determined whether the expression of CNTF in sciatic nerve differed in patients with motor neuron disease compared to controls or patients with another form of axonopathy. We identified 8 patients (7 with ALS and 1 with SMA) with motor neuron disease and 6 patients with diabetic motor neuropathy who had autopsy material available. Immunoperoxidase staining showed reduced CNTF expression in nerves of patients with motor neuron disease but not in patients with diabetic motor neuropathy. Decreased CNTF appears be associated with primary motor neuron disease rather than a generalized process of axon loss. This result supports suggestions that CNTF deficiency may be an important factor in the development of motor neuron disease. 20 refs., 4 figs., 1 tab.

  18. Sporadic lower motor neuron disease with a snake eyes appearance on the cervical anterior horns by MRI.

    Science.gov (United States)

    Sasaki, Shoichi

    2015-09-01

    Lower motor neuron disease (LMND) is the term generally used to describe diseases in which only lower motor neuron signs are detected. A snake eyes appearance on magnetic resonance imaging (MRI) is associated with a wide spectrum of neurological conditions including LMND. The author reports on three unique LMND patients with upper limb muscle weakness and atrophy who show a snake eyes appearance by MRI. The patients were aged 18, 40 and 52 years, respectively, at the onset of the disease and had a longstanding clinical course (more than 10 years for two patients and 8 years for one patient). They were followed up for more than 6 years. Clinical manifestations were characterized by (1) longstanding slow progression or delayed spontaneous arrest of asymmetric lower motor neuron signs localized exclusively in the upper extremities with unilateral predominance and distal or proximal preponderance; (2) the absence of upper motor neuron signs, bulbar signs, sensory disturbances and respiratory involvement; (3) a snake eyes appearance on the anterior horns of the cervical cord over more than 3 vertebrae by axial T2-weighted MRI and a longitudinal linear-shaped T2-signal hyperintensity by sagittal MRI; (4) neurogenic change with fasciculation and denervation potentials (fibrillation and a positive sharp wave) confined to the affected muscles by needle electromyogram; and (5) normal cerebrospinal fluid and a normal creatine kinase level. These cases did not fall into any existing category of LMND, such as progressive muscular atrophy, flail arm syndrome or Hirayama disease. These patients should be classified as sporadic LMND with snake eyes on MRI with a relatively benign prognosis. Copyright © 2015 Elsevier B.V. All rights reserved.

  19. Disruption of the astrocytic TNFR1-GDNF axis accelerates motor neuron degeneration and disease progression in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Brambilla, Liliana; Guidotti, Giulia; Martorana, Francesca; Iyer, Anand M; Aronica, Eleonora; Valori, Chiara F; Rossi, Daniela

    2016-07-15

    Considerable evidence indicates that neurodegeneration in amyotrophic lateral sclerosis (ALS) can be conditioned by a deleterious interplay between motor neurons and astrocytes. Astrocytes are the major glial component in the central nervous system (CNS) and fulfill several activities that are essential to preserve CNS homeostasis. In physiological and pathological conditions, astrocytes secrete a wide range of factors by which they exert multimodal influences on their cellular neighbours. Among others, astrocytes can secrete glial cell line-derived neurotrophic factor (GDNF), one of the most potent protective agents for motor neurons. This suggests that the modulation of the endogenous mechanisms that control the production of astrocytic GDNF may have therapeutic implications in motor neuron diseases, particularly ALS. In this study, we identified TNF receptor 1 (TNFR1) signalling as a major promoter of GDNF synthesis/release from human and mouse spinal cord astrocytes in vitro and in vivo To determine whether endogenously produced TNFα can also trigger the synthesis of GDNF in the nervous system, we then focused on SOD1 G93A ALS transgenic mice, whose affected tissues spontaneously exhibit high levels of TNFα and its receptor 1 at the onset and symptomatic stage of the disease. In SOD1 G93A spinal cords, we verified a strict correlation in the expression of the TNFα, TNFR1 and GDNF triad at different stages of disease progression. Yet, ablation of TNFR1 completely abolished GDNF rises in both SOD1 G93A astrocytes and spinal cords, a condition that accelerated motor neuron degeneration and disease progression. Our data suggest that the astrocytic TNFR1-GDNF axis represents a novel target for therapeutic intervention in ALS. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. Patient iPSC-Derived Neurons for Disease Modeling of Frontotemporal Dementia with Mutation in CHMP2B

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    Yu Zhang

    2017-03-01

    Full Text Available The truncated mutant form of the charged multivesicular body protein 2B (CHMP2B is causative for frontotemporal dementia linked to chromosome 3 (FTD3. CHMP2B is a constituent of the endosomal sorting complex required for transport (ESCRT and, when mutated, disrupts endosome-to-lysosome trafficking and substrate degradation. To understand the underlying molecular pathology, FTD3 patient induced pluripotent stem cells (iPSCs were differentiated into forebrain-type cortical neurons. FTD3 neurons exhibited abnormal endosomes, as previously shown in patients. Moreover, mitochondria of FTD3 neurons displayed defective cristae formation, accompanied by deficiencies in mitochondrial respiration and increased levels of reactive oxygen. In addition, we provide evidence for perturbed iron homeostasis, presenting an in vitro patient-specific model to study the effects of iron accumulation in neurodegenerative diseases. All phenotypes observed in FTD3 neurons were rescued in CRISPR/Cas9-edited isogenic controls. These findings illustrate the relevance of our patient-specific in vitro models and open up possibilities for drug target development.

  1. ALS-Associated Endoplasmic Reticulum Proteins in Denervated Skeletal Muscle: Implications for Motor Neuron Disease Pathology.

    Science.gov (United States)

    Jesse, C M; Bushuven, E; Tripathi, P; Chandrasekar, A; Simon, C M; Drepper, C; Yamoah, A; Dreser, A; Katona, I; Johann, S; Beyer, C; Wagner, S; Grond, M; Nikolin, S; Anink, J; Troost, D; Sendtner, M; Goswami, A; Weis, J

    2017-11-01

    Alpha-motoneurons and muscle fibres are structurally and functionally interdependent. Both cell types particularly rely on endoplasmic reticulum (ER/SR) functions. Mutations of the ER proteins VAPB, SigR1 and HSP27 lead to hereditary motor neuron diseases (MNDs). Here, we determined the expression profile and localization of these ER proteins/chaperons by immunohistochemistry and immunoblotting in biopsy and autopsy muscle tissue of patients with amyotrophic lateral sclerosis (ALS) and other neurogenic muscular atrophies (NMAs) and compared these patterns to mouse models of neurogenic muscular atrophy. Postsynaptic neuromuscular junction staining for VAPB was intense in normal human and mouse muscle and decreased in denervated Nmd 2J mouse muscle fibres. In contrast, VAPB levels together with other chaperones and autophagy markers were increased in extrasynaptic regions of denervated muscle fibres of patients with MNDs and other NMAs, especially at sites of focal myofibrillar disintegration (targets). These findings did not differ between NMAs due to ALS and other causes. G93A-SOD1 mouse muscle fibres showed a similar pattern of protein level increases in denervated muscle fibres. In addition, they showed globular VAPB-immunoreactive structures together with misfolded SOD1 protein accumulations, suggesting a primary myopathic change. Our findings indicate that altered expression and localization of these ER proteins and autophagy markers are part of the dynamic response of muscle fibres to denervation. The ER is particularly prominent and vulnerable in both muscle fibres and alpha-motoneurons. Thus, ER pathology could contribute to the selective build-up of degenerative changes in the neuromuscular axis in MNDs. © 2016 International Society of Neuropathology.

  2. Pigment retinopathy in warmblood horses with equine degenerative myeloencephalopathy and equine motor neuron disease.

    Science.gov (United States)

    Finno, Carrie J; Kaese, Heather J; Miller, Andrew D; Gianino, Giuliana; Divers, Thomas; Valberg, Stephanie J

    2017-07-01

    A pigment retinopathy has been reported in adult horses with equine motor neuron disease (EMND) arising from chronic α-tocopherol (α-TP) deficiency. A pigment retinopathy has not been identified in horses with neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) that affects genetically susceptible young horses with α-TP deficiency. The objective of this report is to describe, for the first time, a pigment retinopathy in a family of α-TP-deficient Warmbloods (WB) with clinically apparent NAD/EDM or EMND. Twenty-five WB horses from one farm underwent complete neurologic and ophthalmic examinations and serum α-TP concentrations were assessed. Two of the most severely ataxic horses were euthanized and postmortem examinations performed. Alpha-TP deficiency was widespread on this farm (22 of 25 horses). Eleven of 25 horses were clinically normal (age range 2-12 years), one had signs of EMND (6 years of age), 10 had signs of ataxia consistent with NAD/EDM (1-10 years), and two of these were postmortem confirmed concurrent NAD/EDM and EMND. A pigment retinopathy characterized by varying amounts of granular dark pigment in the tapetal retina was observed in four clinically apparent NAD/EDM horses (two postmortem confirmed concurrent NAD/EDM and EMND) and one horse with clinical signs of EMND. A pigment retinopathy can be present in young α-TP-deficient Warmblood horses with clinical signs of EMND as well as those with signs of NAD/EDM. © 2016 American College of Veterinary Ophthalmologists.

  3. Dignity Therapy for People with Motor Neuron Disease and Their Family Caregivers: A Feasibility Study

    Science.gov (United States)

    Chochinov, Harvey M.; Kristjanson, Linda J.

    2015-01-01

    Abstract Background: There are calls to explore psychological interventions to reduce distress in patients with motor neuron disease (MND) and their family caregivers. Dignity therapy is a short-term psychotherapy intervention shown to alleviate distress for people with life-limiting illnesses. Objectives: To assess the acceptability, feasibility, and effectiveness of dignity therapy to reduce distress in people with MND and their family caregivers. Methods: The study used a repeated-measures design pre- and post-intervention. Acceptability and feasibility were assessed using participants' ratings of the helpfulness of the intervention across several domains and time and resources required. Effectiveness measures for patients included: dignity-related distress, hopefulness, and spiritual well-being; and those for family caregivers included burden, hopefulness, anxiety, and depression. Results: Twenty-seven patients and 18 family caregivers completed the intervention. Dignity therapy was well accepted, including those patients who required assisted communication devices. The feasibility may be limited in small or not well-resourced services. There were no significant differences in all outcome measures for both groups. However, the high satisfaction and endorsement of dignity therapy by patients suggests it has influenced various important aspects of end-of-life experience. Family caregivers overwhelmingly agreed that the dignity therapy document is and will continue to be a source of comfort to them and they would recommend dignity therapy to others in the same situation. Conclusions: This is the first dignity therapy study to focus on MND and on home-based caregiving. Results established the importance of narrative and generativity for patients with MND and may open the door for other neurodegenerative conditions. PMID:25314244

  4. Different Populations of Human Locus Ceruleus Neurons Contain Heavy Metals or Hyperphosphorylated Tau: Implications for Amyloid-β and Tau Pathology in Alzheimer's Disease.

    Science.gov (United States)

    Pamphlett, Roger; Kum Jew, Stephen

    2015-01-01

    A marked loss of locus ceruleus (LC) neurons is a striking pathological feature of Alzheimer's disease (AD). LC neurons are particularly prone to taking up circulating toxicants such as heavy metals, and hyperphosphorylated tau (tau(HYP)) appears early in these neurons. In an attempt to find out if both heavy metals and tau(HYP) could be damaging LC neurons, we looked in the LC neurons of 21 sporadic AD patients and 43 non-demented controls for the heavy metals mercury, bismuth, and silver using autometallography, and for tau(HYP) using AT8 immunostaining. Heavy metals or tau(HYP) were usually seen in separate LC neurons, and rarely co-existed within the same neuron. The number of heavy metal-containing LC neurons did not correlate with the number containing tau(HYP). Heavy metals therefore appear to occupy a mostly different population of LC neurons to those containing tau(HYP), indicating that the LC in AD is vulnerable to two different assaults. Reduced brain noradrenaline from LC damage is linked to amyloid-β deposition, and tau(HYP) in the LC may seed neurofibrillary tangles in other neurons. A model is described, incorporating the present findings, that proposes that the LC plays a part in both the amyloid-β and tau pathologies of AD.

  5. [Assessment of upper motor neuron dysfunction by triple stimulation technique in patients with Charcot-Marie-Tooth disease].

    Science.gov (United States)

    Xu, Y S; Zhang, S; Liu, X X; Sun, A P; Fan, D S

    2016-06-07

    To investigate the presence of upper motor neuron dysfunction in patients with Charcot-Marie-Tooth disease (CMT) by triple stimulation technique (TST) to provide evidence for gene diagnosis. A total of 65 CMT patients confirmed by genetic testing from Peking University Third Hospital between August 2013 and August 2015, underwent physical examination and routine electrophysiological tests and triple stimulation technique. The TST combined transcranial magnetic stimulation (TMS) of the motor cortex with peripheral collision studies. The results were expressed by the TST amplitude ratio (TST test/ TST control). Based on the result of physical examination and the ratio of TST, the function of upper motor neuron was assessed. All of the CMT patients had typical presentations and were confirmed genetically. Hyperreflexia, Babinski sign and muscular hypertonia were discovered in lower limbs in 7 CMT patients, while 2 patients complicated with hyperreflexia and Hoffmann sign in upper limbs. TST amplitude ratio was significantly altered in 10 patients, including 5 patients with pyramid sign: hyperreflexia, Babinski sign and muscular hypertonia was discovered in lower limbs while 2 patients complicated with hyperreflexia and Hoffmann sign in upper limbs. The disease-causing mutations were: MFN2 mutations in 5 patients, 1 patient with BSCL2 mutation, 3 patients with GJB1 mutations and 1 patient with GDAP mutation. In summary, 18.5% (12 patients) of the 65 CMT patients had upper motor neuron dysfunction based on the result of physical examination and the ratio of TST. Upper motor neuron dysfunction may be found in CMT patients, which may provide clues for the testing of disease-causing mutations.

  6. Natural history of motor neuron disease in adult onset GM2-gangliosidosis: A case report with 25 years of follow-up

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    Mauro Scarpelli

    2014-01-01

    GM2-gangliosidosis can manifest as a motor neuron disease with a slowly progressive course. The correct knowledge of the natural history can be really important to achieve the diagnosis, design new therapies and evaluate clinical trials.

  7. ATF6alpha promotes astroglial activation and neuronal survival in a chronic mouse model of Parkinson's disease.

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    Koji Hashida

    Full Text Available Accumulating evidence suggests a crucial role for the unfolded protein response (UPR in Parkinson's disease (PD. In this study, we investigated the relevance of the UPR in a mouse model of chronic MPTP/probenecid (MPTP/P injection, which causes severe and persistent degeneration of dopaminergic neurons. Enhanced activation of the UPR branches, including ATF6α and PERK/eIF2α/ATF4, was observed after MPTP/P injections into mice. Deletion of the ATF6α gene accelerated neuronal degeneration and ubiquitin accumulation relatively early in the MPTP/P injection course. Surprisingly, astroglial activation was strongly suppressed, and production of the brain-derived neurotrophic factor (BDNF and anti-oxidative genes, such as heme oxygenase-1 (HO-1 and xCT, in astrocytes were reduced in ATF6α -/- mice after MPTP/P injections. Decreased BDNF expression in ATF6α -/- mice was associated with decreased expression of GRP78, an ATF6α-dependent molecular chaperone in the ER. Decreased HO-1 and xCT levels were associated with decreased expression of the ATF4-dependent pro-apoptotic gene CHOP. Consistent with these results, administration of the UPR-activating reagent tangeretin (5,6,7,8,4'-pentamethoxyflavone; IN19 into mice enhanced the expression of UPR-target genes in both dopaminergic neurons and astrocytes, and promoted neuronal survival after MPTP/P injections. These results suggest that the UPR is activated in a mouse model of chronic MPTP/P injection, and contributes to the survival of nigrostriatal dopaminergic neurons, in part, through activated astrocytes.

  8. Transduced PEP-1-PON1 proteins regulate microglial activation and dopaminergic neuronal death in a Parkinson's disease model.

    Science.gov (United States)

    Kim, Mi Jin; Park, Meeyoung; Kim, Dae Won; Shin, Min Jea; Son, Ora; Jo, Hyo Sang; Yeo, Hyeon Ji; Cho, Su Bin; Park, Jung Hwan; Lee, Chi Hern; Kim, Duk-Soo; Kwon, Oh-Shin; Kim, Joon; Han, Kyu Hyung; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2015-09-01

    Parkinson's disease (PD) is an oxidative stress-mediated neurodegenerative disorder caused by selective dopaminergic neuronal death in the midbrain substantia nigra. Paraoxonase 1 (PON1) is a potent inhibitor of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) against oxidation by destroying biologically active phospholipids with potential protective effects against oxidative stress-induced inflammatory disorders. In a previous study, we constructed protein transduction domain (PTD) fusion PEP-1-PON1 protein to transduce PON1 into cells and tissue. In this study, we examined the role of transduced PEP-1-PON1 protein in repressing oxidative stress-mediated inflammatory response in microglial BV2 cells after exposure to lipopolysaccharide (LPS). Moreover, we identified the functions of transduced PEP-1-PON1 proteins which include, mitigating mitochondrial damage, decreasing reactive oxidative species (ROS) production, matrix metalloproteinase-9 (MMP-9) expression and protecting against 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity in SH-SY5Y cells. Furthermore, transduced PEP-1-PON1 protein reduced MMP-9 expression and protected against dopaminergic neuronal cell death in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice model. Taken together, these results suggest a promising therapeutic application of PEP-1-PON1 proteins against PD and other inflammation and oxidative stress-related neuronal diseases. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Allopregnanolone reinstates tyrosine hydroxylase immunoreactive neurons and motor performance in an MPTP-lesioned mouse model of Parkinson's disease.

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    Samuel O Adeosun

    Full Text Available Restorative/protective therapies to restore dopamine neurons in the substantia nigra pars compacta (SNpc are greatly needed to effectively change the debilitating course of Parkinson's disease. In this study, we tested the therapeutic potential of a neurogenic neurosteroid, allopregnanolone, in the restoration of the components of the nigrostriatal pathway in MPTP-lesioned mice by measuring striatal dopamine levels, total and tyrosine hydroxylase immunoreactive neuron numbers and BrdU-positive cells in the SNpc. An acute treatment (once/week for two weeks with allopregnanolone restored the number of tyrosine hydroxylase-positive and total cell numbers in the SNpc of MPTP-lesioned mice, even though this did not increase striatal dopamine. It was also noted that MPTP treated mice to which allopregnanolone was administered had an increase in BrdU-positive cells in the SNpc. The effects of allopregnanolone in MPTP-lesioned mice were more apparent in mice that underwent behavioral tests. Interestingly, mice treated with allopregnanolone after MPTP lesion were able to perform at levels similar to that of non-lesioned control mice in a rotarod test. These data demonstrate that allopregnanolone promotes the restoration of tyrosine hydroxylase immunoreactive neurons and total cells in the nigrostriatal tract, improves the motor performance in MPTP-treated mice, and may serve as a therapeutic strategy for Parkinson's disease.

  10. Characterisation Of Forebrain Neurons Derived From Late-Onset Huntington’s Disease Human Embryonic Stem Cell Lines

    Directory of Open Access Journals (Sweden)

    Jonathan Christos Niclis

    2013-04-01

    Full Text Available Huntington's Disease (HD is an incurable neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the Huntingtin gene. Recently, induced pluripotent stem cell lines carrying atypical and aggressive (CAG60+ HD variants have been generated, and perplexingly exhibit disparate molecular pathologies. Here we investigate two human embryonic stem cell (hESC lines carrying CAG37 and CAG51 repeats to assess whether typical late-onset expansions exhibit HD pathologies. HD hESC properties were assessed in comparison to wildtype control lines at undifferentiated states and throughout forebrain neuronal differentiation. Pluripotent HD lines demonstrate growth, viability, pluripotent gene expression, mitochondrial activity and forebrain specification that is indistinguishable from control lines. Expression profiles of crucial genes known to be dysregulated in HD remain unperturbed in the presence of mutant protein and throughout differentiation; however, elevated glutamate responses were observed in HD CAG51 neurons. These findings suggest typical late-onset HD mutations do not alter pluripotent parameters or differentiation mechanics but that neuronal progeny may possess the capacity to recapitulate neuropathologies seen in human patients. Such HD models will help further our understanding of the cascade of pathological events leading to disease onset and progression, while simultaneously facilitating the identification of candidate HD therapeutics.

  11. Nutritional support teams increase percutaneous endoscopic gastrostomy uptake in motor neuron disease.

    Science.gov (United States)

    Zhang, Lin; Sanders, Leanne; Fraser, Robert J L

    2012-11-28

    To examine factors influencing percutaneous endoscopic gastrostomy (PEG) uptake and outcomes in motor neuron disease (MND) in a tertiary care centre. Case notes from all patients with a confirmed diagnosis of MND who had attended the clinic at the Repatriation General Hospital between January 2007 and January 2011 and who had since died, were audited. Data were extracted for demographics (age and gender), disease characteristics (date of onset, bulbar or peripheral predominance, complications), date and nature of discussion of gastrostomy insertion, nutritional status [weight measurements, body mass index (BMI)], date of gastrostomy insertion and subsequent progress (duration of survival) and quality of life (QoL) [Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)]. In addition, the type of clinician initiating the discussion regarding gastrostomy was recorded as Nutritional Support Team (involved in providing nutrition input viz Gastroenterologist, Speech Pathologist, Dietitian) and other (involved in non-nutritional aspects of patient care). Factors affecting placement and outcomes including length of survival, change in weight and QoL were determined. Case records were available for all 86 patients (49 men, mean age at diagnosis 66.4 years). Thirty-eight patients had bulbar symptoms and 48 had peripheral disease as their presenting feature. Sixty-six patients reported dysphagia. Thirty-one patients had undergone gastrostomy insertion. The major indications for PEG placement were dysphagia and weight loss. Nine patients required immediate full feeding, whereas 17 patients initially used the gastrostomy to supplement oral intake, 4 for medication administration and 1 for hydration. Initially the PEG regime met 73% ± 31% of the estimated total energy requirements, increasing to 87% ± 32% prior to death. There was stabilization of weight in patients undergoing gastrostomy [BMI at 3 mo (22.6 ± 2.2 kg/m(2)) and 6 mo (22.5 ± 2.0 kg/m(2

  12. The digestive neuronal-glial-epithelial unit: a new actor in gut health and disease.

    Science.gov (United States)

    Neunlist, Michel; Van Landeghem, Laurianne; Mahé, Maxime M; Derkinderen, Pascal; des Varannes, Stanislas Bruley; Rolli-Derkinderen, Malvyne

    2013-02-01

    The monolayer of columnar epithelial cells lining the gastrointestinal tract--the intestinal epithelial barrier (IEB)--is the largest exchange surface between the body and the external environment. The permeability of the IEB has a central role in the regulation of fluid and nutrient intake as well as in the control of the passage of pathogens. The functions of the IEB are highly regulated by luminal as well as internal components, such as bacteria or immune cells, respectively. Evidence indicates that two cell types of the enteric nervous system (ENS), namely enteric neurons and enteric glial cells, are potent modulators of IEB functions, giving rise to the novel concept of a digestive 'neuronal-glial-epithelial unit' akin to the neuronal-glial-endothelial unit in the brain. In this Review, we summarize findings demonstrating that the ENS is a key regulator of IEB function and is actively involved in pathologies associated with altered barrier function.

  13. Atypical presentation of probable Creutzfeldt-Jakob disease associated with anti-Zic4 antibody: Literature review of neuronal antibodies in Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Salazar, Richard

    2018-05-01

    Sporadic Creutzfeldt-Jakob disease is a prion disease characterized by rapidly progressive dementia, ataxia and myoclonus. Atypical phenotype masquerading as stroke, movement disorders or autoimmune encephalitis have been described. Here, I report a probable case of sCJD with an atypical presentation associated with anti-Zic4 antibody and review the literature of neuronal antibodies in CJD. A 70 year-old gentleman is admitted with a 2-month history of recurrent stroke-like symptoms associated with behavioral disturbances, gait ataxia and rapidly progressive dementia. His initial examination demonstrated akinetic mutism, diffuse rigidity, dysautononia, and Cheyne-Stokes respiration. Over the following weeks his condition progressed to profound coma. A comprehensive infectious, metabolic, inflammatory and autoimmune work-up yielded negative results. Empiric immunosuppressive therapy ensued. He expired three months after symptoms onset. Autopsy was not performed. After his demise, prion tests came back abnormal for elevated 14-3-3 protein, total tau and positive RTQuIC. Later on, anti-Zic4 antibodies were found in serum. This case underscores the importance of a high index of suspicion for CJD even in case of atypical features or the concurrence of neuronal antibodies. Further larger prospective studies on the prevalence of these neuronal antibodies in CJD and the contribution of these autoantibodies to disease pathophysiology are necessary. Copyright © 2018 Elsevier B.V. All rights reserved.

  14. The human PNMA family: novel neuronal proteins implicated in paraneoplastic neurological disease.

    Science.gov (United States)

    Schüller, Martina; Jenne, Dieter; Voltz, Raymond

    2005-12-01

    Using sera from patients with paraneoplastic neurological syndromes, several novel neuronal autoantigens such as the paraneoplastic Ma antigens (PNMA) have been identified. Here, we report the correction and completion of the previously published prototype member PNMA1, the brain and testis restricted expression of a third member (PNMA3) and the sequences for further partially uncharacterized members of this novel neuronal protein family. Murine and rat orthologs exist for this protein family. By analogy to the pro-apoptotic MOAP1, similar functional interactions may exist between members of the PNMA family and the bcl-2 family.

  15. Stereological estimation of microglial and neuronal cell numbers in Alzheimer's disease and control brains

    DEFF Research Database (Denmark)

    Finsen, Bente; larsen, Anders Elm; Babcock, Alicia

    2017-01-01

    Lactate plays a significant role as an energy supply for neurons and has a neuroprotective effect in hypoglycemia and ischemia (1±5). Further, oligodendrocytes can use lactate for myelination when glucose levels are low. New studies suggest that lactate is not only a metabolic fuel but also a sig...

  16. Induced pluripotent stem cell-derived neuronal cells from a sporadic Alzheimer's disease donor as a model for investigating AD-associated gene regulatory networks.

    Science.gov (United States)

    Hossini, Amir M; Megges, Matthias; Prigione, Alessandro; Lichtner, Bjoern; Toliat, Mohammad R; Wruck, Wasco; Schröter, Friederike; Nuernberg, Peter; Kroll, Hartmut; Makrantonaki, Eugenia; Zouboulis, Christos C; Zoubouliss, Christos C; Adjaye, James

    2015-02-14

    Alzheimer's disease (AD) is a complex, irreversible neurodegenerative disorder. At present there are neither reliable markers to diagnose AD at an early stage nor therapy. To investigate underlying disease mechanisms, induced pluripotent stem cells (iPSCs) allow the generation of patient-derived neuronal cells in a dish. In this study, employing iPS technology, we derived and characterized iPSCs from dermal fibroblasts of an 82-year-old female patient affected by sporadic AD. The AD-iPSCs were differentiated into neuronal cells, in order to generate disease-specific protein association networks modeling the molecular pathology on the transcriptome level of AD, to analyse the reflection of the disease phenotype in gene expression in AD-iPS neuronal cells, in particular in the ubiquitin-proteasome system (UPS), and to address expression of typical AD proteins. We detected the expression of p-tau and GSK3B, a physiological kinase of tau, in neuronal cells derived from AD-iPSCs. Treatment of neuronal cells differentiated from AD-iPSCs with an inhibitor of γ-secretase resulted in the down-regulation of p-tau. Transcriptome analysis of AD-iPS derived neuronal cells revealed significant changes in the expression of genes associated with AD and with the constitutive as well as the inducible subunits of the proteasome complex. The neuronal cells expressed numerous genes associated with sub-regions within the brain thus suggesting the usefulness of our in-vitro model. Moreover, an AD-related protein interaction network composed of APP and GSK3B among others could be generated using neuronal cells differentiated from two AD-iPS cell lines. Our study demonstrates how an iPSC-based model system could represent (i) a tool to study the underlying molecular basis of sporadic AD, (ii) a platform for drug screening and toxicology studies which might unveil novel therapeutic avenues for this debilitating neuronal disorder.

  17. Therapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease.

    Science.gov (United States)

    Dal Bello-Haas, Vanina; Florence, Julaine M

    2013-05-31

    Despite the high incidence of muscle weakness in individuals with amyotrophic lateral sclerosis (ALS) or motor neuron disease (MND), the effects of exercise in this population are not well understood. This is an update of a review first published in 2008. To systematically review randomised and quasi-randomised studies of exercise for people with ALS or MND. We searched The Cochrane Neuromuscular Disease Group Specialized Register (2 July 2012), CENTRAL (2012, Issue 6 in The Cochrane Library), MEDLINE (January 1966 to June 2012), EMBASE (January 1980 to June 2012), AMED (January 1985 to June 2012), CINAHL Plus (January 1938 to June 2012), LILACS (January 1982 to June 2012), Ovid HealthSTAR (January 1975 to December 2012). We also searched ProQuest Dissertations & Theses A&I (2007 to 2012), inspected the reference lists of all papers selected for review and contacted authors with expertise in the field. We included randomised or quasi-randomised controlled trials of people with a diagnosis of definite, probable, probable with laboratory support, or possible ALS, as defined by the El Escorial criteria. We included progressive resistance or strengthening exercise, and endurance or aerobic exercise. The control condition was no exercise or standard rehabilitation management. Our primary outcome measure was improvement in functional ability, decrease in disability or reduction in rate of decline as measured by a validated outcome tool at three months. Our secondary outcome measures were improvement in psychological status or quality of life, decrease in fatigue, increase in, or reduction in rate of decline of muscle strength (strengthening or resistance studies), increase in, or reduction in rate of decline of aerobic endurance (aerobic or endurance studies) at three months and frequency of adverse effects. We did not exclude studies on the basis of measurement of outcomes. Two review authors independently assessed trial quality and extracted the data. We collected

  18. Diffuse glioblastoma resembling acute hemorrhagic leukoencephalitis.

    Science.gov (United States)

    Schettino, Carla; Caranci, Ferdinando; Lus, Giacomo; Signoriello, Elisabetta; Eoli, Marica; Anghileri, Elena; Pollo, Bianca; Melone, Mariarosa A B; Di Iorio, Giuseppe; Finocchiaro, Gaetano; Ugga, Lorenzo; Tedeschi, Enrico

    2017-10-01

    We report the case of a young man with sudden onset of diplopia after an upper respiratory tract infection. Based on the first radiological findings acute hemorrhagic leukoencephalitis, a variant of acute disseminated encephalomyelitis, was suspected and treatment with high dose intravenous dexamethasone was started but it was stopped for intolerance. The patient clinically worsened, developing gait instability, ataxia and ophthalmoplegia; brain MRI performed 20 days later showed severe progression of the disease with subependymal dissemination. After brain biopsy of the right temporal lesion the histological diagnosis was glioblastoma. These findings suggest that MRI features of acute hemorrhagic leukoencephalitis may dissimulate the diagnosis of diffuse glioma/glioblastoma. This case underscores the importance of considering diffuse glioma in the differential diagnosis of atypical signs and symptoms of acute hemorrhagic leukoencephalitis and underlines the relevant role of integrating neuroradiologic findings with neuropathology.

  19. Edaravone, a Free Radical Scavenger, Delayed Symptomatic and Pathological Progression of Motor Neuron Disease in the Wobbler Mouse.

    Directory of Open Access Journals (Sweden)

    Ken Ikeda

    Full Text Available Edaravone, a free radical scavenger is used widely in Japanese patients with acute cerebral infarction. This antioxidant could have therapeutic potentials for other neurological diseases. Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease that affects the upper and the lower motor neuron, leading to death within 3-5 years after onset. A phase III clinical trial of edaravone suggested no significant effects in ALS patients. However, recent 2nd double-blind trial has demonstrated therapeutic benefits of edaravone in definite patients diagnosed by revised El Escorial diagnostic criteria of ALS. Two previous studies showed that edaravone attenuated motor symptoms or motor neuron degeneration in mutant superoxide dismutase 1-transgenic mice or rats, animal models of familial ALS. Herein we examined whether this radical scavenger can retard progression of motor dysfunction and neuropathological changes in wobbler mice, sporadic ALS-like model. After diagnosis of the disease onset at the postnatal age of 3-4 weeks, wobbler mice received edaravone (1 or 10 mg/kg, n = 10/group or vehicle (n = 10, daily for 4 weeks by intraperitoneal administration. Motor symptoms and neuropathological changes were compared among three groups. Higher dose (10 mg/kg of edaravone treatment significantly attenuated muscle weakness and contracture in the forelimbs, and suppressed denervation atrophy in the biceps muscle and degeneration in the cervical motor neurons compared to vehicle. Previous and the present studies indicated neuroprotective effects of edaravone in three rodent ALS-like models. This drug seems to be worth performing the clinical trial in ALS patients in the United States of American and Europe, in addition to Japan.

  20. WES in a family trio suggests involvement of TECPR2 in a complex form of progressive motor neuron disease.

    Science.gov (United States)

    Covone, A E; Fiorillo, C; Acquaviva, M; Trucco, F; Morana, G; Ravazzolo, R; Minetti, C

    2016-08-01

    We have performed whole-exome sequencing in a family trio with a 16-year-old girl suffering of progressive motor neuron disease. There was no family history of the disease and no parental consanguinity. Our exome analysis indicated the proband as a compound heterozygote for two missense variants in the TECPR2 gene according to a recessive mode of inheritance. The TECPR2 gene has been reported as a positive regulator of autophagy which is an essential mechanism for maintaining neuron homeostasis and survival and plays a key role in major adult and pediatric neurodegenerative diseases. Variants in this gene have been found responsible for a recently described form of hereditary spastic paraplegia called SPG49 in two previous reports. We propose that both variants causing amino acid substitution, p.Leu684Val and p.Thr903Met, inherited in trans-phase compound heterozygote form, can be responsible for the phenotype observed in our patient. We also consider the possible contribution of a heterozygous variant in the SPG7 gene. Sanger sequencing confirmed the segregation of variants within the family tree including the patient's unaffected brother. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Neuronal identity genes regulated by super-enhancers are preferentially down-regulated in the striatum of Huntington's disease mice.

    Science.gov (United States)

    Achour, Mayada; Le Gras, Stéphanie; Keime, Céline; Parmentier, Frédéric; Lejeune, François-Xavier; Boutillier, Anne-Laurence; Néri, Christian; Davidson, Irwin; Merienne, Karine

    2015-06-15

    Huntington's disease (HD) is a neurodegenerative disease associated with extensive down-regulation of genes controlling neuronal function, particularly in the striatum. Whether altered epigenetic regulation underlies transcriptional defects in HD is unclear. Integrating RNA-sequencing (RNA-seq) and chromatin-immunoprecipitation followed by massively parallel sequencing (ChIP-seq), we show that down-regulated genes in HD mouse striatum associate with selective decrease in H3K27ac, a mark of active enhancers, and RNA Polymerase II (RNAPII). In addition, we reveal that decreased genes in HD mouse striatum display a specific epigenetic signature, characterized by high levels and broad patterns of H3K27ac and RNAPII. Our results indicate that this signature is that of super-enhancers, a category of broad enhancers regulating genes defining tissue identity and function. Specifically, we reveal that striatal super-enhancers display extensive H3K27 acetylation within gene bodies, drive transcription characterized by low levels of paused RNAPII, regulate neuronal function genes and are enriched in binding motifs for Gata transcription factors, such as Gata2 regulating striatal identity genes. Together, our results provide evidence for preferential down-regulation of genes controlled by super-enhancers in HD striatum and indicate that enhancer topography is a major parameter determining the propensity of a gene to be deregulated in a neurodegenerative disease. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  2. Patient iPSC-derived neurons for disease modeling of frontotemporal dementia with mutation in CHMP2B

    DEFF Research Database (Denmark)

    Zhang, Yu; Schmid, Benjamin; Nikolaisen, Nanett Kvist

    2017-01-01

    The truncated mutant form of the charged multivesicular body protein 2B (CHMP2B) is causative for frontotemporal dementia linked to chromosome 3 (FTD3). CHMP2B is a constituent of the endosomal sorting complex required for transport (ESCRT) and, when mutated, disrupts endosome-to-lysosome traffic...... in neurodegenerative diseases. All phenotypes observed in FTD3 neurons were rescued in CRISPR/Cas9-edited isogenic controls. These findings illustrate the relevance of our patient-specific in vitro models and open up possibilities for drug target development....

  3. Severe motor neuron degeneration in the spinal cord of the Tg2576 mouse model of Alzheimer disease.

    Science.gov (United States)

    Seo, Ji-Seon; Leem, Yea-Hyun; Lee, Kang-Woo; Kim, Seung-Woo; Lee, Ja-Kyeong; Han, Pyung-Lim

    2010-01-01

    The transgenic mouse Tg2576 is widely used as a murine model of Alzheimer's disease (AD) and exhibits plaque pathogenesis in the brain and progressive memory impairments. Here we report that Tg2576 mice also have severe spinal cord deficits. At 10 months of age, Tg2576 mice showed a severe defect in the hindlimb extension reflex test and abnormal body trembling and hindlimb tremors when suspended by the tail. The frequency and severity of these abnormalities were overt at 10 months of age and became gradually worsened. On the foot-printing analysis, Tg2576 mice had shorter and narrower strides than the non-transgenic control. Histological analyses showed that neuronal cells including cholinergic neurons in the lumbar cord of Tg2576 mice were severely reduced in number. At 16 months of age, Tg2576 mice showed high levels of amyloid-beta accumulation in the spinal cord. Consistent with this, Tg2576 mice showed that lipid peroxidation levels were increased and mitochondrial metabolic activity were significantly reduced in the spinal cord. Administration of curcumin, a natural compound that has antioxidant properties, notably reversed motor function deficits of Tg2576 mice. The enhanced lipid peroxidation and neuronal loss in the lumbar cord was also partially suppressed by curcumin. Electron microscopic analysis revealed that the sciatic nerve fibers were severely reduced in number and were demyelinated in Tg2576 mice, which were partially rescued by curcumin. These results showed that Tg2576 mice display severe degeneration of motor neurons in the spinal cord and associated motor function deficits.

  4. Neuronal nicotinic receptor agonists ameliorate spontaneous motor asymmetries and motor discoordination in a unilateral mouse model of Parkinson's disease.

    Science.gov (United States)

    Kucinski, Aaron; Wersinger, Scott; Stachowiak, Ewa K; Corso, Thomas D; Parry, Matthew J; Zhang, Jenny; Jordan, Kristen; Letchworth, Sharon; Bencherif, Merouane; Stachowiak, Michal K

    2013-10-01

    The degeneration of the nigrostriatal dopamine (DA) system underlies the motor deficits in Parkinson's disease (PD). In recent years, epidemiological reports that smokers have lower incidences of PD have brought attention to the nicotinic acetylcholine system as a potential target for novel therapeutics. Nicotine, an agonist of neuronal nicotinic receptors (NNRs), modulates functions relevant to PD via stimulation of dopaminergic transmission in the nigrostriatal pathway, particularly via activation of α6β2* and α4β2* NNRs. Recently, reduced support of DA neurons by neurotrophic growth factors has been described in PD. Fibroblast growth factor (FGF) is critical for the development and protection of adult DA neurons. In FGF-2 knockout mice and the related th-fgfr1(tk-) mouse model there is heightened sensitivity to DA neuronal oxidative neurotoxin 6-hydroxydopamine (6-OHDA). In the present study, FGF-deficient transgenic mice th-fgfr1(tk-) were used to analyze the effects of novel full (TC-8831) and partial (TC-8581) agonists of β2-containing nicotinic receptors on impaired motor behavior following unilateral 6-OHDA lesions. The lesions generated spontaneous (drug-naïve) turning asymmetries that correlated exponentially with the depletion of DA biomarkers in the lesioned striata. These mice also exhibited a reduced capacity to remain on the accelerating rotarod. Oral administration of TC-8831, an NNR agonist with high specificity for β2 subunits and a full agonist at producing DA release from striatal synaptosomes, attenuated unidirectional turning and improved motor coordination. In contrast, partial β2 NNR agonist TC-8581 had no effect on behaviors in this model. This study demonstrates the potential of NNR targeting-compounds to facilitate motor function in PD. © 2013. Published by Elsevier Inc. All rights reserved.

  5. Arginase-1 expressing microglia in close proximity to motor neurons were increased early in disease progression in canine degenerative myelopathy, a model of amyotrophic lateral sclerosis.

    Science.gov (United States)

    Toedebusch, Christine M; Snyder, John C; Jones, Maria R; Garcia, Virginia B; Johnson, Gayle C; Villalón, Eric L; Coates, Joan R; Garcia, Michael L

    2018-02-07

    Toxicity within superoxide dismutase-1 (SOD1)-associated familial amyotrophic lateral sclerosis (ALS) is non-cell autonomous with direct contribution from microglia. Microglia exhibit variable expression of neuroprotective and neurotoxic molecules throughout disease progression. The mechanisms regulating microglial phenotype within ALS are not well understood. This work presents a first study to examine the specific microglial phenotypic response in close association to motor neurons in a naturally occurring disease model of ALS, canine degenerative myelopathy (DM). Microglia closely associated with motor neurons were increased in all stages of DM progression, although only DM Late reached statistical significance. Furthermore, the number of arginase-1 expressing microglia per motor neuron were significantly increased in early stages of DM, whereas the number of inducible nitric oxide synthase (iNOS)-expressing microglia per motor neuron was indistinguishable from aged controls at all stages of disease. Fractalkine, a chemotactic molecule for microglia, was expressed in motor neurons, and the fractalkine receptor was specifically localized to microglia. However, we found no correlation between microglial response and lumbar spinal cord fractalkine levels. Taken together, these data suggest that arginase-1-expressing microglia are recruited to the motor neuron early in DM disease through a fractalkine-independent mechanism. Copyright © 2018 Elsevier Inc. All rights reserved.

  6. Osthole Stimulated Neural Stem Cells Differentiation into Neurons in an Alzheimer's Disease Cell Model via Upregulation of MicroRNA-9 and Rescued the Functional Impairment of Hippocampal Neurons in APP/PS1 Transgenic Mice

    Directory of Open Access Journals (Sweden)

    Shao-Heng Li

    2017-06-01

    Full Text Available Alzheimer's disease (AD is the most serious neurodegenerative disease worldwide and is characterized by progressive cognitive impairment and multiple neurological changes, including neuronal loss in the brain. However, there are no available drugs to delay or cure this disease. Consequently, neuronal replacement therapy may be a strategy to treat AD. Osthole (Ost, a natural coumarin derivative, crosses the blood-brain barrier and exerts strong neuroprotective effects against AD in vitro and in vivo. Recently, microRNAs (miRNAs have demonstrated a crucial role in pathological processes of AD, implying that targeting miRNAs could be a therapeutic approach to AD. In the present study, we investigated whether Ost could enhance cell viability and prevent cell death in amyloid precursor protein (APP-expressing neural stem cells (NSCs as well as promote APP-expressing NSCs differentiation into more neurons by upregulating microRNA (miR-9 and inhibiting the Notch signaling pathway in vitro. In addition, Ost treatment in APP/PS1 double transgenic (Tg mice markedly restored cognitive functions, reduced Aβ plague production and rescued functional impairment of hippocampal neurons. The results of the present study provides evidence of the neurogenesis effects and neurobiological mechanisms of Ost against AD, suggesting that Ost is a promising drug for treatment of AD or other neurodegenerative diseases.

  7. Neuronal energy-sensing pathway promotes energy balance by modulating disease tolerance.

    Science.gov (United States)

    Shen, Run; Wang, Biao; Giribaldi, Maria G; Ayres, Janelle; Thomas, John B; Montminy, Marc

    2016-06-07

    The starvation-inducible coactivator cAMP response element binding protein (CREB)-cAMP-regulated transcription coactivator (Crtc) has been shown to promote starvation resistance in Drosophila by up-regulating CREB target gene expression in neurons, although the underlying mechanism is unclear. We found that Crtc and its binding partner CREB enhance energy homeostasis by stimulating the expression of short neuropeptide F (sNPF), an ortholog of mammalian neuropeptide Y, which we show here is a direct target of CREB and Crtc. Neuronal sNPF was found to promote energy homeostasis via gut enterocyte sNPF receptors, which appear to maintain gut epithelial integrity. Loss of Crtc-sNPF signaling disrupted epithelial tight junctions, allowing resident gut flora to promote chronic increases in antimicrobial peptide (AMP) gene expression that compromised energy balance. Growth on germ-free food reduced AMP gene expression and rescued starvation sensitivity in Crtc mutant flies. Overexpression of Crtc or sNPF in neurons of wild-type flies dampens the gut immune response and enhances starvation resistance. Our results reveal a previously unidentified tolerance defense strategy involving a brain-gut pathway that maintains homeostasis through its effects on epithelial integrity.

  8. Neurons derived from sporadic Alzheimer's disease iPSCs reveal elevated TAU hyperphosphorylation, increased amyloid levels, and GSK3B activation

    DEFF Research Database (Denmark)

    Ochalek, Anna; Mihalik, Balázs; Avci, Hasan X.

    2017-01-01

    , our aim was to establish an in vitro cell model based on patient-specific human neurons to study the pathomechanism of sporadic AD. Methods: We compared neurons derived from induced pluripotent stem cell (iPSC) lines of patients with early-onset familial Alzheimer's disease (fAD), all caused......, a physiological kinase of TAU, in neurons derived from AD iPSCs, as well as significant upregulation of amyloid precursor protein (APP) synthesis and APP carboxy-terminal fragment cleavage. Moreover, elevated sensitivity to oxidative stress, as induced by amyloid oligomers or peroxide, was detected in both f...

  9. An autopsy-verified case of FTLD-TDP type A with upper motor neuron-predominant motor neuron disease mimicking MM2-thalamic-type sporadic Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Hayashi, Yuichi; Iwasaki, Yasushi; Takekoshi, Akira; Yoshikura, Nobuaki; Asano, Takahiko; Mimuro, Maya; Kimura, Akio; Satoh, Katsuya; Kitamoto, Tetsuyuki; Yoshida, Mari; Inuzuka, Takashi

    2016-11-01

    Here we report an autopsy-verified case of frontotemporal lobar degeneration (FTLD)-transactivation responsive region (TAR) DNA binding protein (TDP) type A with upper motor neuron-predominant motor neuron disease mimicking MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD). A 69-year-old woman presented with an 11-month history of progressive dementia, irritability, insomnia, and gait disturbance without a family history of dementia or prion disease. Neurological examination revealed severe dementia, frontal signs, and exaggerated bilateral tendon reflexes. Periodic sharp-wave complexes were not observed on the electroencephalogram. Brain diffusion MRI did not reveal abnormal changes. An easy Z score (eZIS) analysis for 99m Tc-ECD-single photon emission computed tomography ( 99m Tc-ECD-SPECT) revealed a bilateral decrease in thalamic regional cerebral blood flow (rCBF). PRNP gene analysis demonstrated methionine homozygosity at codon 129 without mutation. Cerebrospinal fluid (CSF) analysis showed normal levels of both 14-3-3 and total tau proteins. Conversely, prion protein was slowly amplified in the CSF by a real-time quaking-induced conversion assay. Her symptoms deteriorated to a state of akinetic mutism, and she died of sudden cardiac arrest, one year after symptom onset.  Despite the SPECT results supporting a clinical diagnosis of MM2-thalamic-type sCJD, a postmortem assessment revealed that this was a case of FTLD-TDP type A, and excluded prion disease. Thus, this case indicates that whereas a bilateral decreasing thalamic rCBF detected by 99m Tc-ECD-SPECT can be useful for diagnosing MM2-thalamic-type sCJD, it is not sufficiently specific. Postmortem diagnosis remains the gold standard for the diagnosis of this condition.

  10. Parental Investment and Resemblance: Replications, Refinements, and Revisions

    Directory of Open Access Journals (Sweden)

    Anthony A. Volk

    2007-01-01

    Full Text Available Evolutionary theory predicts that men should be more concerned with issues of false paternity than women should be concerned with false maternity. In an earlier study (Volk and Quinsey, 2002, we studied how infant cues of resemblance influenced adults' hypothetical adoption decisions. We found that self-perceived cues of resemblance were significantly more important in men's decisions than in women's. Since that study was published, conflicting results have been reported regarding a sex-difference in the importance of cues of resemblance for adoption preference. We therefore sought to replicate our findings in three new studies. In all three studies, we replicated the initial finding of a larger correlation between ratings of resemblance and ratings of adoption preference among men than among women. We also found a trend towards slightly higher global resemblance scores in younger children, suggesting that adults view infants as more anonymous and/or less uniquely distinctive than older children. However, there was wide variance in both the global resemblance and developmental changes in resemblance amongst the different child stimuli used.

  11. Theaflavin, a black tea polyphenol, protects nigral dopaminergic neurons against chronic MPTP/probenecid induced Parkinson's disease.

    Science.gov (United States)

    Anandhan, Annadurai; Tamilselvam, Kuppusamy; Radhiga, Thangaiyan; Rao, Shalinee; Essa, Musthafa Mohamed; Manivasagam, Thamilarasan

    2012-01-18

    Parkinson's disease (PD) is a progressive neurodegenerative disorder, characterized by loss of dopominergic neurons in substantia nigra pars compacta, and can be experimentally induced by the neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Chronic administration of MPTP/probenecid (MPTP/p) leads to oxidative stress, induction of apoptosis, and loss of dopominergic neurons which results in motor impairments. Epidemiological studies have shown an inverse relationship between tea consumption and susceptibility to PD. Theaflavin is a black tea polyphenol, which possess a wide variety of pharmacological properties including potent anti oxidative, anti apoptotic and anti inflammatory effects. The current study is aimed to assess the effect of theaflavin against MPTP/p induced neurodegenaration in C57BL/6 mice. We found that the theaflavin attenuates MPTP/p induced apoptosis and neurodegeneration as evidenced by increased expression of nigral tyrosine hydroxylase (TH), dopamine transporter (DAT) and reduced apoptotic markers such as caspase-3, 8, 9 accompanied by normalized behavioral characterization. This may be due to anti oxidative and anti apoptotic activity and these data indicate that theaflavin may provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative diseases such as PD. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

  12. In situ hybridization of nucleus basalis neurons shows increased β-amyloid mRNA in Alzheimer disease

    International Nuclear Information System (INIS)

    Cohen, M.L.; Golde, T.E.; Usiak, M.F.; Younkin, L.H.; Younkin, S.G.

    1988-01-01

    To determine which cells within the brain produce β-amyloid mRNA and to assess expression of the β-amyloid gene in Alzheimer disease, the authors analyzed brain tissue from Alzheimer and control patients by in situ hybridization. The results demonstrate that β-amyloid mRNA is produced by neurons in the nucleus basalis of Meynert and cerebral cortex and that nuclues basalis perikarya from Alzheimer patients consistently hybridize more β-amyloid probe than those from controls. These observations support the hypothesis that increased expression of the β-amyloid gene plays an important role in the deposition of amyloid in the brains of patients with Alzheimer disease

  13. A Para-Canalicular Abscess Resembling an Inflamed Chalazion

    Directory of Open Access Journals (Sweden)

    Diamantis Almaliotis

    2013-01-01

    Full Text Available Background. Lacrimal infections by Actinomyces are rare and commonly misdiagnosed for long periods of time. They account for 2% of all lacrimal diseases. Case Report. We report a case of a 70-year-old female patient suffering from a para-canalicular abscess in the medial canthus of the left eye, beside the lower punctum lacrimale, resembling a chalazion. Purulence exited from the punctum lacrimale due to inflammation of the inferior canaliculus (canaliculitis. When pressure was applied to the mass, a second exit of purulence was also observed under the palpebral conjunctiva below the lacrimal caruncle. A surgical excision was performed followed by administration of local antibiotic therapy. The histopathological examination of the extracted mass revealed the existence of actinomycosis. Conclusion. Persistent or recurrent infections and lumps of the eyelids should be thoroughly investigated. Actinomyces as a causative agent should be considered. Differential diagnosis is broad and should include canaliculitis, chalazion, and multiple types of neoplasias. For this reason, in nonconclusive cases, a histopathological examination should be performed.

  14. A para-canalicular abscess resembling an inflamed chalazion.

    Science.gov (United States)

    Almaliotis, Diamantis; Nakos, Elias; Siempis, Thomas; Koletsa, Triantafyllia; Kostopoulos, Ioannis; Chatzipantazi, Maria; Karampatakis, Vasileios

    2013-01-01

    Background. Lacrimal infections by Actinomyces are rare and commonly misdiagnosed for long periods of time. They account for 2% of all lacrimal diseases. Case Report. We report a case of a 70-year-old female patient suffering from a para-canalicular abscess in the medial canthus of the left eye, beside the lower punctum lacrimale, resembling a chalazion. Purulence exited from the punctum lacrimale due to inflammation of the inferior canaliculus (canaliculitis). When pressure was applied to the mass, a second exit of purulence was also observed under the palpebral conjunctiva below the lacrimal caruncle. A surgical excision was performed followed by administration of local antibiotic therapy. The histopathological examination of the extracted mass revealed the existence of actinomycosis. Conclusion. Persistent or recurrent infections and lumps of the eyelids should be thoroughly investigated. Actinomyces as a causative agent should be considered. Differential diagnosis is broad and should include canaliculitis, chalazion, and multiple types of neoplasias. For this reason, in nonconclusive cases, a histopathological examination should be performed.

  15. Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension.

    Science.gov (United States)

    Ghobadi, G; Bartelds, B; van der Veen, S J; Dickinson, M G; Brandenburg, S; Berger, R M F; Langendijk, J A; Coppes, R P; van Luijk, P

    2012-04-01

    Pulmonary arterial hypertension (PAH) is a commonly fatal pulmonary vascular disease that is often diagnosed late and is characterised by a progressive rise in pulmonary vascular resistance resulting from typical vascular remodelling. Recent data suggest that vascular damage plays an important role in the development of radiation-induced pulmonary toxicity. Therefore, the authors investigated whether irradiation of the lung also induces pulmonary hypertension. Different sub-volumes of the rat lung were irradiated with protons known to induce different levels of pulmonary vascular damage. Early loss of endothelial cells and vascular oedema were observed in the irradiation field and in shielded parts of the lung, even before the onset of clinical symptoms. 8 weeks after irradiation, irradiated volume-dependent vascular remodelling was observed, correlating perfectly with pulmonary artery pressure, right ventricle hypertrophy and pulmonary dysfunction. The findings indicate that partial lung irradiation induces pulmonary vascular remodelling resulting from acute pulmonary endothelial cell loss and consequential pulmonary hypertension. Moreover, the close resemblance of the observed vascular remodelling with vascular lesions in PAH makes partial lung irradiation a promising new model for studying PAH.

  16. Extended retroperitoneal necrotizing fasciitis with genital involvement, resembling fournier gangrene.

    Science.gov (United States)

    Sugimoto, Motokazu; Matsuura, Kenji; Takayama, Hiroshi; Kayo, Munefumi; Ie, Tomotsugu

    2010-10-01

    Necrotizing fasciitis is a serious infection that originates in the subcutaneous tissues. Although many reports have been published about necrotizing infections of other anatomical sites, retroperitoneal necrotizing soft tissue infection is a rare entity that has been described in only a few case reports. The etiology and clinical course of retroperitoneal necrotizing fasciitis can be variable and it is often difficult to identify the etiology of the infective process. We report a 58-year-old man with rapidly progressive, gas-producing, necrotizing inflammation in the retroperitoneum, complicated with genital involvement resembling Fournier gangrene. The patient was managed successfully by aggressive drainage, debridement, and sequential laparotomies to track and control the extensive necrosis of the retroperitoneum and perineum, in addition to systemic care to control sepsis. After his general condition stabilized, early rectosigmoid adenocarcinoma was identified and resected curatively. He remained well at follow up, six months after discharge. In retrospect, the trigger of the disease process was unclear. Although it was believed possibly to be due to the colon lesion, adenocarcinoma of the rectosigmoid colon was identified and the patient was managed successfully. Similar to necrotizing infections at other anatomical sites, early diagnosis and timely surgical intervention and systemic antimicrobial therapy are mandatory for treating patients with retroperitoneal necrotizing fasciitis.

  17. From the axons of the SNc dopamine neurons to their dendritic processes: further clues to susceptibility in Parkinson’s disease (PD?

    Directory of Open Access Journals (Sweden)

    Eleftheria Kyriaki Pissadaki

    2014-04-01

    Full Text Available Dopamine neurons of the substantia nigra pars compacta (SNc are uniquely sensitive to degeneration in Parkinson’s disease (PD and its models. Although a variety of molecular characteristics have been proposed to underlie this sensitivity, one possible contributory factor is their massive, unmyelinated, axonal arbor that is orders of magnitude larger than other neuronal types. In our previously published work, we examined the energetic impact imposed on SNc dopamine neurons by their extensive, unmyelinated axonal arbor and attempted to calculate the energy cost of action potential (AP propagation throughout the axonal arbors. Among our main findings were that a the energy demand associated with AP conduction is related in a supra-linear manner to the axonal size and complexity and, b that synaptic stimulation is necessary to ensure reliable propagation throughout the axonal arbors of neurons with higher levels of branching. Indeed, predictions of our biophysical model of SNc dopamine neurons suggest that tonic activity for the reliable propagation of APs throughout the axonal arbour of neurons with small-to-moderate size arbours, whereas synaptic stimulation is required for for reliable propagation in neurons with larger and more complex arbors (Pissadaki and Bolam 2013. SNc dopamine neurons may thus be classified into functionally distinct groups according to the size of their axonal arborisation. Furthermore, SNc dopamine neurons are divided into ventral tier neurons, which are more susceptible in PD and extend their dendrites in both SN pars reticulata (SNr and SNc, and dorsal tier neurons that restrict their dendrites within SNc. As SNr dendrites receive proportionally greater inhibitory input than SNc dendrites (Henny et al 2012, we examined the relationship between the dendritic compartmentalisation, synaptic input, burst generation and the extent of axonal arborisation. Because spatiotemporal interplay of synaptic stimulation has been

  18. Reconstruction of multicompartment oriented neuronal networks for the study of neurodegenerative diseases

    DEFF Research Database (Denmark)

    Vignes, Maéva; Deleglise, Bérangère; Gougis, Paul

    2010-01-01

    Experimental models used to study brain development and degeneration range from whole animal models, which preserve the anatomical structures but greatly limit the experimentation at the cellular level, to dissociated cell culture systems, that allow detailed manipulation of cell phenotype but lack...... the highly ordered and instructive brain environment. Thus new experimental models are needed to facilitate both individual cell manipulation and brain connectivity reconstruction. Here we present powerful microfluidic cell culture systems that allow us to handle neurons and axons in micron size environments...

  19. Application of the Physical Disector Principle for Quantification of Dopaminergic Neuronal Loss in a Rat 6-Hydroxydopamine Nigral Lesion Model of Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Katrine Fabricius

    2017-12-01

    Full Text Available Stereological analysis is the optimal tool for quantitative assessment of brain morphological and cellular changes induced by neurotoxic lesions or treatment interventions. Stereological methods based on random sampling techniques yield unbiased estimates of particle counts within a defined volume, thereby providing a true quantitative estimate of the target cell population. Neurodegenerative diseases involve loss of specific neuron types, such as the midbrain tyrosine hydroxylase-positive dopamine neurons in Parkinson's disease and in animal models of nigrostriatal degeneration. Therefore, we applied an established automated physical disector principle in a fractionator design for efficient stereological quantitative analysis of tyrosine hydroxylase (TH-positive dopamine neurons in the substantia nigra pars compacta of hemiparkinsonian rats with unilateral 6-hydroxydopamine (6-OHDA lesions. We obtained reliable estimates of dopamine neuron numbers, and established the relationship between behavioral asymmetry and dopamine neuron loss on the lesioned side. In conclusion, the automated physical disector principle provided a useful and efficient tool for unbiased estimation of TH-positive neurons in rat midbrain, and should prove valuable for investigating neuroprotective strategies in 6-OHDA model of parkinsonism, while generalizing to other immunohistochemically-defined cell populations.

  20. Cholesterol contributes to dopamine-neuronal loss in MPTP mouse model of Parkinson's disease: Involvement of mitochondrial dysfunctions and oxidative stress.

    Directory of Open Access Journals (Sweden)

    Rajib Paul

    Full Text Available Hypercholesterolemia is a known contributor to the pathogenesis of Alzheimer's disease while its role in the occurrence of Parkinson's disease (PD is only conjecture and far from conclusive. Altered antioxidant homeostasis and mitochondrial functions are the key mechanisms in loss of dopaminergic neurons in the substantia nigra (SN region of the midbrain in PD. Hypercholesterolemia is reported to cause oxidative stress and mitochondrial dysfunctions in the cortex and hippocampus regions of the brain in rodents. However, the impact of hypercholesterolemia on the midbrain dopaminergic neurons in animal models of PD remains elusive. We tested the hypothesis that hypercholesterolemia in MPTP model of PD would potentiate dopaminergic neuron loss in SN by disrupting mitochondrial functions and antioxidant homeostasis. It is evident from the present study that hypercholesterolemia in naïve animals caused dopamine neuronal loss in SN with subsequent reduction in striatal dopamine levels producing motor impairment. Moreover, in the MPTP model of PD, hypercholesterolemia exacerbated MPTP-induced reduction of striatal dopamine as well as dopaminergic neurons in SN with motor behavioral depreciation. Activity of mitochondrial complexes, mainly complex-I and III, was impaired severely in the nigrostriatal pathway of hypercholesterolemic animals treated with MPTP. Hypercholesterolemia caused oxidative stress in the nigrostriatal pathway with increased generation of hydroxyl radicals and enhanced activity of antioxidant enzymes, which were further aggravated in the hypercholesterolemic mice with Parkinsonism. In conclusion, our findings provide evidence of increased vulnerability of the midbrain dopaminergic neurons in PD with hypercholesterolemia.

  1. Beyond weakness: Characterization of pain, sensory profile and conditioned pain modulation in patients with motor neuron disease: A controlled study.

    Science.gov (United States)

    Lopes, L C G; Galhardoni, R; Silva, V; Jorge, F M H; Yeng, L T; Callegaro, D; Chadi, G; Teixeira, M J; Ciampi de Andrade, D

    2018-01-01

    Motor neuron diseases (MND) represent a group of disorders that evolve with inexorable muscle weakness and medical management is based on symptom control. However, deeper characterization of non-motor symptoms in these patients have been rarely reported. This cross-sectional study aimed to describe non-motor symptoms in MND and their impact on quality of life and functional status, with a focus on pain and sensory changes. Eighty patients (31 females, 55.7 ± 12.9 years old) with MND underwent a neurological examination, pain, mood, catastrophizing and psychophysics assessments [quantitative sensory testing (QST) and conditioned pain modulation (CPM)], and were compared to sex- and age-matched healthy controls (HC). Chronic pain was present in 46% of patients (VAS =5.18 ± 2.0). Pain of musculoskeletal origin occurred in 40.5% and was mainly located in the head/neck (51%) and lower back (35%). Neuropathic pain was not present in this sample. Compared to HC, MND patients had a lower cold detection threshold (p catastrophism, and spasticity scores were inversely correlated with CPM (ρ = -0.30, p = 0.026). Pain is frequently reported by patients with MNDs. Somatosensory and CPM changes exist in MNDs and may be related to the neurodegenerative nature of the disease. Further studies should investigate the most appropriate treatment strategies for these patients. We report a comprehensive evaluation of pain and sensory abnormalities in motor neuron disease (MND) patients. We assessed the different pain syndromes present in MND with validated tools, and described the QST and conditioned pain modulation profiles in a controlled design. © 2017 European Pain Federation - EFIC®.

  2. Influence of electroencephalograph bionic electrical stimulation on neuronal activities in patients with Alzheimer's disease: A functional magnetic resonance imaging study

    Directory of Open Access Journals (Sweden)

    Liling Jiang

    2018-03-01

    Full Text Available Purpose: To investigate the influence of electroencephalograph bionic electrical stimulation on neuronal activity in patients with Alzheimer's disease (AD using resting-state blood oxygen level dependent functional MRI (BOLD-fMRI and amplitude of low-frequency fluctuation (ALFF and fraction ALFF (fALFF analysis. Methods: 42 AD patients were divided into two groups in accordance with the randomized double blind principle, every group was 21. Treatment group received electroencephalograph bionic electrical stimulation. Both groups received resting-state BOLD-fMRI scanning before and after treatment and comparing differences in ALFF and fALFF in each group by statistical methods. Correlation analysis was performed between ALFF or fALFF images and neuropsychological tests scale after treatment. Results: Post-therapy brain regions with higher ALFF included left cerebellum posterior lobe, right cerebellum posterior lobe, left hippocampus/parahippocampus, left posterior cingulated cortex, left dorsolateral prefrontal cortex, right inferior parietal lobule in treatment group. Higher fALFF was observed in the right inferior parietal lobule. In the placebo group lower ALFF was observed in bilateral cerebellum posterior lobe and left posterior cingulated cortex. Alzheimer's Disease Assessment Scale-Cognitive section was closely correlated with ALFF in left cerebellum posterior lobe and right cerebellum posterior lobe. Conclusion: These results indicated improved neuronal activity in some brain areas could be achieved in AD after treatment of electroencephalograph bionic electrical stimulation. The change of BOLD-fMRI signal might provide a potential imaging strategy for studying neural mechanisms of electroencephalograph bionic electrical stimulation for AD. Keywords: Electroencephalograph bionic electrical stimulation, Alzheimer's disease, Low-frequency fluctuation, Fraction low-frequency fluctuation

  3. Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy.

    Science.gov (United States)

    Cortes, Constanza J; Ling, Shuo-Chien; Guo, Ling T; Hung, Gene; Tsunemi, Taiji; Ly, Linda; Tokunaga, Seiya; Lopez, Edith; Sopher, Bryce L; Bennett, C Frank; Shelton, G Diane; Cleveland, Don W; La Spada, Albert R

    2014-04-16

    X-linked spinal and bulbar muscular atrophy (SBMA) is characterized by adult-onset muscle weakness and lower motor neuron degeneration. SBMA is caused by CAG-polyglutamine (polyQ) repeat expansions in the androgen receptor (AR) gene. Pathological findings include motor neuron loss, with polyQ-AR accumulation in intranuclear inclusions. SBMA patients exhibit myopathic features, suggesting a role for muscle in disease pathogenesis. To determine the contribution of muscle, we developed a BAC mouse model featuring a floxed first exon to permit cell-type-specific excision of human AR121Q. BAC fxAR121 mice develop systemic and neuromuscular phenotypes, including shortened survival. After validating termination of AR121 expression and full rescue with ubiquitous Cre, we crossed BAC fxAR121 mice with Human Skeletal Actin-Cre mice. Muscle-specific excision prevented weight loss, motor phenotypes, muscle pathology, and motor neuronopathy and dramatically extended survival. Our results reveal a crucial role for muscle expression of polyQ-AR in SBMA and suggest muscle-directed therapies as effective treatments. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Prion replication occurs in endogenous adult neural stem cells and alters their neuronal fate: involvement of endogenous neural stem cells in prion diseases.

    Directory of Open Access Journals (Sweden)

    Aroa Relaño-Ginès

    Full Text Available Prion diseases are irreversible progressive neurodegenerative diseases, leading to severe incapacity and death. They are characterized in the brain by prion amyloid deposits, vacuolisation, astrocytosis, neuronal degeneration, and by cognitive, behavioural and physical impairments. There is no treatment for these disorders and stem cell therapy therefore represents an interesting new approach. Gains could not only result from the cell transplantation, but also from the stimulation of endogenous neural stem cells (NSC or by the combination of both approaches. However, the development of such strategies requires a detailed knowledge of the pathology, particularly concerning the status of the adult neurogenesis and endogenous NSC during the development of the disease. During the past decade, several studies have consistently shown that NSC reside in the adult mammalian central nervous system (CNS and that adult neurogenesis occurs throughout the adulthood in the subventricular zone of the lateral ventricle or the Dentate Gyrus of the hippocampus. Adult NSC are believed to constitute a reservoir for neuronal replacement during normal cell turnover or after brain injury. However, the activation of this system does not fully compensate the neuronal loss that occurs during neurodegenerative diseases and could even contribute to the disease progression. We investigated here the status of these cells during the development of prion disorders. We were able to show that NSC accumulate and replicate prions. Importantly, this resulted in the alteration of their neuronal fate which then represents a new pathologic event that might underlie the rapid progression of the disease.

  5. Clinical utility of neuronal cells directly converted from fibroblasts of patients for neuropsychiatric disorders: studies of lysosomal storage diseases and channelopathy

    Science.gov (United States)

    Kano, Shin-ichi; Yuan, Ming; Cardarelli, Ross A.; Maegawa, Gustavo; Higurashi, Norimichi; Gaval-Cruz, Meriem; Wilson, Ashley M.; Tristan, Carlos; Kondo, Mari A.; Chen, Yian; Koga, Minori; Obie, Cassandra; Ishizuka, Koko; Seshadri, Saurav; Srivastava, Rupali; Kato, Takahiro A.; Horiuchi, Yasue; Sedlak, Thomas W.; Lee, Yohan; Rapoport, Judith L.; Hirose, Shinichi; Okano, Hideyuki; Valle, David; O'Donnell, Patricio; Sawa, Akira; Kai, Mihoko

    2015-01-01

    Methodologies for generating functional neuronal cells directly from human fibroblasts [induced neuronal (iN) cells] have been recently developed, but the research so far has only focused on technical refinements or recapitulation of known pathological phenotypes. A critical question is whether this novel technology will contribute to elucidation of novel disease mechanisms or evaluation of therapeutic strategies. Here we have addressed this question by studying Tay-Sachs disease, a representative lysosomal storage disease, and Dravet syndrome, a form of severe myoclonic epilepsy in infancy, using human iN cells with feature of immature postmitotic glutamatergic neuronal cells. In Tay-Sachs disease, we have successfully characterized canonical neuronal pathology, massive accumulation of GM2 ganglioside, and demonstrated the suitability of this novel cell culture for future drug screening. In Dravet syndrome, we have identified a novel functional phenotype that was not suggested by studies of classical mouse models and human autopsied brains. Taken together, the present study demonstrates that human iN cells are useful for translational neuroscience research to explore novel disease mechanisms and evaluate therapeutic compounds. In the future, research using human iN cells with well-characterized genomic landscape can be integrated into multidisciplinary patient-oriented research on neuropsychiatric disorders to address novel disease mechanisms and evaluate therapeutic strategies. PMID:25732146

  6. Co-transplantation of GDNF-overexpressing neural stem cells and fetal dopaminergic neurons mitigates motor symptoms in a rat model of Parkinson's disease.

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    Xingli Deng

    Full Text Available Striatal transplantation of dopaminergic (DA neurons or neural stem cells (NSCs has been reported to improve the symptoms of Parkinson's disease (PD, but the low rate of cell survival, differentiation, and integration in the host brain limits the therapeutic efficacy. We investigated the therapeutic effects of intracranial co-transplantation of mesencephalic NSCs stably overexpressing human glial-derived neurotrophic factor (GDNF-mNSCs together with fetal DA neurons in the 6-OHDA rat model of PD. Striatal injection of mNSCs labeled by the contrast enhancer superparamagnetic iron oxide (SPIO resulted in a hypointense signal in the striatum on T2-weighted magnetic resonance images that lasted for at least 8 weeks post-injection, confirming the long-term survival of injected stem cells in vivo. Co-transplantation of GDNF-mNSCs with fetal DA neurons significantly reduced apomorphine-induced rotation, a behavioral endophenotype of PD, compared to sham-treated controls, rats injected with mNSCs expressing empty vector (control mNSCs plus fetal DA neurons, or rats injected separately with either control mNSCs, GDNF-mNSCs, or fetal DA neurons. In addition, survival and differentiation of mNSCs into DA neurons was significantly greater following co-transplantation of GDNF-mNSCs plus fetal DA neurons compared to the other treatment groups as indicated by the greater number of cell expressing both the mNSCs lineage tracer enhanced green fluorescent protein (eGFP and the DA neuron marker tyrosine hydroxylase. The success of cell-based therapies for PD may be greatly improved by co-transplantation of fetal DA neurons with mNSCs genetically modified to overexpress trophic factors such as GDNF that support differentiation into DA cells and their survival in vivo.

  7. Deep brain stimulation of the internal pallidum in Huntington's disease patients: clinical outcome and neuronal firing patterns.

    Science.gov (United States)

    Delorme, Cécile; Rogers, Alister; Lau, Brian; Francisque, Hélène; Welter, Marie-Laure; Vidal, Sara Fernandez; Yelnik, Jérôme; Durr, Alexandra; Grabli, David; Karachi, Carine

    2016-02-01

    Deep brain stimulation (DBS) of the internal globus pallidus (GPi) could treat chorea in Huntington's disease patients. The objectives of this study were to evaluate the efficacy of GPi-DBS to reduce abnormal movements of three patients with Huntington's disease and assess tolerability. Three non-demented patients with severe pharmacoresistant chorea underwent bilateral GPi-DBS and were followed for 30, 24, and 12 months, respectively. Primary outcome measure was the change of the chorea and total motor scores of the Unified Huntington's Disease Rating Scale between pre- and last postoperative assessments. Secondary outcome measures were motor changes between ventral versus dorsal and between on- and off- GPi-DBS. GPi neuronal activities were analyzed and compared to those obtained in patients with Parkinson's disease. No adverse effects occurred. Chorea decreased in all patients (13, 67 and 29%) postoperatively. Total motor score decreased in patient 2 (19.6%) and moderately increased in patients 1 and 3 (17.5 and 1.7%), due to increased bradykinesia and dysarthria. Ventral was superior to dorsal GPi-DBS to control chorea. Total motor score increased dramatically off-stimulation compared to ventral GPi-DBS (70, 63 and 19%). Cognitive and psychic functions were overall unchanged. Lower mean rate and less frequent bursting activity were found in Huntington's disease compared to Parkinson's disease patients. Ventral GPi-DBS sustainably reduced chorea, but worsened bradykinesia and dysarthria. Based on these results and previous published reports, we propose to select non-demented HD patients with severe chorea, and a short disease evolution as the best candidates for GPi-DBS.

  8. Aberrant Levels of Hematopoietic/Neuronal Growth and Differentiation Factors in Euthyroid Women at Risk for Autoimmune Thyroid Disease.

    Directory of Open Access Journals (Sweden)

    Elske T Massolt

    Full Text Available Subjects at risk for major mood disorders have a higher risk to develop autoimmune thyroid disease (AITD and vice-versa, implying a shared pathogenesis. In mood disorder patients, an abnormal profile of hematopoietic/neuronal growth factors is observed, suggesting that growth/differentiation abnormalities of these cell lineages may predispose to mood disorders. The first objective of our study was to investigate whether an aberrant profile of these hematopoietic/neuronal growth factors is also detectable in subjects at risk for AITD. A second objective was to study the inter relationship of these factors with previously determined and published growth factors/cytokines in the same subjects.We studied 64 TPO-Ab-negative females with at least 1 first- or second-degree relative with AITD, 32 of whom did and 32 who did not seroconvert to TPO-Ab positivity in 5-year follow-up. Subjects were compared with 32 healthy controls (HCs. We measured serum levels of brain-derived neurotrophic factor (BDNF, Stem Cell Factor (SCF, Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2, Epidermal Growth Factor (EGF and IL-7 at baseline.BDNF was significantly lower (8.2 vs 18.9 ng/ml, P<0.001, while EGF (506.9 vs 307.6 pg/ml, P = 0.003 and IGFBP-2 (388.3 vs 188.5 ng/ml, P = 0.028 were significantly higher in relatives than in HCs. Relatives who seroconverted in the next 5 years had significantly higher levels of SCF than non-seroconverters (26.5 vs 16.7 pg/ml, P = 0.017. In a cluster analysis with the previously published growth factors/cytokines SCF clustered together with IL-1β, IL-6 and CCL-3, of which high levels also preceded seroconversion.Relatives of AITD patients show aberrant serum levels of 4 hematopoietic/neuronal growth factors similar to the aberrancies found in mood disorder patients, suggesting that shared growth and differentiation defects in both the hematopoietic and neuronal system may underlie thyroid autoimmunity and mood disorders. A

  9. DNA polymerase-beta is expressed early in neurons of Alzheimer's disease brain and is loaded into DNA replication forks in neurons challenged with beta-amyloid

    NARCIS (Netherlands)

    Copani, Agata; Hoozemans, Jeroen J. M.; Caraci, Filippo; Calafiore, Marco; van Haastert, Elise S.; Veerhuis, Robert; Rozemuller, Annemieke J. M.; Aronica, Eleonora; Sortino, Maria Angela; Nicoletti, Ferdinando

    2006-01-01

    Cultured neurons exposed to synthetic beta-amyloid (Abeta) fragments reenter the cell cycle and initiate a pathway of DNA replication that involves the repair enzyme DNA polymerase-beta (DNA pol-beta) before undergoing apoptotic death. In this study, by performing coimmunoprecipitation experiments

  10. New cases of adult-onset Sandhoff disease with a cerebellar or lower motor neuron phenotype.

    NARCIS (Netherlands)

    Delnooz, C.C.S.; Lefeber, D.J.; Langemeijer, S.M.C.; Hoffjan, S.; Dekomien, G.; Zwarts, M.J.; Engelen, B.G.M. van; Wevers, R.A.; Schelhaas, H.J.; Warrenburg, B.P.C. van de

    2010-01-01

    Sandhoff disease is a lipid-storage disorder caused by a defect in ganglioside metabolism. It is caused by a lack of functional N-acetyl-beta-d-glucosaminidase A and B due to mutations in the HEXB gene. Typical, early-onset Sandhoff disease presents before 9 months of age with progressive

  11. Dental pulp stem cells promote regeneration of damaged neuron cells on the cellular model of Alzheimer's disease.

    Science.gov (United States)

    Wang, Feixiang; Jia, Yali; Liu, Jiajing; Zhai, Jinglei; Cao, Ning; Yue, Wen; He, Huixia; Pei, Xuetao

    2017-06-01

    Alzheimer's disease (AD) is an incurable neurodegenerative disease and many types of stem cells have been used in AD therapy with some favorable effects. In this study, we investigated the potential therapeutical effects of human dental pulp stem cells (hDPSCs) on AD cellular model which established by okadaic acid (OA)-induced damage to human neuroblastoma cell line, SH-SY5Y, in vitro for 24 h. After confirmed the AD cellular model, the cells were co-culture with hDPSCs by transwell co-culture system till 24 h for treatment. Then the cytomorphology of the hDPSCs-treated cells were found to restore gradually with re-elongation of retracted dendrites. Meanwhile, Cell Counting Kit-8 assay and Hoechst 33258 staining showed that hDPSCs caused significant increase in the viability and decrease in apoptosis of the model cells, respectively. Observation of DiI labeling also exhibited the prolongation dendrites in hDPSCs-treated cells which were obviously different from the retraction dendrites in AD model cells. Furthermore, specific staining of α-tubulin and F-actin demonstrated that the hDPSCs-treated cells had the morphology of restored neurons, with elongated dendrites, densely arranged microfilaments, and thickened microtubular fibrils. In addition, results from western blotting revealed that phosphorylation at Ser 396 of Tau protein was significantly suppressed by adding of hDPSCs. These results indicate that hDPSCs may promote regeneration of damaged neuron cells in vitro model of AD and may serve as a useful cell source for treatment of AD. © 2017 International Federation for Cell Biology.

  12. Wheat germ agglutinin-conjugated liposomes incorporated with cardiolipin to improve neuronal survival in Alzheimer’s disease treatment

    Directory of Open Access Journals (Sweden)

    Kuo YC

    2017-03-01

    Full Text Available Yung-Chih Kuo,1 Che-Yu Lin,1 Jay-Shake Li,2 Yung-I Lou3 1Department of Chemical Engineering, 2Department of Psychology, National Chung Cheng University, Chia-Yi, 3Department of Accounting, Providence University, Taichung, Taiwan, Republic of China Abstract: Curcumin (CRM and nerve growth factor (NGF were entrapped in liposomes (LIP with surface wheat germ agglutinin (WGA to downregulate the phosphorylation of kinases in Alzheimer’s disease (AD therapy. Cardiolipin (CL-conjugated LIP carrying CRM (CRM-CL/LIP and also carrying NGF (NGF-CL/LIP were used with AD models of SK-N-MC cells and Wistar rats after an insult with β-amyloid peptide (Aβ. We found that CRM-CL/LIP inhibited the expression of phosphorylated p38 (p-p38, phosphorylated c-Jun N-terminal kinase (p-JNK, and p-tau protein at serine 202 and prevented neurodegeneration of SK-N-MC cells. In addition, NGF-CL/LIP could enhance the quantities of p-neurotrophic tyrosine kinase receptor type 1 and p-extracellular signal-regulated kinase 5 for neuronal rescue. Moreover, WGA-grafted CRM-CL/LIP and WGA-grafted NGF-CL/LIP significantly improved the permeation of CRM and NGF across the blood–brain barrier, reduced Aβ plaque deposition and the malondialdehyde level, and increased the percentage of normal neurons and cholinergic activity in the hippocampus of AD rats. Based on the marker expressions and in vivo evidence, current LIP carriers can be promising drug delivery systems to protect nervous tissue against Aβ-induced apoptosis in the brain during the clinical management of AD. Keywords: liposome, Alzheimer’s disease, β-amyloid, neurodegeneration, blood–brain barrier, wheat germ agglutinin

  13. Three-dimensional functional human neuronal networks in uncompressed low-density electrospun fiber scaffolds.

    Science.gov (United States)

    Jakobsson, Albin; Ottosson, Maximilian; Zalis, Marina Castro; O'Carroll, David; Johansson, Ulrica Englund; Johansson, Fredrik

    2017-05-01

    We demonstrate an artificial three-dimensional (3D) electrical active human neuronal network system, by the growth of brain neural progenitors in highly porous low density electrospun poly-ε-caprolactone (PCL) fiber scaffolds. In neuroscience research cell-based assays are important experimental instruments for studying neuronal function in health and disease. Traditional cell culture at 2D-surfaces induces abnormal cell-cell contacts and network formation. Hence, there is a tremendous need to explore in vivo-resembling 3D neural cell culture approaches. We present an improved electrospinning method for fabrication of scaffolds that promote neuronal differentiation into highly 3D integrated networks, formation of inhibitory and excitatory synapses and extensive neurite growth. Notably, in 3D scaffolds in vivo-resembling intermixed neuronal and glial cell network were formed, whereas in parallel 2D cultures a neuronal cell layer grew separated from an underlying glial cell layer. Hence, the use of the 3D cell assay presented will most likely provide more physiological relevant results. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  14. Is the risk of motor neuron disease increased or decreased after cancer? An Australian case-control study.

    Directory of Open Access Journals (Sweden)

    Alex Stoyanov

    Full Text Available Cancer appears to be inversely associated with both Alzheimer's and Parkinson's disease. The relationship between cancer and sporadic motor neuron disease (SMND, however, remains uncertain. Most previous cancer-SMND studies have been undertaken in northern hemisphere populations. We therefore undertook a case-control study to see if a link between cancer and SMND exists in an Australian population. A questionnaire was used to compare past cancer diagnoses in 739 SMND patients and 622 controls, recruited across Australia. Odds ratios with 95% confidence intervals were calculated to look for associations between cancer and SMND. A history of cancer was not associated either positively or negatively with a risk of subsequent SMND. This result remained when age, gender, smoking status, and the four SMND diagnostic subgroups were taken into account. No association was observed between SMND and specific tumours, including melanoma, a common malignancy in Australia. In conclusion, this Australian case-control study does not support an association between a past history of cancer and the development of SMND. This suggests that some pathogenetic mechanisms, such as apoptosis, are less relevant in SMND than in other neurodegenerative diseases where negative associations with cancer have been found.

  15. NABi, a novel β-sheet breaker, inhibits Aβ aggregation and neuronal toxicity: Therapeutic implications for Alzheimer's disease.

    Science.gov (United States)

    Jang, Ja-Young; Rhim, Hyangshuk; Kang, Seongman

    2018-01-01

    Amyloid beta (Aβ) aggregates are an important therapeutic target for Alzheimer's disease (AD), a fatal neurodegenerative disease. To date, AD still remains a big challenge due to no effective treatments. Based on the property that Aβ aggregates have the cross-β-structure, a common structural feature in amyloids, we systemically designed the Aβ-aggregation inhibitor that maintains Aβ-interacting ability but removes toxic part from SOD1 (superoxide dismutase 1)-G93A. We identified NABi (Natural Aβ Binder and Aβ-aggregation inhibitor) composed of β2-3 strands, a novel breaker of Aβ aggregation, which does not self-aggregate and has no cytotoxicity at all. The NABi blocks Aβ-fibril formation in vitro and in vivo and prevents neuronal cell death, a hallmark of AD pathogenesis. Such anti-amyloidogenic properties can provide novel strategies for treating AD. Furthermore, our study provides molecular insights into the design of amyloidogenic inhibitors to cure various neurodegenerative and amyloid-associated diseases, as NABi would regulate aggregation of other toxic β-sheet proteins other than Aβ. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Enteric neurons show a primary cilium.

    Science.gov (United States)

    Luesma, Ma José; Cantarero, Irene; Castiella, Tomás; Soriano, Mario; Garcia-Verdugo, José Manuel; Junquera, Concepción

    2013-01-01

    The primary cilium is a non-motile cilium whose structure is 9+0. It is involved in co-ordinating cellular signal transduction pathways, developmental processes and tissue homeostasis. Defects in the structure or function of the primary cilium underlie numerous human diseases, collectively termed ciliopathies. The presence of single cilia in the central nervous system (CNS) is well documented, including some choroid plexus cells, neural stem cells, neurons and astrocytes, but the presence of primary cilia in differentiated neurons of the enteric nervous system (ENS) has not yet been described in mammals to the best of our knowledge. The enteric nervous system closely resembles the central nervous system. In fact, the ultrastructure of the ENS is more similar to the CNS ultrastructure than to the rest of the peripheral nervous system. This research work describes for the first time the ultrastructural characteristics of the single cilium in neurons of rat duodenum myenteric plexus, and reviews the cilium function in the CNS to propose the possible role of cilia in the ENS cells. © 2012 The Authors. Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

  17. [Ventilatory dysfunction in motor neuron disease: when and how to act?].

    Science.gov (United States)

    Rocha, J Afonso; Miranda, M J

    2007-01-01

    Amyotrophic lateral sclerosis is a devastating progressive neurodegenerative disorder, involving motor neurons in the cerebral cortex, brainstem and spinal cord. Mean duration of survival from the time of diagnosis is around 15 months, being pulmonary complications and respiratory failure responsible for more than 85% of deaths. Albeit the inevitability of respiratory failure and short-term death, standardized intervention protocols have been shown to significantly delay the need for invasive ventilatory support, thus prolonging survival and enhancing quality of life. The authors present an intervention protocol based on clinical progression and respiratory parameters. Decisions regarding initiation of non-invasive positive pressure ventilation (NIPPV) and mechanically assisted coughing, depend on development of symptoms of hypoventilation and on objective deterioration of respiratory parameters especially in what concerns bulbar muscle function. These include maximum inspiratory capacity (MIC), difference between MIC and vital capacity (MIC-VC), and assisted peak cough flow (PCF). These standardized protocols along with patient and caregivers education, allow for improved quality of life, prolonged survival and delay or eventually prevent the need for tracheotomy and invasive ventilatory support. Supplemental oxygen should be avoided in these patients, since it precludes use of oxymetry as feedback for titrating NIPPV and MAC, and is associated with decreased ventilatory drive and aggravated hypercapnia.

  18. Microglia under psychosocial stressors along the aging trajectory: Consequences on neuronal circuits, behavior, and brain diseases.

    Science.gov (United States)

    Tian, Li; Hui, Chin Wai; Bisht, Kanchan; Tan, Yunlong; Sharma, Kaushik; Chen, Song; Zhang, Xiangyang; Tremblay, Marie-Eve

    2017-10-03

    Mounting evidence indicates the importance of microglia for proper brain development and function, as well as in complex stress-related neuropsychiatric disorders and cognitive decline along the aging trajectory. Considering that microglia are resident immune cells of the brain, a homeostatic maintenance of their effector functions that impact neuronal circuitry, such as phagocytosis and secretion of inflammatory factors, is critical to prevent the onset and progression of these pathological conditions. However, the molecular mechanisms by which microglial functions can be properly regulated under healthy and pathological conditions are still largely unknown. We aim to summarize recent progress regarding the effects of psychosocial stress and oxidative stress on microglial phenotypes, leading to neuroinflammation and impaired microglia-synapse interactions, notably through our own studies of inbred mouse strains, and most importantly, to discuss about promising therapeutic strategies that take advantage of microglial functions to tackle such brain disorders in the context of adult psychosocial stress or aging-induced oxidative stress. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Reduced miR-512 and the Elevated Expression of Its Targets cFLIP and MCL1 Localize to Neurons With Hyperphosphorylated Tau Protein in Alzheimer Disease.

    Science.gov (United States)

    Mezache, Louisa; Mikhail, Madison; Garofalo, Michela; Nuovo, Gerard J

    2015-10-01

    The cause for the neurofibrillary tangles and plaques in Alzheimer disease likely relates to an abnormal accumulation of their key components, which include β-amyloid and hyperphosphorylated tau protein. We segregated Alzheimer brain sections from people with end-stage disease into those with abundant hyperphosphorylated tau protein and those without and compared each to normal brains for global microRNA patterns. A significant reduced expression of several microRNAs, including miR-512, was evident in the Alzheimer brain sections with abundant hyperphosphorylated tau. Immunohistochemistry documented that 2 known targets of microRNA-512, cFLIP and MCL1, were significantly over expressed and each colocalized to neurons with the abnormal tau protein. Analysis for apoptosis including activated caspase-3, increased caspase-4 and caspase-8, apoptosis initiating factor, APAF-1 activity, and the TUNEL assay was negative in the areas where neurons showed hyperphosphorylated tau. MCM2 expression, a marker of neuroprogenitor cells, was significantly reduced in the Alzheimer sections that contained the hyperphosphorylated tau. These results suggest that a basic defect in Alzheimer disease may be the reduced microRNA-driven increased expression of proteins that may alter the apoptotic/antiapoptotic balance of neurons. This, in turn, could lead to the accumulation of key Alzheimer proteins such as hyperphosphorylated tau that ultimately prevent normal neuronal function and lead to disease symptomatology.

  20. The Strain-Encoded Relationship between PrPSc Replication, Stability and Processing in Neurons is Predictive of the Incubation Period of Disease

    Science.gov (United States)

    Ayers, Jacob I.; Schutt, Charles R.; Shikiya, Ronald A.; Aguzzi, Adriano; Kincaid, Anthony E.; Bartz, Jason C.

    2011-01-01

    Prion strains are characterized by differences in the outcome of disease, most notably incubation period and neuropathological features. While it is established that the disease specific isoform of the prion protein, PrPSc, is an essential component of the infectious agent, the strain-specific relationship between PrPSc properties and the biological features of the resulting disease is not clear. To investigate this relationship, we examined the amplification efficiency and conformational stability of PrPSc from eight hamster-adapted prion strains and compared it to the resulting incubation period of disease and processing of PrPSc in neurons and glia. We found that short incubation period strains were characterized by more efficient PrPSc amplification and higher PrPSc conformational stabilities compared to long incubation period strains. In the CNS, the short incubation period strains were characterized by the accumulation of N-terminally truncated PrPSc in the soma of neurons, astrocytes and microglia in contrast to long incubation period strains where PrPSc did not accumulate to detectable levels in the soma of neurons but was detected in glia similar to short incubation period strains. These results are inconsistent with the hypothesis that a decrease in conformational stability results in a corresponding increase in replication efficiency and suggest that glia mediated neurodegeneration results in longer survival times compared to direct replication of PrPSc in neurons. PMID:21437239

  1. The Impact of Exercise on the Vulnerability of Dopamine Neurons to Cell Death in Animal Models of Parkinson’s Disease

    Science.gov (United States)

    2008-07-01

    protein efficiently protects against paraquat -induced dopaminergic neuron damage in a Parkinson disease mouse model. Free Radic. Biol. Med. 41, 1058–1068...miR398 and important for oxidative stress tolerance. Plant Cell 18, 2051–2065. Tiffany-Castiglioni E., Saneto R. P., Proctor P. H. and Perez-Polo J

  2. Predictors of activity and participation across neurodegenerative conditions: a comparison of people with motor neurone disease, multiple sclerosis and Parkinson's disease.

    Science.gov (United States)

    Morley, David; Dummett, Sarah; Kelly, Laura; Fitzpatrick, Ray; Jenkinson, Crispin

    2018-02-17

    Comparisons between neurological conditions have the potential to inform service providers by identifying particular areas of difficulty experienced by affected individuals. This study aimed to identify predictors of activity and participation in people with motor neurone disease (MND), people with multiple sclerosis (MS) and people with Parkinson's Disease (PD). The Oxford Participation and Activities Questionnaire (Ox-PAQ) and Medical Outcomes Study 36-Item Short Form Survey (MOS SF-36) were administered by postal survey to 386 people with a confirmed diagnosis of MND, MS or PD. Data analyses focused on stepwise regression analyses in order to identify predictors of activity and participation in the three conditions assessed. Three hundred and thirty four participants completed the survey, a response rate of 86.5%. Regression analyses identified multiple predictors of activity and participation dependent on Ox-PAQ domain and disease group, the most prominent being social and physical functioning as measured by the MOS SF-36. Results indicate that the physical and social consequences of neurological illness are of greatest relevance to people experiencing the conditions assessed. Whilst the largely inevitable physical implications of disease take hold, emphasis should be placed on the avoidance of social withdrawal and isolation, and the maintenance of social engagement should become a significant priority.

  3. Efferent neurons to the labyrinth of Salamandra salamandra as revealed by retrograde transport of horseradish peroxidase.

    Science.gov (United States)

    Fritzsch, B

    1981-11-04

    Application of horseradish peroxidase to the severed VIIIth nerve of Salamandra salamandra resulted in heavy bilateral labeling of neurons of the medullary reticular formation. These neurons closely resemble the Mauthner neuron in their widespread dendritic ramification. In most preparations axon collaterals are seen to leave the medulla via the contralateral VIIIth nerve. It is suggested that these neurons are labyrinthine efferents.

  4. Motor neuron disease (amyotrophic lateral sclerosis) arising from longstanding primary lateral sclerosis

    NARCIS (Netherlands)

    Bruyn, R. P.; Koelman, J. H.; Troost, D.; de Jong, J. M.

    1995-01-01

    Three men were initially diagnosed as having primary lateral sclerosis (PLS), but eventually developed amyotrophic lateral sclerosis (ALS) after 7.5, 9, and at least 27 years. Non-familial ALS and PLS might be different manifestations of a single disease or constitute completely distinct entities.

  5. Regional neuronal network failure and cognition in late-onset sporadic Alzheimer disease.

    Science.gov (United States)

    Carter, S F; Embleton, K V; Anton-Rodriguez, J M; Burns, A; Ralph, M A L; Herholz, K

    2014-06-01

    The severe cognitive deficits in Alzheimer disease are associated with structural lesions in gray and white matter in addition to changes in synaptic function. The current investigation studied the breakdown of the structure and function in regional networks involving the Papez circuit and extended neocortical association areas. Cortical volumetric and diffusion tensor imaging (3T MR imaging), positron-emission tomography with (18)F fluorodeoxyglucose on a high-resolution research tomograph, and comprehensive neuropsychological assessments were performed in patients with late-onset sporadic Alzheimer disease, those with mild cognitive impairment, and elderly healthy controls. Atrophy of the medial temporal lobes was the strongest and most consistent abnormality in patients with mild cognitive impairment and Alzheimer disease. Atrophy in the temporal, frontal, and parietal regions was most strongly related to episodic memory deficits, while deficits in semantic cognition were also strongly related to reductions of glucose metabolism in the posterior cingulate cortex and temporoparietal regions. Changes in fractional anisotropy within white matter tracts, particularly in the left cingulum bundle, uncinate fasciculus, superior longitudinal fasciculus, and inferior fronto-occipital fasciculus, were significantly associated with the cognitive deficits in multiple regression analyses. Posterior cingulate and orbitofrontal metabolic deficits appeared to be related to microstructural changes in projecting white matter tracts. Many lesioned network components within the Papez circuit and extended neocortical association areas were significantly associated with cognitive dysfunction in both mild cognitive impairment and late-onset sporadic Alzheimer disease. Hippocampal atrophy was the most prominent lesion, with associated impairment of the uncinate and cingulum white matter microstructures and hippocampal and posterior cingulate metabolic impairment. © 2014 by American

  6. Proteomic Profiling of Animal Models of Myotonia and Motor Neuron Disease

    OpenAIRE

    Staunton, Lisa

    2011-01-01

    Skeletal muscle provides an organism with a means of reacting to its environments. It is a complex and versatile tissue that is capable of change under a variety of conditions. For example extensive literature has shown muscle transformation from slow-to-fast by decreased motor nerve activity, hypogravity, physical inactivity and in diseased states. Similarly muscle transformation from fast-to-slow can be evoked by increased muscle nerve activity or exercise. The multitude of protein changes ...

  7. Neuronal substrate of eating disorders

    OpenAIRE

    Timofeeva, Elena; Calvez, Juliane

    2014-01-01

    Eating disorders are devastating and life-threatening psychiatric diseases. Although clinical and experimental investigations have significantly progressed in discovering the neuronal causes of eating disorders, the exact neuronal and molecular mechanisms of the development and maintenance of these pathologies are not fully understood. The complexity of the neuronal substrate of eating disorders hampers progress in revealing the precise mechanisms. The present re...

  8. Novel information on the non-neuronal cholinergic system in orthopedics provides new possible treatment strategies for inflammatory and degenerative diseases

    Directory of Open Access Journals (Sweden)

    Sture Forsgren

    2009-07-01

    Full Text Available Anti-cholinergic agents are used in the treatment of several pathological conditions. Therapy regimens aimed at up-regulating cholinergic functions, such as treatment with acetylcholinesterase inhibitors, are also currently prescribed. It is now known that not only is there a neuronal cholinergic system but also a non-neuronal cholinergic system in various parts of the body. Therefore, interference with the effects of acetylcholine (ACh brought about by the local production and release of ACh should also be considered. Locally produced ACh may have proliferative, angiogenic, wound-healing, and immunomodulatory functions. Interestingly, cholinergic stimulation may lead to anti-inflammatory effects. Within this review, new findings for the locomotor system of a more widespread non-neuronal cholinergic system than previously expected will be discussed in relation to possible new treatment strategies. The conditions discussed are painful and degenerative tendon disease (tendinopathy/tendinosis, rheumatoid arthritis, and osteoarthritis.

  9. Royal Jelly Reduces Cholesterol Levels, Ameliorates Aβ Pathology and Enhances Neuronal Metabolic Activities in a Rabbit Model of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Yongming Pan

    2018-03-01

    Full Text Available Alzheimer’s disease (AD is the most common form of dementia characterized by aggregation of amyloid β (Aβ and neuronal loss. One of the risk factors for AD is high cholesterol levels, which are known to promote Aβ deposition. Previous studies have shown that royal jelly (RJ, a product of worker bees, has potential neuroprotective effects and can attenuate Aβ toxicity. However, little is known about how RJ regulates Aβ formation and its effects on cholesterol levels and neuronal metabolic activities. Here, we investigated whether RJ can reduce cholesterol levels, regulate Aβ levels and enhance neuronal metabolic activities in an AD rabbit model induced by 2% cholesterol diet plus copper drinking water. Our results suggest that RJ significantly reduced the levels of plasma total cholesterol (TC and low density lipoprotein-cholesterol (LDL-C, and decreased the level of Aβ in rabbit brains. RJ was also shown to markedly ameliorate amyloid deposition in AD rabbits from Aβ immunohistochemistry and thioflavin-T staining. Furthermore, our study suggests that RJ can reduce the expression levels of β-site APP cleaving enzyme-1 (BACE1 and receptor for advanced glycation end products (RAGE, and increase the expression levels of low density lipoprotein receptor-related protein 1 (LRP-1 and insulin degrading enzyme (IDE. In addition, we found that RJ remarkably increased the number of neurons, enhanced antioxidant capacities, inhibited activated-capase-3 protein expression, and enhanced neuronal metabolic activities by increasing N-acetyl aspartate (NAA and glutamate and by reducing choline and myo-inositol in AD rabbits. Taken together, our data demonstrated that RJ could reduce cholesterol levels, regulate Aβ levels and enhance neuronal metabolic activities in AD rabbits, providing preclinical evidence that RJ treatment has the potential to protect neurons and prevent AD.

  10. Maximal COX-2 and ppRb expression in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Arendt Thomas

    2005-11-01

    Full Text Available Abstract Neuronal expression of cyclooxygenase-2 (COX-2 and cell cycle proteins is suggested to contribute to neurodegeneration during Alzheimer's disease (AD. The stimulus that induces COX-2 and cell cycle protein expression in AD is still elusive. Activated glia cells are shown to secrete substances that can induce expression of COX-2 and cell cycle proteins in vitro. Using post mortem brain tissue we have investigated whether activation of microglia and astrocytes in AD brain can be correlated with the expression of COX-2 and phosphorylated retinoblastoma protein (ppRb. The highest levels of neuronal COX-2 and ppRb immunoreactivity are observed in the first stages of AD pathology (Braak 0–II, Braak A. No significant difference in COX-2 or ppRb neuronal immunoreactivity is observed between Braak stage 0 and later Braak stages for neurofibrillary changes or amyloid plaques. The mean number of COX-2 or ppRb immunoreactive neurons is significantly decreased in Braak stage C compared to Braak stage A for amyloid deposits. Immunoreactivity for glial markers KP1, CR3/43 and GFAP appears in the later Braak stages and is significantly increased in Braak stage V-VI compared to Braak stage 0 for neurofibrillary changes. In addition, a significant negative correlation is observed between the presence of KP1, CR3/43 and GFAP immunoreactivity and the presence of neuronal immunoreactivity for COX-2 and ppRb. These data show that maximal COX-2 and ppRb immunoreactivity in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia. In contrast to in vitro studies, post mortem data do not support a causal relation between the activation of microglia and astrocytes and the expression of neuronal COX-2 and ppRb in the pathological cascade of AD.

  11. PrPSc accumulation in neuronal plasma membranes links Notch-1 activation to dendritic degeneration in prion diseases

    Directory of Open Access Journals (Sweden)

    DeArmond Stephen J

    2010-01-01

    Full Text Available Abstract Prion diseases are disorders of protein conformation in which PrPC, the normal cellular conformer, is converted to an abnormal, protease-resistant conformer rPrPSc. Approximately 80% of rPrPSc accumulates in neuronal plasma membranes where it changes their physical properties and profoundly affects membrane functions. In this review we explain how rPrPSc is transported along axons to presynaptic boutons and how we envision the conversion of PrPC to rPrPSc in the postsynaptic membrane. This information is a prerequisite to the second half of this review in which we present evidence that rPrPSc accumulation in synaptic regions links Notch-1 signaling with the dendritic degeneration. The hypothesis that the Notch-1 intracellular domain, NICD, is involved in prion disease was tested by treating prion-infected mice with the γ-secretase inhibitor (GSI LY411575, with quinacrine (Qa, and with the combination of GSI + Qa. Surprisingly, treatment with GSI alone markedly decreased NICD but did not prevent dendritic degeneration. Qa alone produced near normal dendritic trees. The combined GSI + Qa treatment resulted in a richer dendritic tree than in controls. We speculate that treatment with GSI alone inhibited both stimulators and inhibitors of dendritic growth. With the combined GSI + Qa treatment, Qa modulated the effect of GSI perhaps by destabilizing membrane rafts. GSI + Qa decreased PrPSc in the neocortex and the hippocampus by 95%, but only by 50% in the thalamus where disease was begun by intrathalamic inoculation of prions. The results of this study indicate that GSI + Qa work synergistically to prevent dendrite degeneration and to block formation of PrPSc.

  12. A metabolomic comparison of mouse models of the Neuronal Ceroid Lipofuscinoses

    International Nuclear Information System (INIS)

    Salek, Reza M.; Pears, Michael R.; Cooper, Jonathan D.; Mitchison, Hannah M.; Pearce, David A.; Mortishire-Smith, Russell J.; Griffin, Julian L.

    2011-01-01

    The Neuronal Ceroid Lipofuscinoses (NCL) are a group of fatal inherited neurodegenerative diseases in humans distinguished by a common clinical pathology, characterized by the accumulation of storage body material in cells and gross brain atrophy. In this study, metabolic changes in three NCL mouse models were examined looking for pathways correlated with neurodegeneration. Two mouse models; motor neuron degeneration (mnd) mouse and a variant model of late infantile NCL, termed the neuronal ceroid lipofuscinosis (nclf) mouse were investigated experimentally. Both models exhibit a characteristic accumulation of autofluorescent lipopigment in neuronal and non neuronal cells. The NMR profiles derived from extracts of the cortex and cerebellum from mnd and nclf mice were distinguished according to disease/wildtype status. In particular, a perturbation in glutamine and glutamate metabolism, and a decrease in γ-amino butyric acid (GABA) in the cerebellum and cortices of mnd (adolescent mice) and nclf mice relative to wildtype at all ages were detected. Our results were compared to the Cln3 mouse model of NCL. The metabolism of mnd mice resembled older (6 month) Cln3 mice, where the disease is relatively advanced, while the metabolism of nclf mice was more akin to younger (1-2 months) Cln3 mice, where the disease is in its early stages of progression. Overall, our results allowed the identification of metabolic traits common to all NCL subtypes for the three animal models.

  13. A metabolomic comparison of mouse models of the Neuronal Ceroid Lipofuscinoses

    Energy Technology Data Exchange (ETDEWEB)

    Salek, Reza M.; Pears, Michael R. [University of Cambridge, Department of Biochemistry and Cambridge Systems Biology Centre (United Kingdom); Cooper, Jonathan D. [King' s College London, Pediatric Storage Disorders Laboratory, Department of Neuroscience, Institute of Psychiatry (United Kingdom); Mitchison, Hannah M. [Royal Free and University College Medical School, Department of Paediatrics and Child Health (United Kingdom); Pearce, David A. [Sanford School of Medicine of the University of South Dakota, Department of Pediatrics (United States); Mortishire-Smith, Russell J. [Johnson and Johnson PR and D (Belgium); Griffin, Julian L., E-mail: jlg40@mole.bio.cam.ac.uk [University of Cambridge, Department of Biochemistry and the Cambridge Systems Biology Centre (United Kingdom)

    2011-04-15

    The Neuronal Ceroid Lipofuscinoses (NCL) are a group of fatal inherited neurodegenerative diseases in humans distinguished by a common clinical pathology, characterized by the accumulation of storage body material in cells and gross brain atrophy. In this study, metabolic changes in three NCL mouse models were examined looking for pathways correlated with neurodegeneration. Two mouse models; motor neuron degeneration (mnd) mouse and a variant model of late infantile NCL, termed the neuronal ceroid lipofuscinosis (nclf) mouse were investigated experimentally. Both models exhibit a characteristic accumulation of autofluorescent lipopigment in neuronal and non neuronal cells. The NMR profiles derived from extracts of the cortex and cerebellum from mnd and nclf mice were distinguished according to disease/wildtype status. In particular, a perturbation in glutamine and glutamate metabolism, and a decrease in {gamma}-amino butyric acid (GABA) in the cerebellum and cortices of mnd (adolescent mice) and nclf mice relative to wildtype at all ages were detected. Our results were compared to the Cln3 mouse model of NCL. The metabolism of mnd mice resembled older (6 month) Cln3 mice, where the disease is relatively advanced, while the metabolism of nclf mice was more akin to younger (1-2 months) Cln3 mice, where the disease is in its early stages of progression. Overall, our results allowed the identification of metabolic traits common to all NCL subtypes for the three animal models.

  14. Mesenchymal stem cell transplantation attenuates blood brain barrier damage and neuroinflammation and protects dopaminergic neurons against MPTP toxicity in the substantia nigra in a model of Parkinson's disease.

    Science.gov (United States)

    Chao, Yin Xia; He, Bei Ping; Tay, Samuel Sam Wah

    2009-11-30

    Immunomodulatory effects of transplanted mesenchymal stem cells (MSCs) in the treatment of Parkinson's disease were studied in the MPTP-induced mouse model. MPTP treatment induced a significant loss of dopaminergic neurons, decreased expressions of claudin 1, claudin 5 and occludin in the substantia nigra compacta (SNc), and functional damage of the blood brain barrier (BBB). Our study further discovered that infiltration of MBLs into the brain to bind with microglia was detected in the SNc of MPTP-treated mice, suggesting that the BBB compromise and MBL infiltration might be involved in the pathogenesis of MPTP-induced PD. In addition, MPTP treatment also increased the expression of mannose-binding lectins (MBLs) in the liver tissue. Intravenous transplantation of MSCs into MPTP-treated mice led to recovery of BBB integrity, suppression of MBL infiltration at SNc and MBL expression in the liver, suppression of microglial activation and prevention of dopaminergic neuron death. No transplanted MSCs were observed to differentiate into dopaminergic neurons, while the MSCs migrated into the SNc and released TGF-beta1 there. Therefore, intravenous transplantation of MSCs which protect dopaminergic neurons from MPTP toxicity may be engaged in anyone or a combination of these mechanisms: repair of the BBB, reduction of MBL in the brain, inhibition of microglial cytotoxicity, and direct protection of dopaminergic neurons.

  15. Spousal resemblance in psychopathology: A comparison of parents of children with and without psychopathology

    NARCIS (Netherlands)

    Wesseldijk, L. W.; Dieleman, G. C.; Lindauer, R. J. L.; Bartels, M.; Willemsen, G.; Hudziak, J. J.; Boomsma, D. I.; Middeldorp, C. M.

    2016-01-01

    Spouses resemble each other for psychopathology, but data regarding spousal resemblance in externalizing psychopathology, and data regarding spousal resemblance across different syndromes (e.g. anxiety in wives and attention deficit/hyperactivity disorder [ADHD] in husbands) are limited. Moreover,

  16. RESEMBLANCE OF INDIRECTNESS IN POLITENESS OF EFL LEARNERS’ REQUEST REALIZATIONS

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    Indawan Syahri

    2013-07-01

    Full Text Available Abstract: Politeness principles are universally utilized by the speakers of any language when realizing various speech acts. However, the speakers of particular languages relatively apply politeness due to the cultural norms embedded. The present study attempts to delineate how the Indonesian learners of English (ILE apply the politeness principles in request realizations. Specifically it devotes to the types of politeness strategies applied and resemblance of the indirectness in politeness strategies in requesting acts. The FTAs and indirectness are the theoretical bases used to trace the typologies of both politeness and request strategies. The data werere collected by means of certain elicitation techniques, i.e. DCTs and Role-plays. The analyses werere done through three stages; determining request strategies, politeness strategies, and resemblance of indirectness in politeness. The results show that the indirectness generally is parallel to politeness. Besides, some pragmatic transfers are found in terms of applying native-culture norms in realizing target speech acts.

  17. Transcriptional induction of the heat shock protein B8 mediates the clearance of misfolded proteins responsible for motor neuron diseases.

    Science.gov (United States)

    Crippa, Valeria; D'Agostino, Vito G; Cristofani, Riccardo; Rusmini, Paola; Cicardi, Maria E; Messi, Elio; Loffredo, Rosa; Pancher, Michael; Piccolella, Margherita; Galbiati, Mariarita; Meroni, Marco; Cereda, Cristina; Carra, Serena; Provenzani, Alessandro; Poletti, Angelo

    2016-03-10

    Neurodegenerative diseases (NDs) are often associated with the presence of misfolded protein inclusions. The chaperone HSPB8 is upregulated in mice, the human brain and muscle structures affected during NDs progression. HSPB8 exerts a potent pro-degradative activity on several misfolded proteins responsible for familial NDs forms. Here, we demonstrated that HSPB8 also counteracts accumulation of aberrantly localized misfolded forms of TDP-43 and its 25 KDa fragment involved in most sporadic cases of Amyotrophic Lateral Sclerosis (sALS) and of Fronto Lateral Temporal Dementia (FLTD). HSPB8 acts with BAG3 and the HSP70/HSC70-CHIP complex enhancing the autophagic removal of misfolded proteins. We performed a high-through put screening (HTS) to find small molecules capable of inducing HSPB8 in neurons for therapeutic purposes. We identified two compounds, colchicine and doxorubicin, that robustly up-regulated HSPB8 expression. Both colchicine and doxorubicin increased the expression of the master regulator of autophagy TFEB, the autophagy linker p62/SQSTM1 and the autophagosome component LC3. In line, both drugs counteracted the accumulation of TDP-43 and TDP-25 misfolded species responsible for motoneuronal death in sALS. Thus, analogs of colchicine and doxorubicin able to induce HSPB8 and with better safety and tolerability may result beneficial in NDs models.

  18. CNB-001 a Novel Curcumin Derivative, Guards Dopamine Neurons in MPTP Model of Parkinson’s Disease

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    Richard L. Jayaraj

    2014-01-01

    Full Text Available Copious experimental and postmortem studies have shown that oxidative stress mediated degeneration of nigrostriatal dopaminergic neurons underlies Parkinson’s disease (PD pathology. CNB-001, a novel pyrazole derivative of curcumin, has recently been reported to possess various neuroprotective properties. This study was designed to investigate the neuroprotective mechanism of CNB-001 in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP rodent model of PD. Administration of MPTP (30 mg/kg for four consecutive days exacerbated oxidative stress and motor impairment and reduced tyrosine hydroxylase (TH, dopamine transporter, and vesicular monoamine transporter 2 (VMAT2 expressions. Moreover, MPTP induced ultrastructural changes such as distorted cristae and mitochondrial enlargement in substantia nigra and striatum region. Pretreatment with CNB-001 (24 mg/kg not only ameliorated behavioral anomalies but also synergistically enhanced monoamine transporter expressions and cosseted mitochondria by virtue of its antioxidant action. These findings support the neuroprotective property of CNB-001 which may have strong therapeutic potential for treatment of PD.

  19. "Anything that makes life's journey better." Exploring the use of digital technology by people living with motor neurone disease.

    Science.gov (United States)

    Hobson, Esther V; Fazal, Saima; Shaw, Pamela J; McDermott, Christopher J

    2017-08-01

    Our aim was to explore the attitudes of those living with motor neuron disease towards digital technology. Postal and online questionnaires surveyed 83 people with MND (pwMND) and 54 friends and family members (fMND). Five pwMND and five fMND underwent semi-structured interviews. 82% of pwMND and 87% of fMND use technology every day with iPads and laptops being the devices most commonly used. pwMND used technology to help them continue to participate in everyday activities such as socialising, entertainment and accessing the internet. The internet provided peer support and information about MND but information could be distressing or unreliable. Participants preferred information from professionals and official organisations. Participants were generally supportive of using of technology to access medical care. Barriers to technology, such as lack of digital literacy skills and upper limb dysfunction, and potential solutions were identified. More challenging barriers included language and cognitive difficulties, and the fear of becoming dependent on technology. Addressing the barriers identified in this research could help pwMND access technology. However, as healthcare delivery becomes more reliant on digital technology, care should be taken to ensure that those who are unable or unwilling to use technology continue to have their needs met in alternative ways.

  20. Transcription factors Foxa1 and Foxa2 are required for adult dopamine neurons maintenance

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    Andrii eDomanskyi

    2014-09-01

    Full Text Available The proteins Foxa1 and Foxa2 belong to the forkhead family of transcription factors and are involved in the development of several tissues, including liver, pancreas, lung, prostate, and the neural system. Both Foxa1 and Foxa2 are also crucial for the specification and differentiation of dopamine (DA neurons during embryonic development, while about 30% of mice with an embryonic deletion of a single allele of the Foxa2 gene exhibit an age-related asymmetric loss of DA neurons and develop locomotor symptoms resembling Parkinson’s disease (PD. Notably, both Foxa1 and Foxa2 factors continue to be expressed in the adult dopamine system. To directly assess their functions selectively in adult DA neurons, we induced genetic deletions of Foxa1/2 transcription factors in mice using a tamoxifen inducible tissue-specific CreERT2 recombinase expressed under control of the dopamine transporter (DAT promoter (DATCreERT2. The conditional DA neurons-specific ablation of both genes, but not of Foxa2 alone, in early adulthood, caused a decline of striatal dopamine and its metabolites, along with locomotor deficits. At early pre-symptomatic stages, we observed a decline in aldehyde dehydrogenase family 1, subfamily A1 (Aldh1a1 protein expression in DA neurons. Further analyses revealed a decline of aromatic amino acid decarboxylase (AADC and a complete loss of DAT expression in these neurons. These molecular changes ultimately led to a reduction of DA neuron numbers in the substantia nigra pars compacta (SNpc of aged cFoxa1/2-/- mice, resembling the progressive course of PD in humans. Altogether, in this study, we address the molecular, cellular and functional role of both Foxa1 and Foxa2 factors in the maintenance of the adult dopamine system which may help to find better approaches for PD treatment.

  1. Transcription factors Foxa1 and Foxa2 are required for adult dopamine neurons maintenance.

    Science.gov (United States)

    Domanskyi, Andrii; Alter, Heike; Vogt, Miriam A; Gass, Peter; Vinnikov, Ilya A

    2014-01-01

    The proteins Foxa1 and Foxa2 belong to the forkhead family of transcription factors and are involved in the development of several tissues, including liver, pancreas, lung, prostate, and the neural system. Both Foxa1 and Foxa2 are also crucial for the specification and differentiation of dopamine (DA) neurons during embryonic development, while about 30% of mice with an embryonic deletion of a single allele of the Foxa2 gene exhibit an age-related asymmetric loss of DA neurons and develop locomotor symptoms resembling Parkinson's disease (PD). Notably, both Foxa1 and Foxa2 factors continue to be expressed in the adult dopamine system. To directly assess their functions selectively in adult DA neurons, we induced genetic deletions of Foxa1/2 transcription factors in mice using a tamoxifen inducible tissue-specific CreERT2 recombinase expressed under control of the dopamine transporter (DAT) promoter (DATCreERT2). The conditional DA neurons-specific ablation of both genes, but not of Foxa2 alone, in early adulthood, caused a decline of striatal dopamine and its metabolites, along with locomotor deficits. At early pre-symptomatic stages, we observed a decline in aldehyde dehydrogenase family 1, subfamily A1 (Aldh1a1) protein expression in DA neurons. Further analyses revealed a decline of aromatic amino acid decarboxylase (AADC) and a complete loss of DAT expression in these neurons. These molecular changes ultimately led to a reduction of DA neuron numbers in the substantia nigra pars compacta (SNpc) of aged cFoxa1/2 (-/-) mice, resembling the progressive course of PD in humans. Altogether, in this study, we address the molecular, cellular, and functional role of both Foxa1 and Foxa2 factors in the maintenance of the adult dopamine system which may help to find better approaches for PD treatment.

  2. Allergic Contact Dermatitis to Benzoyl Peroxide Resembling Impetigo.

    Science.gov (United States)

    Kim, Changhyun; Craiglow, Brittany G; Watsky, Kalman L; Antaya, Richard J

    2015-01-01

    A 17-year-old boy presented with recurring severe dermatitis of the face of 5-months duration that resembled impetigo. He had been treated with several courses of antibiotics without improvement. Biopsy showed changes consistent with allergic contact dermatitis and patch testing later revealed sensitization to benzoyl peroxide, which the patient had been using for the treatment of acne vulgaris. © 2015 Wiley Periodicals, Inc.

  3. Functional integration of grafted neural stem cell-derived dopaminergic neurons monitored by optogenetics in an in vitro Parkinson model.

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    Jan Tønnesen

    Full Text Available Intrastriatal grafts of stem cell-derived dopamine (DA neurons induce behavioral recovery in animal models of Parkinson's disease (PD, but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral mesencephalon of tyrosine hydroxylase-GFP transgenic mice were expanded as neurospheres and transplanted into organotypic cultures of wild type mouse striatum. Differentiated GFP-labeled DA neurons in the grafts exhibited mature neuronal properties, including spontaneous firing of action potentials, presence of post-synaptic currents, and functional expression of DA D₂ autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation or inhibition of grafted cells and host neurons using channelrhodopsin-2 (ChR2 and halorhodopsin (NpHR, respectively, revealed complex, bi-directional synaptic interactions between grafted cells and host neurons and extensive synaptic connectivity within the graft. Our data demonstrate for the first time using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying behavioral recovery as well as adverse effects following stem cell-based DA cell replacement strategies in PD.

  4. Detecting analogical resemblance without retrieving the source analogy.

    Science.gov (United States)

    Kostic, Bogdan; Cleary, Anne M; Severin, Kaye; Miller, Samuel W

    2010-06-01

    We examined whether people can detect analogical resemblance to an earlier experimental episode without being able to recall the experimental source of the analogical resemblance. We used four-word analogies (e.g., robin-nest/beaver-dam), in a variation of the recognition-without-cued-recall method (Cleary, 2004). Participants studied word pairs (e.g., robin-nest) and were shown new word pairs at test, half of which analogically related to studied word pairs (e.g., beaver-dam) and half of which did not. For each test pair, participants first attempted to recall an analogically similar pair from the study list. Then, regardless of whether successful recall occurred, participants were prompted to rate the familiarity of the test pair, which was said to indicate the likelihood that a pair that was analogically similar to the test pair had been studied. Across three experiments, participants demonstrated an ability to detect analogical resemblance without recalling the source analogy. Findings are discussed in terms of their potential relevance to the study of analogical reasoning and insight, as well as to the study of familiarity and recognition memory.

  5. Supporting wellbeing in motor neurone disease for patients, carers, social networks, and health professionals: A scoping review and synthesis.

    Science.gov (United States)

    Harris, Melanie; Thomas, Geoff; Thomas, Mary; Cafarella, Paul; Stocks, Allegra; Greig, Julia; McEvoy, R Doug

    2018-04-01

    ABSTRACTObjective:Disease management in motor neurone disease (MND) is focused on preserving quality of life. However, the emphasis has so far been on physical symptoms and functioning and not psychosocial wellbeing. MND affects the wellbeing of carers, of family and social network members, and of healthcare providers, as well as of the patients. We therefore aimed to assess and synthesize the knowledge about maximizing MND-related psychosocial wellbeing across all these groups. We used a systematic search and selection process to assess the scope of the literature along with a narrative synthesis of recent high-quality reviews. The original studies were mainly observational studies of patients and, to a lesser extent, of carers. There were few interventional studies, mainly of patients. There were very few studies of any type on wellbeing in their wider social network or in healthcare professionals. All the review literature looked at MND patient or carer wellbeing, with some covering both. No reviews were found of wellbeing in other family members, patients' social networks, or their healthcare professionals. The reviews demonstrated wellbeing problems for patients linked to psychosocial issues. Carer wellbeing is also compromised. Psychotherapies, social supports, improved decision supports, and changes to healthcare delivery are among the suggested strategies for improved patient and carer wellbeing, but no proven interventions were identified for either. Early access to palliative care, also not well-tested but recommended, is poorly implemented. Work on interventions to deal with well-established wellbeing problems for patients and carers is now a research priority. Explicit use of current methods for patient and public involvement and for design and testing of interventions provide a toolkit for this research. Observational research is needed in other groups. There is a potential in considering needs across patients' social networks rather than looking

  6. Sodium phenylbutyrate controls neuroinflammatory and antioxidant activities and protects dopaminergic neurons in mouse models of Parkinson's disease.

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    Avik Roy

    Full Text Available Neuroinflammation and oxidative stress underlie the pathogenesis of various neurodegenerative disorders. Here we demonstrate that sodium phenylbutyrate (NaPB, an FDA-approved therapy for reducing plasma ammonia and glutamine in urea cycle disorders, can suppress both proinflammatory molecules and reactive oxygen species (ROS in activated glial cells. Interestingly, NaPB also decreased the level of cholesterol but involved only intermediates, not the end product of cholesterol biosynthesis pathway for these functions. While inhibitors of both geranylgeranyl transferase (GGTI and farnesyl transferase (FTI inhibited the activation of NF-κB, inhibitor of GGTI, but not FTI, suppressed the production of ROS. Accordingly, a dominant-negative mutant of p21(rac, but not p21(ras, attenuated the production of ROS from activated microglia. Inhibition of both p21(ras and p21(rac activation by NaPB in microglial cells suggests that NaPB exerts anti-inflammatory and antioxidative effects via inhibition of these small G proteins. Consistently, we found activation of both p21(ras and p21(racin vivo in the substantia nigra of acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP mouse model of Parkinson's disease. Oral administration of NaPB reduced nigral activation of p21(ras and p21(rac, protected nigral reduced glutathione, attenuated nigral activation of NF-κB, inhibited nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Consistently, FTI and GGTI also protected nigrostriata in MPTP-intoxicated mice. Furthermore, NaPB also halted the disease progression in a chronic MPTP mouse model. These results identify novel mode of action of NaPB and suggest that NaPB may be of therapeutic benefit for neurodegenerative disorders.

  7. Genetic heterogeneity in neuronal ceroid lipofuscinosis (NCL): Evidence that the late-infantile subtype (Jansky-Bielschowsky disease; CLN2) is not an allelic form of the juvenile or infantile subtypes

    OpenAIRE

    Williams, Ruth; Vesa, Jouni; Järvelä, Irma; McKay, Tristan; Mitchison, Hannah; Hellsten, Elina; Thompson, Andrew; Callen, David; Sutherland, Grant; Luna-Battadano, David; Stallings, Ray; Peltonen, Leena; Gardiner, Mark

    1993-01-01

    The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in neurons and other cell types. Inheritance is autosomal recessive. Three main childhood subtypes are recognized: infantile (Haltia-Santavuori disease; MIM 256743), late infantile (Jansky-Bielschowsky disease; MIM 204500), and juvenile (Spielmeyer-Sjögren-Vogt, or Batten, disease; MIM 204200). The gene loci for the juvenile (CLN3) and...

  8. The Effects of Cues on Neurons in the Basal Ganglia in Parkinson’s Disease

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    Sridevi V. Sarma

    2012-07-01

    Full Text Available Visual cues open a unique window to the understanding of Parkinson’s disease (PD. These cues can temporarily but dramatically improve PD motor symptoms. Although details are unclear, cues are believed to suppress pathological basal ganglia (BG activity through activation of corticostriatal pathways. In this study, we investigated human BG neurophysiology under different cued conditions. We evaluated bursting, 10-30Hz oscillations (OSCs, and directional tuning (DT dynamics in the subthalamic nucleus activity while 7 patients executed a two-step motor task. In the first step (predicted +cue, the patient moved to a target when prompted by a visual go cue that appeared 100% of the time. Here, the timing of the cue is predictable and the cue serves an external trigger to execute a motor plan. In the second step, the cue appeared randomly 50% of the time, and the patient had to move to the same target as in the first step. When it appeared (unpredicted +cue, the motor plan was to be triggered by the cue, but its timing was not predictable. When the cue failed to appear (unpredicted -cue, the motor plan was triggered by the absence of the visual cue. We found that during predicted +cue and unpredicted -cue trials, OSCs significantly decreased and DT significantly increased above baseline, though these modulations occurred an average of 640 milliseconds later in unpredicted -cue trials. Movement and reaction times were comparable in these trials. During unpredicted +cue trials, OSCs and DT failed to modulate though bursting significantly decreased after movement. Correspondingly, movement performance deteriorated. These findings suggest that during motor planning either a predictably timed external cue or an internally generated cue (generated by the absence of a cue trigger the execution of a motor plan in premotor cortex, whose increased activation then suppresses pathological activity in STN through direct pathways, leading to motor facilitation in

  9. The Neuroprotective Mechanism of Low-Frequency rTMS on Nigral Dopaminergic Neurons of Parkinson’s Disease Model Mice

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    Qiaoyun Dong

    2015-01-01

    Full Text Available Background. Parkinson’s disease is a neurodegenerative disease in elder people, pathophysiologic basis of which is the severe deficiency of dopamine in the striatum. The purpose of the present study was to evaluate the neuroprotective effect of low-frequency rTMS on Parkinson’s disease in model mice. Methods. The effects of low-frequency rTMS on the motor function, cortex excitability, neurochemistry, and neurohistopathology of MPTP-induced Parkinson’s disease mice were investigated through behavioral detection, electrophysiologic technique, high performance liquid chromatography-electrochemical detection, immunohistochemical staining, and western blot. Results. Low-frequency rTMS could improve the motor coordination impairment of Parkinson’s disease mice: the resting motor threshold significantly decreased in the Parkinson’s disease mice; the degeneration of nigral dopaminergic neuron and the expression of tyrosine hydroxylase were significantly improved by low-frequency rTMS; moreover, the expressions of brain derived neurotrophic factor and glial cell line derived neurotrophic factor were also improved by low-frequency rTMS. Conclusions. Low-frequency rTMS had a neuroprotective effect on the nigral dopaminergic neuron which might be due to the improved expressions of brain derived neurotrophic factor and glial cell line-derived neurotrophic factor. The present study provided a theoretical basis for the application of low-frequency rTMS in the clinical treatment and recovery of Parkinson’s disease.

  10. Phrenic long-term facilitation following intrapleural CTB-SAP-induced respiratory motor neuron death.

    Science.gov (United States)

    Nichols, Nicole L; Craig, Taylor A; Tanner, Miles A

    2017-08-16

    Amyotrophic lateral sclerosis (ALS) is a devastating disease leading to progressive motor neuron degeneration and death by ventilatory failure. In a rat model of ALS (SOD1 G93A ), phrenic long-term facilitation (pLTF) following acute intermittent hypoxia (AIH) is enhanced greater than expected at disease end-stage but the mechanism is unknown. We suggest that one trigger for this enhancement is motor neuron death itself. Intrapleural injections of cholera toxin B fragment conjugated to saporin (CTB-SAP) selectively kill respiratory motor neurons and mimic motor neuron death observed in SOD1 G93A rats. This CTB-SAP model allows us to study the impact of respiratory motor neuron death on breathing without many complications attendant to ALS. Here, we tested the hypothesis that phrenic motor neuron death is sufficient to enhance pLTF. pLTF was assessed in anesthetized, paralyzed and ventilated Sprague Dawley rats 7 and 28days following bilateral intrapleural injections of: 1) CTB-SAP (25μg), or 2) un-conjugated CTB and SAP (control). CTB-SAP enhanced pLTF at 7 (CTB-SAP: 162±18%, n=8 vs. 63±3%; n=8; p0.05). Thus, pLTF at 7 (not 28) days post-CTB-SAP closely resembles pLTF in end-stage ALS rats, suggesting that processes unique to the early period of motor neuron death enhance pLTF. This project increases our understanding of respiratory plasticity and its implications for breathing in motor neuron disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Modulation of Neuronal Activity in the Motor Thalamus during GPi-DBS in the MPTP Nonhuman Primate Model of Parkinson's Disease.

    Science.gov (United States)

    Muralidharan, Abirami; Zhang, Jianyu; Ghosh, Debabrata; Johnson, Mathew D; Baker, Kenneth B; Vitek, Jerrold L

    The motor thalamus is a key nodal point in the pallidothalamocortical "motor" circuit, which has been implicated in the pathogenesis of Parkinson's disease (PD) and other movement disorders. Although a critical structure in the motor circuit, the role of the motor thalamus in mediating the therapeutic effects of deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) is not fully understood. To characterize the changes in neuronal activity in the pallidal (ventralis lateralis pars oralis (VLo) and ventralis anterior (VA)) and cerebellar (ventralis posterior lateralis pars oralis (VPLo)) receiving areas of the motor thalamus during therapeutic GPi DBS. Neuronal activity from the VA/VLo (n = 134) and VPLo (n = 129) was recorded from two non-human primates made parkinsonian using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. For each isolated unit, one minute of data was recorded before, during and after DBS; a pulse width of 90 µs and a frequency of 135 Hz were used for DBS to replicate commonly used clinical settings. Stimulation amplitude was determined based on the parameters required to improve motor signs. Severity of motor signs was assessed using the UPDRS modified for nonhuman primates. Discharge rate, presence and characteristics of bursts, and oscillatory activity were computed and compared across conditions (pre-, during, and post-stimulation). Neurons in both the pallidal and cerebellar receiving areas demonstrated significant changes in their pattern of activity during therapeutic GPi DBS. A majority of the neurons in each nucleus were inhibited during DBS (VA/VLo: 47% and VPLo: 49%), while a smaller subset was excited (VA/VLo: 21% and VPLo: 17%). Bursts changed in structure, becoming longer in duration and both intra-burst and inter-spike intervals and variability were increased in both subnuclei. High frequency oscillatory activity was significantly increased during stimulation with 33% of VA

  12. Licochalcone A Prevents the Loss of Dopaminergic Neurons by Inhibiting Microglial Activation in Lipopolysaccharide (LPS-Induced Parkinson’s Disease Models

    Directory of Open Access Journals (Sweden)

    Bingxu Huang

    2017-09-01

    Full Text Available The neuroprotective effects of Licochalcone A (Lico.A, a flavonoid isolated from the herb licorice, in Parkinson’s disease (PD have not been elucidated. The prominent pathological feature of PD is the loss of dopaminergic neurons. The crucial role of neuroinflammation induced by activated microglia in dopaminergic neurodegeneration has been validated. In this study, we explore the therapeutic effects of Lico.A in lipopolysaccharide (LPS-induced PD models in vivo and in vitro. We find that Lico.A significantly inhibits LPS-stimulated production of pro-inflammatory mediators and microglial activation by blocking the phosphorylation of extracellular signal-regulated kinase (ERK1/2 and nuclear factor κB (NF-κB p65 in BV-2 cells. In addition, through cultured primary mesencephalic neuron-glia cell experiments, we illustrate that Lico.A attenuates the decrease in [3H] dopamine (DA uptake and the loss of tyrosine hydroxylase-immunoreactive (TH-ir neurons in LPS-induced PD models in vitro. Furthermore, LPS intoxication in rats results in microglial activation, dopaminergic neurodegeneration and significant behavioral deficits in vivo. Lico.A treatment prevents microglial activation and reduction of dopaminergic neuron and ameliorates PD-like behavioral impairments. Thus, these results demonstrate for the first time that the neuroprotective effects of Lico.A are associated with microglia and anti-inflammatory effects in PD models.

  13. Differential changes in thalamic and cortical excitatory synapses onto striatal spiny projection neurons in a Huntington disease mouse model.

    Science.gov (United States)

    Kolodziejczyk, Karolina; Raymond, Lynn A

    2016-02-01

    Huntington disease (HD), a neurodegenerative disorder caused by CAG repeat expansion in the gene encoding huntingtin, predominantly affects the striatum, especially the spiny projection neurons (SPN). The striatum receives excitatory input from cortex and thalamus, and the role of the former has been well-studied in HD. Here, we report that mutated huntingtin alters function of thalamostriatal connections. We used a novel thalamostriatal (T-S) coculture and an established corticostriatal (C-S) coculture, generated from YAC128 HD and WT (FVB/NJ background strain) mice, to investigate excitatory neurotransmission onto striatal SPN. SPN in T-S coculture from WT mice showed similar mini-excitatory postsynaptic current (mEPSC) frequency and amplitude as in C-S coculture; however, both the frequency and amplitude were significantly reduced in YAC128 T-S coculture. Further investigation in T-S coculture showed similar excitatory synapse density in WT and YAC128 SPN dendrites by immunostaining, suggesting changes in total dendritic length or probability of release as possible explanations for mEPSC frequency changes. Synaptic N-methyl-D-aspartate receptor (NMDAR) current was similar, but extrasynaptic current, associated with cell death signaling, was enhanced in YAC128 SPN in T-S coculture. Employing optical stimulation of cortical versus thalamic afferents and recording from striatal SPN in brain slice, we found increased glutamate release probability and reduced AMPAR/NMDAR current ratios in thalamostriatal synapses, most prominently in YAC128. Enhanced extrasynaptic NMDAR current in YAC128 SPN was apparent with both cortical and thalamic stimulation. We conclude that thalamic afferents to the striatum are affected early, prior to an overt HD phenotype; however, changes in NMDAR localization in SPN are independent of the source of glutamatergic input. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. 'All in the same boat'? Patient and carer attitudes to peer support and social comparison in Motor Neurone Disease (MND).

    Science.gov (United States)

    Locock, Louise; Brown, Janice B

    2010-10-01

    This paper explores attitudes to peer support among people with Motor Neurone Disease (MND) and their family carers. It reports findings from a secondary analysis of data from two UK interview studies conducted by the authors. The process of secondary analysis is reported in detail. 48 people with MND and 22 carers were interviewed in 2005-2007. The authors identified narrative extracts on peer support from their own datasets and exchanged them for independent thematic analysis. Subsequent discussion, drawing on literature on support groups and social comparison, led to an exploration of two overarching themes: valuing camaraderie and comparison, and choosing isolation. Findings suggest that social comparison theory is a useful framework for analysing attitudes to MND support groups, but that on its own it is insufficient. 'Valuing camaraderie and comparison' explains how support groups offer practical and social support, as well as beneficial opportunities for social comparison. Seeing others coping well with the condition can provide hope, while downward comparison with those worse off can also make people feel better about their own situation. However, most people are also shocked and saddened by seeing others with the condition. Tension of identity can occur when group membership starts to define the individual as 'a person with MND, rather than the person I am that happens to have MND'. Choosing isolation can be a deliberate defensive strategy, to protect oneself from witnessing one's possible future. Levels of involvement may change over time as people struggle with their changing needs and fears. Copyright © 2010 Elsevier Ltd. All rights reserved.

  15. Ceftriaxone prevents and reverses behavioral and neuronal deficits in an MPTP-induced animal model of Parkinson's disease dementia.

    Science.gov (United States)

    Hsu, Chao-Yu; Hung, Ching-Sui; Chang, Hung-Ming; Liao, Wen-Chieh; Ho, Shih-Chun; Ho, Ying-Jui

    2015-04-01

    Glutamatergic hyperactivity plays an important role in the pathophysiology of Parkinson's disease (PD). Ceftriaxone increases expression of glutamate transporter 1 (GLT-1) and affords neuroprotection. This study was aimed at clarifying whether ceftriaxone prevented, or reversed, behavioral and neuronal deficits in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats were injected daily with either ceftriaxone starting 5 days before or 3 days after MPTP lesioning (day 0) or saline and underwent a bar-test on days 1-7, a T-maze test on days 9-11, and an object recognition test on days 12-14, then the brains were taken for histological evaluation on day 15. Dopaminergic degeneration in the substantia nigra pars compacta and striatum was observed on days 3 and 15. Motor dysfunction in the bar test was observed on day 1, but disappeared by day 7. In addition, lesioning resulted in deficits in working memory in the T-maze test and in object recognition in the object recognition task, but these were not observed in rats treated pre- or post-lesioning with ceftriaxone. Lesioning also caused neurodegeneration in the hippocampal CA1 area and induced glutamatergic hyperactivity in the subthalamic nucleus, and both changes were suppressed by ceftriaxone. Increased GLT-1 expression and its co-localization with astrocytes were observed in the striatum and hippocampus in the ceftriaxone-treated animals. To our knowledge, this is the first study showing a relationship between ceftriaxone-induced GLT-1 expression, neuroprotection, and improved cognition in a PD rat model. Ceftriaxone may have clinical potential for the prevention and treatment of dementia associated with PD. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Disruption of murine Hexa gene leads to enzymatic deficiency and to neuronal lysosomal storage, similar to that observed in Tay-Sachs disease.

    Science.gov (United States)

    Cohen-Tannoudji, M; Marchand, P; Akli, S; Sheardown, S A; Puech, J P; Kress, C; Gressens, P; Nassogne, M C; Beccari, T; Muggleton-Harris, A L

    1995-12-01

    Tay-Sachs disease is an autosomal recessive lysosomal storage disease caused by beta-hexosaminidase A deficiency and leads to death in early childhood. The disease results from mutations in the HEXA gene, which codes for the alpha chain of beta-hexosaminidase. The castastrophic neurodegenerative progression of the disease is thought to be a consequence of massive neuronal accumulation of GM2 ganglioside and related glycolipids in the brain and nervous system of the patients. Fuller understanding of the pathogenesis and the development of therapeutic procedures have both suffered from the lack of an animal model. We have used gene targeting in embryonic stem (ES) cells to disrupt the mouse Hexa gene. Mice homozygous for the disrupted allele mimic several biochemical and histological features of human Tay-Sachs disease. Hexa-/- mice displayed a total deficiency of beta-hexosaminidase A activity, and membranous cytoplasmic inclusions typical of GM2 gangliosidoses were found in the cytoplasm of their neurons. However, while the number of storage neurons increased with age, it remained low compared with that found in human, and no apparent motor or behavioral disorders could be observed. This suggests that the presence of beta-hexosaminidase A is not an absolute requirement of ganglioside degradation in mice. These mice should help us to understand several aspects of the disease as well as the physiological functions of hexosaminidase in mice. They should also provide a valuable animal model in which to test new forms of therapy, and in particular gene delivery into the central nervous system.

  17. The Neuronal Ceroid-Lipofuscinoses

    Science.gov (United States)

    Bennett, Michael J.; Rakheja, Dinesh

    2013-01-01

    The neuronal ceroid-lipofuscinoses (NCL's, Batten disease) represent a group of severe neurodegenerative diseases, which mostly present in childhood. The phenotypes are similar and include visual loss, seizures, loss of motor and cognitive function, and early death. At autopsy, there is massive neuronal loss with characteristic storage in…

  18. The Endocrine Dyscrasia that Accompanies Menopause and Andropause Induces Aberrant Cell Cycle Signaling that Triggers Cell Cycle Reentry of Post-mitotic Neurons, Neurodysfunction, Neurodegeneration and Cognitive Disease

    Science.gov (United States)

    Atwood, Craig S.; Bowen, Richard L.

    2016-01-01

    Sex hormones are the physiological factors that regulate neurogenesis during embryogenesis and continuing through adulthood. These hormones support the formation of brain structures such as dendritic spines, axons and synapses required for the capture of information (memories). Intriguingly, a recent animal study has demonstrated that induction of neurogenesis results in the loss of previously encoded memories in animals (e.g. infantile amnesia). In this connection, much evidence now indicates that Alzheimer’s disease (AD) also involves aberrant re-entry of post-mitotic neurons into the cell cycle. Cell cycle abnormalities appear very early in the disease, prior to the appearance of plaques and tangles, and explain the biochemical, neuropathological and cognitive changes observed with disease progression. Since sex hormones control when and how neurons proliferate and differentiate, the endocrine dyscrasia that accompanies menopause and andropause is a key signaling event that impacts neurogenesis and the acquisition, processing, storage and recall of memories. Here we review the biochemical, epidemiological and clinical evidence that alterations in endocrine signaling with menopause and andropause drive the aberrant re-entry of post-mitotic neurons into an abortive cell cycle with neurite retraction that leads to neuron dysfunction and death. When the reproductive axis is in balance, luteinizing hormone (LH), and its fetal homolog, human chorionic gonadotropin (hCG), promote pluripotent human and totipotent murine embryonic stem cell and neuron proliferation. However, strong evidence supports menopausal/andropausal elevations in the ratio of LH:sex steroids as driving aberrant mitotic events mediated by the upregulation of tumor necrosis factor, amyloid-β precursor protein processing towards the production of mitogenic Aβ, and the activation of Cdk5, a key regulator of cell cycle progression and tau phosphorylation (a cardinal feature of both neurogenesis and

  19. Motor Neuron Diseases

    Science.gov (United States)

    ... most often affected. Complications include scoliosis and joint contractures—chronic shortening of muscles or tendons around joints, ... a normal lifespan. Congenital SMA with arthrogryposis (persistent contracture of joints with fixed abnormal posture of the ...

  20. Motor Neuron Diseases

    Science.gov (United States)

    ... some patients retain independence. Proper nutrition and a balanced diet are essential to maintaining weight and strength. × Treatment ... some patients retain independence. Proper nutrition and a balanced diet are essential to maintaining weight and strength. View ...

  1. Resemblance operations and conceptual complexity in animal metaphors

    Directory of Open Access Journals (Sweden)

    Aneider Iza Ervitia

    2012-07-01

    Full Text Available For over thirty years cognitive linguists have devoted much effort to the study of metaphors based on the correlation of events in human experience to the detriment of the more traditional notion of resemblance metaphor, which exploits perceived similarities among objects. Grady (1999 draws attention to this problem and calls for a more serious study of the latter type of metaphor. The present paper takes up this challenge on the basis of a small corpus of ‘animal’ metaphors in English, which are essentially based on resemblance. Contrary to previous analyses by cognitive linguists (e.g. Lakoff & Turner 1989, Ruiz de Mendoza Ibáñez, 1998, who claim that such metaphors are based on a single mapping generally involving comparable behavioral attributes, I will argue that we have a more complex situation which involves different patterns of conceptual interaction. In this respect, I have identified cases of (i animal metaphors interacting with high-level (i.e. grammatical metaphors and metonymies, of (ii (situational animal metaphors whose source domains are constructed metonymically (cf. Goossens 1990; Ruiz de Mendoza Ibáñez & Díez Velasco 2002, and of (iii animal metaphors interacting with other metaphors thereby giving rise to metaphoric amalgams (cf. Ruiz de Mendoza Ibáñez & Galera Masegosa 2011.

  2. Neurotoxicity of cerebro-spinal fluid from patients with Parkinson's disease on mesencephalic primary cultures as an in vitro model of dopaminergic neurons.

    Science.gov (United States)

    Kong, Ping; Zhang, Ben-Shu; Lei, Ping; Kong, Xiao-Dong; Zhang, Shi-Shuang; Li, Dai; Zhang, Yun

    2015-08-01

    Parkinson's disease is a degenerative disorder of the central nervous system. In spite of extensive research, neither the cause nor the mechanisms have been firmly established thus far. One assumption is that certain toxic substances may exist in the cerebro-spinal fluid (CSF) of Parkinson's disease patients. To confirm the neurotoxicity of CSF and study the potential correlation between neurotoxicity and the severity of Parkinson's disease, CSF was added to cultured cells. By observation of cell morphology, changes in the levels of lactate dehydrogenase, the ratio of tyrosine hydroxylase-positive cells, and the expression of tyrosine hydroxylase mRNA and protein, the differences between the two groups were shown. The created in vitro model of dopaminergic neurons using primary culture of mouse embryonic mesencephalic tissue is suitable for the study of neurotoxicity. The observations of the present study indicated that CSF from Parkinson's disease patients contains factors that can cause specific injury to cultured dopaminergic neurons. However, no obvious correlation was found between the neurotoxicity of CSF and the severity of Parkinson's disease.

  3. cAMP/PKA signaling pathway contributes to neuronal apoptosis via regulating IDE expression in a mixed model of type 2 diabetes and Alzheimer's disease.

    Science.gov (United States)

    Li, Huajie; Yang, Song; Wu, Jian; Ji, Lei; Zhu, Linfeng; Cao, Liping; Huang, Jinzhong; Jiang, Qingqing; Wei, Jiang; Liu, Meng; Mao, Keshi; Wei, Ning; Xie, Wei; Yang, Zhilong

    2018-02-01

    Type 2 diabetes (T2D) may play a relevant role in the development of Alzheimer's disease (AD), however, the underlying mechanism was not clear yet. We developed an animal model presenting both AD and T2D, morris water maze (MWM) test and recognition task were performed to trace the cognitive function. Fasting plasma glucose (FPG) and oral glucose tolerance test (OGTT) were determined to trace the metabolism evolution. TUNEL assay and apoptosis-related protein levels were analyzed for the detection of neuronal apoptosis. Cyclic adenosine monophosphate (cAMP) agonist bucladesine or protein kinase (PKA) inhibitor H-89 were used to determine the effects of cAMP/PKA signaling pathway on IDE expression and neuronal apoptosis. The results showed that T2D contributes to the AD progress by accelerating and worsening spatial memory and recognition dysfunctions. Metabolic parameters and glucose tolerance were significantly changed in the presence of the AD and T2D. The significantly induced neuronal apoptosis and increased pro-apoptotic proteins in mice with AD and T2D were also observed. We showed the decreased expression level of IDE and the activating of cAMP/PKA signaling pathway in AD and T2D mice. Further studies indicated that cAMP agonist decreased the expression level of IDE and induced the neuronal apoptosis in mice with AD and T2D; whereas PKA inhibitor H-89 treatment showed the completely opposite results. Our study indicated that, in the T2D and AD mice, cAMP/PKA signaling pathway and IDE may participate in the contribute role of T2D in accelerating the pathological process of AD via causing the accumulation of Aβ and neuronal apoptosis. © 2017 Wiley Periodicals, Inc.

  4. Relative importance of redox buffers GSH and NAD(P)H in age-related neurodegeneration and Alzheimer disease-like mouse neurons.

    Science.gov (United States)

    Ghosh, Debolina; Levault, Kelsey R; Brewer, Gregory J

    2014-08-01

    Aging, a major risk factor in Alzheimer's disease (AD), is associated with an oxidative redox shift, decreased redox buffer protection, and increased free radical reactive oxygen species (ROS) generation, probably linked to mitochondrial dysfunction. While NADH is the ultimate electron donor for many redox reactions, including oxidative phosphorylation, glutathione (GSH) is the major ROS detoxifying redox buffer in the cell. Here, we explored the relative importance of NADH and GSH to neurodegeneration in aging and AD neurons from nontransgenic and 3xTg-AD mice by inhibiting their synthesis to determine whether NADH can compensate for the GSH loss to maintain redox balance. Neurons stressed by either depleting NAD(P)H or GSH indicated that NADH redox control is upstream of GSH levels. Further, although depletion of NAD(P)H or GSH correlated linearly with neuron death, compared with GSH depletion, higher neurodegeneration was observed when NAD(P)H was extrapolated to zero, especially in old age, and in the 3xTg-AD neurons. We also observed an age-dependent loss of gene expression of key redox-dependent biosynthetic enzymes, NAMPT (nicotinamide phosphoribosyltransferase), and NNT (nicotinamide nucleotide transhydrogenase). Moreover, age-related correlations between brain NNT or NAMPT gene expression and NADPH levels suggest that these genes contribute to the age-related declines in NAD(P)H. Our data indicate that in aging and more so in AD-like neurons, NAD(P)H redox control is upstream of GSH and an oxidative redox shift that promotes neurodegeneration. Thus, NAD(P)H generation may be a more efficacious therapeutic target upstream of GSH and ROS. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

  5. Amentoflavone protects dopaminergic neurons in MPTP-induced Parkinson's disease model mice through PI3K/Akt and ERK signaling pathways

    International Nuclear Information System (INIS)

    Cao, Qin; Qin, Liyue; Huang, Fei; Wang, Xiaoshuang; Yang, Liu; Shi, Hailian; Wu, Hui; Zhang, Beibei; Chen, Ziyu; Wu, Xiaojun

    2017-01-01

    Parkinson's disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Mitochondrial dysfunction and cell apoptosis are suggested to be actively involved in the pathogenesis of PD. In the present study, the neuroprotective effect of amentoflavone (AF), a naturally occurring biflavonoid from Selaginella tamariscina, was examined in PD models both in vitro and in vivo. On SH-SY5Y cells, AF treatment dose-dependently reduced 1-methyl-4-phenylpyridinium (MPP + )-induced nuclear condensation and loss of cell viability without obvious cytotoxicity. It inhibited the activation of caspase-3 and p21 but increased the Bcl-2/Bax ratio. Further study disclosed that AF enhanced the phosphorylation of PI3K, Akt and ERK1/2 down-regulated by MPP + in SH-SY5Y cells, the effect of which could be blocked by LY294002, the inhibitor of PI3K. Consistently, AF alleviated the behavioral deterioration in pole and traction tests and rescued the loss of dopaminergic neurons in SNpc and fibers in striatum in methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mice. It also could enhance the activation of PI3K and Akt as well as Bcl-2/Bax ratio in SN. Moreover, AF alleviated gliosis as well as the gene expression levels of IL-1β and iNOS in SN. Collectively, these results suggested that AF protected dopaminergic neurons against MPTP/MPP + -induced neurotoxicity, which might be mediated through activation of PI3K/Akt and ERK signaling pathways in dopaminergic neurons and attenuation of neuroinflammation. - Highlights: • AF protected dopaminergic neurons against MPTP/MPP + -induced neurotoxicity. • AF modulated PI3K/Akt and ERK signaling pathways. • AF could alleviate neuroinflammation in SN.

  6. Calcium-Sensing Receptors of Human Astrocyte-Neuron Teams: Amyloid-β-Driven Mediators and Therapeutic Targets of Alzheimer's Disease.

    Science.gov (United States)

    Dal Prà, I; Chiarini, A; Pacchiana, R; Gardenal, E; Chakravarthy, B; Whitfield, J F; Armato, U

    2014-07-01

    It is generally assumed that the neuropathology of sporadic (late-onset or nonfamilial) Alzheimer's disease (AD) is driven by the overproduction and spreading of first Amyloid-βx-42 (Aβ42) and later hyperphosphorylated (hp)-Tau oligomeric "infectious seeds". Hitherto, only neurons were held to make and spread both oligomer types; astrocytes would just remove debris. However, we have recently shown that exogenous fibrillar or soluble Aβ peptides specifically bind and activate the Ca(2+)-sensing receptors (CaSRs) of untransformed human cortical adult astrocytes and postnatal neurons cultured in vitro driving them to produce, accrue, and secrete surplus endogenous Aβ42. While the Aβ-exposed neurons start dying, astrocytes survive and keep oversecreting Aβ42, nitric oxide (NO), and vascular endothelial growth factor (VEGF)-A. Thus astrocytes help neurons' demise. Moreover, we have found that a highly selective allosteric CaSR agonist ("calcimimetic"), NPS R-568, mimics the just mentioned neurotoxic actions triggered by Aβ●CaSR signaling. Contrariwise, and most important, NPS 2143, a highly selective allosteric CaSR antagonist ("calcilytic"), fully suppresses all the Aβ●CaSR signaling-driven noxious actions. Altogether our findings suggest that the progression of AD neuropathology is promoted by unceasingly repeating cycles of accruing exogenous Aβ42 oligomers interacting with the CaSRs of swelling numbers of astrocyte-neuron teams thereby recruiting them to overrelease additional Aβ42 oligomers, VEGF-A, and NO. Calcilytics would beneficially break such Aβ/CaSR-driven vicious cycles and hence halt or at least slow the otherwise unstoppable spreading of AD neuropathology.

  7. Impairment of the nerve growth factor pathway driving amyloid accumulation in cholinergic neurons: the incipit of the Alzheimer′s disease story?

    Directory of Open Access Journals (Sweden)

    Viviana Triaca

    2016-01-01

    Full Text Available The current idea behind brain pathology is that disease is initiated by mild disturbances of common physiological processes. Overtime, the disruption of the neuronal homeostasis will determine irreversible degeneration and neuronal apoptosis. This could be also true in the case of nerve growth factor (NGF alterations in sporadic Alzheimer′s disease (AD, an age-related pathology characterized by cholinergic loss, amyloid plaques and neurofibrillary tangles. In fact, the pathway activated by NGF, a key neurotrophin for the metabolism of basal forebrain cholinergic neurons (BFCN, is one of the first homeostatic systems affected in prodromal AD. NGF signaling dysfunctions have been thought for decades to occur in AD late stages, as a mere consequence of amyloid-driven disruption of the retrograde axonal transport of neurotrophins to BFCN. Nowadays, a wealth of knowledge is potentially opening a new scenario: NGF signaling impairment occurs at the onset of AD and correlates better than amyloid load with cognitive decline. The recent acceleration in the characterization of anatomical, functional and molecular profiles of early AD is aimed at maximizing the efficacy of existing treatments and setting novel therapies. Accordingly, the elucidation of the molecular events underlying APP metabolism regulation by the NGF pathway in the septo-hippocampal system is crucial for the identification of new target molecules to slow and eventually halt mild cognitive impairment (MCI and its progression toward AD.

  8. Neuroprotective Effects of β-Caryophyllene against Dopaminergic Neuron Injury in a Murine Model of Parkinson’s Disease Induced by MPTP

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    Juan M. Viveros-Paredes

    2017-07-01

    Full Text Available Parkinson’s disease (PD is one of the most common neurodegenerative disorders and is characterized by the loss of dopaminergic neurons in the substantia nigra (SN. Although the causes of PD are not understood, evidence suggests that its pathogenesis is associated with oxidative stress and inflammation. Recent studies have suggested a protective role of the cannabinoid signalling system in PD. β-caryophyllene (BCP is a natural bicyclic sesquiterpene that is an agonist of the cannabinoid type 2 receptor (CB2R. Previous studies have suggested that BCP exerts prophylactic and/or curative effects against inflammatory bowel disease through its antioxidative and/or anti-inflammatory action. The present study describes the neuroprotective effects of BCP in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP-induced murine model of PD, and we report the results of our investigation of its neuroprotective mechanism in neurons and glial cells. In the murine model, BCP pretreatment ameliorated motor dysfunction, protected against dopaminergic neuronal losses in the SN and striatum, and alleviated MPTP-induced glia activation. Additionally, BCP inhibited the levels of inflammatory cytokines in the nigrostriatal system. The observed neuroprotection and inhibited glia activation were reversed upon treatment with the CB2R selective antagonist AM630, confirming the involvement of the CB2R. These results indicate that BCP acts via multiple neuroprotective mechanisms in our murine model and suggest that BCP may be viewed as a potential treatment and/or preventative agent for PD.

  9. Multiple intracerebroventricular injections of human umbilical cord mesenchymal stem cells delay motor neurons loss but not disease progression of SOD1G93A mice.

    Science.gov (United States)

    Sironi, Francesca; Vallarola, Antonio; Violatto, Martina Bruna; Talamini, Laura; Freschi, Mattia; De Gioia, Roberta; Capelli, Chiara; Agostini, Azzurra; Moscatelli, Davide; Tortarolo, Massimo; Bigini, Paolo; Introna, Martino; Bendotti, Caterina

    2017-12-01

    Stem cell therapy is considered a promising approach in the treatment of amyotrophic lateral sclerosis (ALS) and mesenchymal stem cells (MSCs) seem to be the most effective in ALS animal models. The umbilical cord (UC) is a source of highly proliferating fetal MSCs, more easily collectable than other MSCs. Recently we demonstrated that human (h) UC-MSCs, double labeled with fluorescent nanoparticles and Hoechst-33258 and transplanted intracerebroventricularly (ICV) into SOD1G93A transgenic mice, partially migrated into the spinal cord after a single injection. This prompted us to assess the effect of repeated ICV injections of hUC-MSCs on disease progression in SOD1G93A mice. Although no transplanted cells migrated to the spinal cord, a partial but significant protection of motor neurons (MNs) was found in the lumbar spinal cord of hUC-MSCs-treated SOD1G93A mice, accompanied by a shift from a pro-inflammatory (IL-6, IL-1β) to anti-inflammatory (IL-4, IL-10) and neuroprotective (IGF-1) environment in the lumbar spinal cord, probably linked to the activation of p-Akt survival pathway in both motor neurons and reactive astrocytes. However, this treatment neither prevented the muscle denervation nor delayed the disease progression of mice, emphasizing the growing evidence that protecting the motor neuron perikarya is not sufficient to delay the ALS progression. Copyright © 2017. Published by Elsevier B.V.

  10. Human iPSC-Derived Endothelial Cells and Microengineered Organ-Chip Enhance Neuronal Development

    Directory of Open Access Journals (Sweden)

    Samuel Sances

    2018-04-01

    Full Text Available Summary: Human stem cell-derived models of development and neurodegenerative diseases are challenged by cellular immaturity in vitro. Microengineered organ-on-chip (or Organ-Chip systems are designed to emulate microvolume cytoarchitecture and enable co-culture of distinct cell types. Brain microvascular endothelial cells (BMECs share common signaling pathways with neurons early in development, but their contribution to human neuronal maturation is largely unknown. To study this interaction and influence of microculture, we derived both spinal motor neurons and BMECs from human induced pluripotent stem cells and observed increased calcium transient function and Chip-specific gene expression in Organ-Chips compared with 96-well plates. Seeding BMECs in the Organ-Chip led to vascular-neural interaction and specific gene activation that further enhanced neuronal function and in vivo-like signatures. The results show that the vascular system has specific maturation effects on spinal cord neural tissue, and the use of Organ-Chips can move stem cell models closer to an in vivo condition. : Sances et al. combine Organ-Chip technology with human induced pluripotent stem cell-derived spinal motor neurons to study the maturation effects of Organ-Chip culture. By including microvascular cells also derived from the same patient line, the authors show enhancement of neuronal function, reproduction of vascular-neuron pathways, and specific gene activation that resembles in vivo spinal cord development. Keywords: organ-on-chip, spinal cord, iPSC, disease modeling, amyotrophic lateral sclerosis, microphysiological system, brain microvascular endothelial cells, spinal motor neurons, vasculature, microfluidic device

  11. Altered neuronal firing pattern of the basal ganglia nucleus plays a role in levodopa-induced dyskinesia in patients with Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Xiaoyu eLi

    2015-11-01

    Full Text Available Background: Levodopa therapy alleviates the symptoms of Parkinson's disease (PD, but long-term treatment often leads to motor complications such as levodopa-induced dyskinesia (LID. Aim: To explore the neuronal activity in the basal ganglia nuclei in patients with PD and LID. Methods: Thirty patients with idiopathic PD (age, 55.1±11.0 years; disease duration, 8.7±5.6 years were enrolled between August 2006 and August 2013 at the Xuanwu Hospital, Capital Medical University, China. Their Hoehn and Yahr scores ranged from 2 to 4 and their UPDRS III scores were 28.5±5.2. Fifteen of them had severe LID (UPDRS IV scores of 6.7±1.6. Microelectrode recording was performed in the globus pallidus internus (GPi and subthalamic nucleus (STN during pallidotomy (n=12 or STN deep brain stimulation (DBS; bilateral, n=12; unilateral, n=6. The firing patterns and frequencies of various cell types were analyzed by assessing single cell interspike intervals (ISIs and the corresponding coefficient of variation (CV. Results: A total of 295 neurons were identified from the GPi (n=12 and STN (n=18. These included 26 (8.8% highly grouped discharge, 30 (10.2% low frequency firing, 78 (26.4% rapid tonic discharge, 103 (34.9% irregular activity, and 58 (19.7% tremor-related activity. There were significant differences between the two groups (P<0.05 for neurons with irregular firing, highly irregular cluster-like firing, and low-frequency firing. Conclusion: Altered neuronal activity was observed in the basal ganglia nucleus of GPi and STN, and may play important roles in the pathophysiology of PD and LID.

  12. Young Human Cholinergic Neurons Respond to Physiological Regulators and Improve Cognitive Symptoms in an Animal Model of Alzheimer’s Disease

    Science.gov (United States)

    Morelli, Annamaria; Sarchielli, Erica; Guarnieri, Giulia; Coppi, Elisabetta; Pantano, Daniela; Comeglio, Paolo; Nardiello, Pamela; Pugliese, Anna M.; Ballerini, Lara; Matucci, Rosanna; Ambrosini, Stefano; Castronovo, Giuseppe; Valente, Rosa; Mazzanti, Benedetta; Bucciantini, Sandra; Maggi, Mario; Casamenti, Fiorella; Gallina, Pasquale; Vannelli, Gabriella B.

    2017-01-01

    The degeneration of cholinergic neurons of the nucleus basalis of Meynert (NBM) in the basal forebrain (BF) is associated to the cognitive decline of Alzheimer’s disease (AD) patients. To date no resolutive therapies exist. Cell-based replacement therapy is a strategy currently under consideration, although the mechanisms underlying the generation of stem cell-derived NBM cholinergic neurons able of functional integration remain to be clarified. Since fetal brain is an optimal source of neuronal cells committed towards a specific phenotype, this study is aimed at isolating cholinergic neurons from the human fetal NBM (hfNBMs) in order to study their phenotypic, maturational and functional properties. Extensive characterization confirmed the cholinergic identity of hfNBMs, including positivity for specific markers (such as choline acetyltransferase) and acetylcholine (Ach) release. Electrophysiological measurements provided the functional validation of hfNBM cells, which exhibited the activation of peculiar sodium (INa) and potassium (IK) currents, as well as the presence of functional cholinergic receptors. Accordingly, hfNBMs express both nicotinic and muscarinic receptors, which were activated by Ach. The hfNBMs cholinergic phenotype was regulated by the nerve growth factor (NGF), through the activation of the high-affinity NGF receptor TrkA, as well as by 17-β-estradiol through a peculiar recruitment of its own receptors. When intravenously administered in NBM-lesioned rats, hfNBMs determined a significant improvement in memory functions. Histological examination of brain sections showed that hfNBMs (labeled with PKH26 fluorescent dye prior to administration) reached the damaged brain areas. The study provides a useful model to study the ontogenetic mechanisms regulating the development and maintenance of the human brain cholinergic system and to assess new lines of research, including disease modeling, drug discovery and cell-based therapy for AD. PMID

  13. Young Human Cholinergic Neurons Respond to Physiological Regulators and Improve Cognitive Symptoms in an Animal Model of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Annamaria Morelli

    2017-10-01

    Full Text Available The degeneration of cholinergic neurons of the nucleus basalis of Meynert (NBM in the basal forebrain (BF is associated to the cognitive decline of Alzheimer’s disease (AD patients. To date no resolutive therapies exist. Cell-based replacement therapy is a strategy currently under consideration, although the mechanisms underlying the generation of stem cell-derived NBM cholinergic neurons able of functional integration remain to be clarified. Since fetal brain is an optimal source of neuronal cells committed towards a specific phenotype, this study is aimed at isolating cholinergic neurons from the human fetal NBM (hfNBMs in order to study their phenotypic, maturational and functional properties. Extensive characterization confirmed the cholinergic identity of hfNBMs, including positivity for specific markers (such as choline acetyltransferase and acetylcholine (Ach release. Electrophysiological measurements provided the functional validation of hfNBM cells, which exhibited the activation of peculiar sodium (INa and potassium (IK currents, as well as the presence of functional cholinergic receptors. Accordingly, hfNBMs express both nicotinic and muscarinic receptors, which were activated by Ach. The hfNBMs cholinergic phenotype was regulated by the nerve growth factor (NGF, through the activation of the high-affinity NGF receptor TrkA, as well as by 17-β-estradiol through a peculiar recruitment of its own receptors. When intravenously administered in NBM-lesioned rats, hfNBMs determined a significant improvement in memory functions. Histological examination of brain sections showed that hfNBMs (labeled with PKH26 fluorescent dye prior to administration reached the damaged brain areas. The study provides a useful model to study the ontogenetic mechanisms regulating the development and maintenance of the human brain cholinergic system and to assess new lines of research, including disease modeling, drug discovery and cell-based therapy for AD.

  14. RESEMBLANCE OPERATIONS AND CONCEPTUAL COMPLEXY IN ANIMAL METAPHORS

    Directory of Open Access Journals (Sweden)

    Aneider Iza Ervitia

    2012-07-01

    Full Text Available

    For over thirty years cognitive linguists have devoted much effort to the study of metaphors based on the correlation of events in human experience to the detriment of the more traditional notion of resemblance metaphor, which exploits perceived similarities among objects. Grady (1999 draws attention to this problem and calls for a more serious study of the latter type of metaphor. The present paper takes up this challenge on the basis of a small corpus of ‘animal’ metaphors in English, which are essentially based on resemblance. Contrary to previous analyses by cognitive linguists (e.g. Lakoff & Turner 1989, Ruiz de Mendoza Ibáñez, 1998, who claim that such metaphors are based on a single mapping generally involving comparable behavioral attributes, I will argue that we have a more complex situation which involves different patterns of conceptual interaction. In this respect, I have identified cases of (i animal metaphors interacting with high-level (i.e. grammatical metaphors and metonymies, of (ii (situational animal metaphors whose source domains are constructed metonymically (cf. Goossens 1990; Ruiz de Mendoza Ibáñez & Díez Velasco 2002, and of (iii animal metaphors interacting with other metaphors thereby giving rise to metaphoric amalgams (cf. Ruiz de Mendoza Ibáñez & Galera Masegosa 2011.

  15. Lack of TNF-alpha receptor type 2 protects motor neurons in a cellular model of amyotrophic lateral sclerosis and in mutant SOD1 mice but does not affect disease progression.

    Science.gov (United States)

    Tortarolo, Massimo; Vallarola, Antonio; Lidonnici, Dario; Battaglia, Elisa; Gensano, Francesco; Spaltro, Gabriella; Fiordaliso, Fabio; Corbelli, Alessandro; Garetto, Stefano; Martini, Elisa; Pasetto, Laura; Kallikourdis, Marinos; Bonetto, Valentina; Bendotti, Caterina

    2015-10-01

    Changes in the homeostasis of tumor necrosis factor α (TNFα) have been demonstrated in patients and experimental models of amyotrophic lateral sclerosis (ALS). However, the contribution of TNFα to the development of ALS is still debated. TNFα is expressed by glia and neurons and acts through the membrane receptors TNFR1 and TNFR2, which may have opposite effects in neurodegeneration. We investigated the role of TNFα and its receptors in the selective motor neuron death in ALS in vitro and in vivo. TNFR2 expressed by astrocytes and neurons, but not TNFR1, was implicated in motor neuron loss in primary SOD1-G93A co-cultures. Deleting TNFR2 from SOD1-G93A mice, there was partial but significant protection of spinal motor neurons, sciatic nerves, and tibialis muscles. However, no improvement of motor impairment or survival was observed. Since the sciatic nerves of SOD1-G93A/TNFR2-/- mice showed high phospho-TAR DNA-binding protein 43 (TDP-43) accumulation and low levels of acetyl-tubulin, two indices of axonal dysfunction, the lack of symptom improvement in these mice might be due to impaired function of rescued motor neurons. These results indicate the interaction between TNFR2 and membrane-bound TNFα as an innovative pathway involved in motor neuron death. Nevertheless, its inhibition is not sufficient to stop disease progression in ALS mice, underlining the complexity of this pathology. We show evidence of the involvement of neuronal and astroglial TNFR2 in the motor neuron degeneration in ALS. Both concur to cause motor neuron death in primary astrocyte/spinal neuron co-cultures. TNFR2 deletion partially protects motor neurons and sciatic nerves in SOD1-G93A mice but does not improve their symptoms and survival. However, TNFR2 could be a new target for multi-intervention therapies. © 2015 International Society for Neurochemistry.

  16. Quantification of surviving cerebellar granule neurones and abnormal prion protein (PrPSc) deposition in sporadic Creutzfeldt-Jakob disease supports a pathogenic role for small PrPSc deposits common to the various molecular subtypes.

    Science.gov (United States)

    Faucheux, B A; Morain, E; Diouron, V; Brandel, J-P; Salomon, D; Sazdovitch, V; Privat, N; Laplanche, J-L; Hauw, J-J; Haïk, S

    2011-08-01

    Neuronal death is a major neuropathological hallmark in prion diseases. The association between the accumulation of the disease-related prion protein (PrP(Sc) ) and neuronal loss varies within the wide spectrum of prion diseases and their experimental models. In this study, we investigated the relationships between neuronal loss and PrP(Sc) deposition in the cerebellum from cases of the six subtypes of sporadic Creutzfeldt-Jakob disease (sCJD; n=100) that can be determined according to the M129V polymorphism of the human prion protein gene (PRNP) and PrP(Sc) molecular types. The numerical density of neurones was estimated with a computer-assisted image analysis system and the accumulation of PrP(Sc) deposits was scored. The scores of PrP(Sc) immunoreactive deposits of the punctate type (synaptic type) were correlated with neurone counts - the higher the score the higher the neuronal loss - in all sCJD subtypes. Large 5- to 50-µm-wide deposits (focal type) were found in sCJD-MV2 and sCJD-VV2 subtypes, and occasionally in a few cases of the other studied groups. By contrast, the highest scores for 5- to 50-µm-wide deposits observed in sCJD-MV2 subtype were not associated with higher neuronal loss. In addition, these scores were inversely correlated with neuronal counts in the sCJD-VV2 subtype. These results support a putative pathogenic role for small PrP(Sc) deposits common to the various sCJD subtypes. Furthermore, the observation of a lower loss of neurones associated with PrP(Sc) type-2 large deposits is consistent with a possible 'protective' role of aggregated deposits in both sCJD-MV2 and sCJD-VV2 subtypes. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.

  17. Homer1 knockdown protects dopamine neurons through regulating calcium homeostasis in an in vitro model of Parkinson's disease.

    Science.gov (United States)

    Chen, Tao; Yang, Yue-fan; Luo, Peng; Liu, Wei; Dai, Shu-hui; Zheng, Xin-rui; Fei, Zhou; Jiang, Xiao-fan

    2013-12-01

    Homer1 protein is an important scaffold protein at postsynaptic density and has been demonstrated to play a central role in calcium signaling in the central nervous system. The aim of this study was to investigate the effects of Homer1 knockdown on MPP(+) induced neuronal injury in cultured dopamine (DA) neurons. We found that down-regulating Homer1 expression with specific small interfering RNA (siRNA) significantly suppressed LDH release, reduced Propidium iodide (PI) or Hoechst staining, increased the number of tyrosine hydroxylase (TH) positive cells and DA uptake, and attenuated apoptotic and necrotic cell death after MPP(+) injury. Homer1 knockdown decreased intracellular reactive oxygen species (ROS) generation through inhibition of intracellular calcium overload, but did not affect the endogenous antioxidant enzyme activities. Calcium imaging was used to examine the changes of intracellular Ca(2+) concentration ([Ca(2+)]cyt) and Ca(2+) in endoplasmic reticulum (ER) ([Ca(2+)]ER), and the results showed that Homer1 siRNA transfection attenuated ER Ca(2+) release up to 120min after MPP(+) injury. Furthermore, decrease of [Ca(2+)]cyt induced by Homer1 knockdown in MPP(+) treated neurons was further enhanced by NMDA receptor antagonists MK-801 and AP-5, but not canonical transient receptor potential (TRPC) channel antagonist SKF-96365. l-type calcium antagonist isradipine but not nimodipine further inhibited intracellular calcium overload after MPP(+) insult in Homer1 down-regulated neurons. These results suggest that Homer1 knockdown has protective effects against neuronal injury in in vitro PD model by reducing calcium overload mediated ROS generation, and this protection may be dependent at least in part on the regulatory effects on the function of calcium channels in both plasma membrane and ER. © 2013.

  18. Noisy Neurons

    Indian Academy of Sciences (India)

    IAS Admin

    Nerves are fibres that conduct electrical signals and hence pass on information from and to the brain. Nerves are made of nerve cells called neurons (Figure 1). Instructions in our body are sent via electrical signals that present themselves as variations in the potential across neuronal membranes. These potential differences ...

  19. Diverse Short-Term Dynamics of Inhibitory Synapses Converging on Striatal Projection Neurons: Differential Changes in a Rodent Model of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Janet Barroso-Flores

    2015-01-01

    Full Text Available Most neurons in the striatum are projection neurons (SPNs which make synapses with each other within distances of approximately 100 µm. About 5% of striatal neurons are GABAergic interneurons whose axons expand hundreds of microns. Short-term synaptic plasticity (STSP between fast-spiking (FS interneurons and SPNs and between SPNs has been described with electrophysiological and optogenetic techniques. It is difficult to obtain pair recordings from some classes of interneurons and due to limitations of actual techniques, no other types of STSP have been described on SPNs. Diverse STSPs may reflect differences in presynaptic release machineries. Therefore, we focused the present work on answering two questions: Are there different identifiable classes of STSP between GABAergic synapses on SPNs? And, if so, are synapses exhibiting different classes of STSP differentially affected by dopamine depletion? Whole-cell voltage-clamp recordings on SPNs revealed three classes of STSPs: depressing, facilitating, and biphasic (facilitating-depressing, in response to stimulation trains at 20 Hz, in a constant ionic environment. We then used the 6-hydroxydopamine (6-OHDA rodent model of Parkinson’s disease to show that synapses with different STSPs are differentially affected by dopamine depletion. We propose a general model of STSP that fits all the dynamics found in our recordings.

  20. DJ-1-dependent protective activity of DJ-1-binding compound no. 23 against neuronal cell death in MPTP-treated mouse model of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Kazuko Takahashi-Niki

    2015-03-01

    Full Text Available Parkinson's disease (PD is caused by dopaminergic cell death in the substantia nigra, leading to a reduced level of dopamine in the striatum. Oxidative stress is one of the causes of PD. Since symptomatic PD therapies are used, identification of compounds or proteins that inhibit oxidative stress-induced neuronal cell death is necessary. DJ-1 is a causative gene product of familial PD and plays a role in anti-oxidative stress reaction. We have identified various DJ-1-binding compounds, including compound-23, that restored neuronal cell death and locomotion defects observed in neurotoxin-induced PD models. In this study, wild-type and DJ-1-knockout mice were injected intraperitoneally with 1 mg/kg of compound-23 and then with 30 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP at 1 h after injection. Five days after administration, the effects of compound-23 on MPTP-induced locomotion deficits, on dopaminergic cell death and on brain dopamine levels were analyzed by rotor rod tests, by staining cells with an anti-TH antibody and by an HPLC, respectively. The results showed that compound-23 inhibited MPTP-induced reduction of retention time on the rotor rod bar, neuronal cell death in the substantia nigra and striatum and dopamine content in wild-type mice but not in DJ-1-knockout mice, indicating a DJ-1-dependent effect of compound-23.

  1. Caprylic triglyceride as a novel therapeutic approach to effectively improve the performance and attenuate the symptoms due to the motor neuron loss in ALS disease.

    Directory of Open Access Journals (Sweden)

    Wei Zhao

    Full Text Available Amyotrophic lateral sclerosis (ALS is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and finally death. ALS patients suffer from asthenia and their progressive weakness negatively impacts quality of life, limiting their daily activities. They have impaired energy balance linked to lower activity of mitochondrial electron transport chain enzymes in ALS spinal cord, suggesting that improving mitochondrial function may present a therapeutic approach for ALS. When fed a ketogenic diet, the G93A ALS mouse shows a significant increase in serum ketones as well as a significantly slower progression of weakness and lower mortality rate. In this study, we treated SOD1-G93A mice with caprylic triglyceride, a medium chain triglyceride that is metabolized into ketone bodies and can serve as an alternate energy substrate for neuronal metabolism. Treatment with caprylic triglyceride attenuated progression of weakness and protected spinal cord motor neuron loss in SOD1-G93A transgenic animals, significantly improving their performance even though there was no significant benefit regarding the survival of the ALS transgenic animals. We found that caprylic triglyceride significantly promoted the mitochondrial oxygen consumption rate in vivo. Our results demonstrated that caprylic triglyceride alleviates ALS-type motor impairment through restoration of energy metabolism in SOD1-G93A ALS mice, especially during the overt stage of the disease. These data indicate the feasibility of using caprylic acid as an easily administered treatment with a high impact on the quality of life of ALS patients.

  2. Quality of life issues in motor neurone disease: the development and validation of a coping strategies questionnaire, the MND Coping Scale.

    Science.gov (United States)

    Lee, J N; Rigby, S A; Burchardt, F; Thornton, E W; Dougan, C; Young, C A

    2001-10-15

    A person's ability to cope with having motor neurone disease may be an important factor in determining their quality of life. We have developed a scale to measure coping strategies in people with MND. A disease-specific and patient-focused approach was employed. Open-ended interviews were used to generate initial items. Coping with the condition was an important consideration for all subjects. The final scale was administered to a sample of 44 people with MND. A factor analysis of the results demonstrated subscales comprised of distinct styles of coping. Reliability and validity were demonstrated within individual subscales. Significant correlations were shown between coping styles and psychological well being, disease duration and disability. Although still at a preliminary stage of development, the MND Coping Scale is proposed as a useful tool for further longitudinal study of coping in MND, with the potential to discover cause effect relationships between coping and psychological outcome.

  3. VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington's disease.

    Science.gov (United States)

    Díaz-Alonso, Javier; Paraíso-Luna, Juan; Navarrete, Carmen; Del Río, Carmen; Cantarero, Irene; Palomares, Belén; Aguareles, José; Fernández-Ruiz, Javier; Bellido, María Luz; Pollastro, Federica; Appendino, Giovanni; Calzado, Marco A; Galve-Roperh, Ismael; Muñoz, Eduardo

    2016-07-19

    Cannabinoids have shown to exert neuroprotective actions in animal models by acting at different targets including canonical cannabinoid receptors and PPARγ. We previously showed that VCE-003, a cannabigerol (CBG) quinone derivative, is a novel neuroprotective and anti-inflammatory cannabinoid acting through PPARγ. We have now generated a non-thiophilic VCE-003 derivative named VCE-003.2 that preserves the ability to activate PPARγ and analyzed its neuroprotective activity. This compound exerted a prosurvival action in progenitor cells during neuronal differentiation, which was prevented by a PPARγ antagonist, without affecting neural progenitor cell proliferation. In addition, VCE-003.2 attenuated quinolinic acid (QA)-induced cell death and caspase-3 activation and also reduced mutant huntingtin aggregates in striatal cells. The neuroprotective profile of VCE-003.2 was analyzed using in vivo models of striatal neurodegeneration induced by QA and 3-nitropropionic acid (3NP) administration. VCE-003.2 prevented medium spiny DARPP32(+) neuronal loss in these Huntington's-like disease mice models improving motor deficits, reactive astrogliosis and microglial activation. In the 3NP model VCE-003.2 inhibited the upregulation of proinflammatory markers and improved antioxidant defenses in the brain. These data lead us to consider VCE-003.2 to have high potential for the treatment of Huntington's disease (HD) and other neurodegenerative diseases with neuroinflammatory traits.

  4. “Anything that makes life’s journey better.” Exploring the use of digital technology by people living with motor neurone disease

    OpenAIRE

    Hobson, E.V.; Fazal, S.; Shaw, P.J.; McDermott, C.J.

    2017-01-01

    Our aim was to explore the attitudes of those living with motor neuron disease towards digital technology. Postal and online questionnaires surveyed 83 people with MND (pwMND) and 54 friends and family members (fMND). Five pwMND and five fMND underwent semi-structured interviews. 82% of pwMND and 87% of fMND use technology every day with iPads and laptops being the devices most commonly used. pwMND used technology to help them continue to participate in everyday activities such as socialising...

  5. Motor neuronal repletion of the NMJ organizer, Agrin, modulates the severity of the spinal muscular atrophy disease phenotype in model mice.

    Science.gov (United States)

    Kim, Jeong-Ki; Caine, Charlotte; Awano, Tomoyuki; Herbst, Ruth; Monani, Umrao R

    2017-07-01

    Spinal muscular atrophy (SMA) is a common and often fatal neuromuscular disorder caused by low levels of the Survival Motor Neuron (SMN) protein. Amongst the earliest detectable consequences of SMN deficiency are profound defects of the neuromuscular junctions (NMJs). In model mice these synapses appear disorganized, fail to mature and are characterized by poorly arborized nerve terminals. Given one role of the SMN protein in orchestrating the assembly of spliceosomal snRNP particles and subsequently regulating the alternative splicing of pre-mRNAs, a plausible link between SMN function and the distal neuromuscular SMA phenotype is an incorrectly spliced transcript or transcripts involved in establishing or maintaining NMJ structure. In this study, we explore the effects of one such transcript-Z+Agrin-known to be a critical organizer of the NMJ. We confirm that low SMN protein reduces motor neuronal levels of Z+Agrin. Repletion of this isoform of Agrin in the motor neurons of SMA model mice increases muscle fiber size, enhances the post-synaptic NMJ area, reduces the abnormal accumulation of intermediate filaments in nerve terminals of the neuromuscular synapse and improves the innervation of muscles. While these effects are independent of changes in SMN levels or increases in motor neuron numbers they nevertheless have a significant effect on the overall disease phenotype, enhancing mean survival in severely affected SMA model mice by ∼40%. We conclude that Agrin is an important target of the SMN protein and that mitigating NMJ defects may be one strategy in treating human spinal muscular atrophy. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  6. Calcium-Sensing Receptors of Human Astrocyte-Neuron Teams: Amyloid-β-Driven Mediators and Therapeutic Targets of Alzheimer’s Disease

    Science.gov (United States)

    Dal Prà, I; Chiarini, A; Pacchiana, R; Gardenal, E; Chakravarthy, B; Whitfield, J. F; Armato, U

    2014-01-01

    It is generally assumed that the neuropathology of sporadic (late-onset or nonfamilial) Alzheimer’s disease (AD) is driven by the overproduction and spreading of first Amyloid-βx-42 (Aβ42) and later hyperphosphorylated (hp)-Tau oligomeric “infectious seeds”. Hitherto, only neurons were held to make and spread both oligomer types; astrocytes would just remove debris. However, we have recently shown that exogenous fibrillar or soluble Aβ peptides specifically bind and activate the Ca2+-sensing receptors (CaSRs) of untransformed human cortical adult astrocytes and postnatal neurons cultured in vitro driving them to produce, accrue, and secrete surplus endogenous Aβ42. While the Aβ-exposed neurons start dying, astrocytes survive and keep oversecreting Aβ42, nitric oxide (NO), and vascular endothelial growth factor (VEGF)-A. Thus astrocytes help neurons’ demise. Moreover, we have found that a highly selective allosteric CaSR agonist (“calcimimetic”), NPS R-568, mimics the just mentioned neurotoxic actions triggered by Aβ●CaSR signaling. Contrariwise, and most important, NPS 2143, a highly selective allosteric CaSR antagonist (“calcilytic”), fully suppresses all the Aβ●CaSR signaling-driven noxious actions. Altogether our findings suggest that the progression of AD neuropathology is promoted by unceasingly repeating cycles of accruing exogenous Aβ42 oligomers interacting with the CaSRs of swelling numbers of astrocyte-neuron teams thereby recruiting them to overrelease additional Aβ42 oligomers, VEGF-A, and NO. Calcilytics would beneficially break such Aβ/CaSR-driven vicious cycles and hence halt or at least slow the otherwise unstoppable spreading of AD neuropathology PMID:25342943

  7. Pedigree with frontotemporal lobar degeneration – motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9

    Directory of Open Access Journals (Sweden)

    Loy Clement T

    2008-08-01

    Full Text Available Abstract Background Frontotemporal lobar degeneration (FTLD represents a clinically, pathologically and genetically heterogenous neurodegenerative disorder, often complicated by neurological signs such as motor neuron-related limb weakness, spasticity and paralysis, parkinsonism and gait disturbances. Linkage to chromosome 9p had been reported for pedigrees with the neurodegenerative disorder, frontotemporal lobar degeneration (FTLD and motor neuron disease (MND. The objective in this study is to identify the genetic locus in a multi-generational Australian family with FTLD-MND. Methods Clinical review and standard neuropathological analysis of brain sections from affected pedigree members. Genome-wide scan using microsatellite markers and single nucleotide polymorphism fine mapping. Examination of candidate genes by direct DNA sequencing. Results Neuropathological examination revealed cytoplasmic deposition of the TDP-43 protein in three affected individuals. Moreover, we identify a family member with clinical Alzheimer's disease, and FTLD-Ubiquitin neuropathology. Genetic linkage and haplotype analyses, defined a critical region between markers D9S169 and D9S1845 on chromosome 9p21. Screening of all candidate genes within this region did not reveal any novel genetic alterations that co-segregate with disease haplotype, suggesting that one individual carrying a meiotic recombination may represent a phenocopy. Re-analysis of linkage data using the new affection status revealed a maximal two-point LOD score of 3.24 and a multipoint LOD score of 3.41 at marker D9S1817. This provides the highest reported LOD scores from a single FTLD-MND pedigree. Conclusion Our reported increase in the minimal disease region should inform other researchers that the chromosome 9 locus may be more telomeric than predicted by published recombination boundaries. Moreover, the existence of a family member with clinical Alzheimer's disease, and who shares the disease

  8. Intratelencephalic corticostriatal neurons equally excite striatonigral and striatopallidal neurons and their discharge activity is selectively reduced in experimental parkinsonism

    OpenAIRE

    Ballion, B. (B.); Mallet, N. (Nicolas); Bezard, E. (E.); Lanciego, J.L. (José Luis); Gonon, F. (Francois)

    2008-01-01

    Striatonigral and striatopallidal neurons form distinct populations of striatal projection neurons. Their discharge activity is imbalanced after dopaminergic degeneration in Parkinson's disease. Striatal projection neurons receive massive cortical excitatory inputs from bilateral intratelencephalic (IT) neurons projecting to both the ipsilateral and contralateral striatum and from collateral axons of ipsilateral neurons that send their main axon through the pyramidal tract (PT). Previous anat...

  9. A case of Scabies with Lesions Resembling Perforating Folliculitis and Uremic Pruritus

    Directory of Open Access Journals (Sweden)

    Hülya Akgün

    2010-10-01

    Full Text Available Scabies is an infestation caused by Sarcoptes scabiei and characterised by polymorphous lesions that may include burrows, papules, pustules, crusts and excoriations. Several pruritic diseases may be confused with scabies. Herein, we present a case of scabies with lesions resembling perforating folliculitis diagnosed on the basis of both clinical and histopathological view. A 72-year-old man with type 2 diabetes mellitus and receiving hemodialysis for ten years due to end-stage renal disease was admitted to our dermatology department with a 6-month history of severe pruritus. Based on the results of skin biopsy revealing Sarcoptes scabiei in the epidermis, the patient was diagnosed as scabies and was successfully treated with 5% permethrin. This case is presented to emphasize that scabies should be considered in the differential diagnosis in cases of chronic pruritus.

  10. Autosomal dominant syndrome resembling Coffin-Siris syndrome.

    Science.gov (United States)

    Flynn, Maureen A; Milunsky, Jeff M

    2006-06-15

    Coffin-Siris syndrome is a multiple congenital anomaly/mental retardation syndrome with phenotypic variability [OMIM 135900]. The diagnosis is based solely on clinical findings, as there is currently no molecular, biochemical, or cytogenetic analysis available to confirm a diagnosis. Although typically described as an autosomal recessive disorder, autosomal dominant inheritance has also been infrequently reported. We describe a mother and her two daughters who all have features that resemble Coffin-Siris syndrome. However, this is not a completely convincing diagnosis given that hypertelorism is not a feature of Coffin-Siris syndrome and the family is relatively mildly affected. Yet, this family provides further evidence of an autosomal dominant mode of inheritance for a likely variant of Coffin-Siris syndrome (at least in some families). In addition, Sibling 1 had premature thelarche. She is the second reported individual within the spectrum of Coffin-Siris syndrome to have premature thelarche, indicating that it may be a rare clinical feature. Copyright 2006 Wiley-Liss, Inc.

  11. Atypical mycobacterial infection resembles sporotrichosis in elderly patient

    Directory of Open Access Journals (Sweden)

    Siti Nurani Fauziah

    2016-06-01

    Full Text Available Atypical mycobacterial (AM infection is caused by Mycobacterium species other than M.tuberculosis. AM skin infection has clinical manifestations that resemble M. tuberculosis infection and deep fungal infection. Laboratory workup is necessary to confirm the diagnosis. An 83-year old female came with a painful lump and swelling on her right lower extremity since three months before admission. Physical examination revealed a plaque consisting, of multiple erythematous and hyperpigmented papules and nodules, diffuse erythematous lesion, and shallow ulcers partially covered with pus and crust. Histopathological features showed tuberculoid granuloma. Direct test and periodic acid-Schiff (PAS staining of the skin biopsy found no fungal element nor acid-fast bacilli (AFB. Culture and polymerase chain reaction (PCR of M. tuberculosis were negative. The working diagnosis was atypical mycobacterial infection and treatment with 450 mg rifampicin and 100 mg minocycline daily were administered accordingly. In two months observation following the treatment, the pain was no longer exist, the ulcers were completely healed, and some nodules were in the process of healing Among other Mycobacterium spp, M.marinum is the most common cause of AM infrections. Clinical manifestation of M. marinum infection may present as solitary or multiple nodules on the hands, feet, elbows and knees with sporotrichoid spreading patern. The diagnosis of AM was established based on clinical and laboratory examination. The diagnosis was also confirmed by good clinical response to minocycline and rifampicin.

  12. Mouse and Human Models for Investigating Influences of Tau on Progression of Alzheimer’s Disease Following Traumatic Neuronal Injury

    Science.gov (United States)

    2017-10-01

    Distribution Unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT We have completed the design, fabrication , and validation of a new biomedical device to impose... production , and tau phosphorylation (i.e., multiple Alzheimer’s-associated outcomes) following rapid stretch of iPSC-derived neurons. Results suggest that...transport was perturbed, amyloid production was increased, and tau phosphorylation unchanged following a single bout of mechanical loading. Multiple

  13. Immunoglobulins from Animal Models of Motor Neuron Disease and from Human Amyotrophic Lateral Sclerosis Patients Passively Transfer Physiological Abnormalities to the Neuromuscular Junction

    Science.gov (United States)

    Apel, Stanley H.; Engelhardt, Jozsef I.; Garcia, Jesus; Stefani, Enrico

    1991-01-01

    Amyotrophic lateral sclerosis (ALS) is a devastating human disease of upper and lower motoneurons of unknown etiology. In support of the potential role of autoimmunity in ALS, two immune-mediated animal models of motoneuron disease have been developed that resemble ALS with respect to the loss of motoneurons, the presence of IgG within motoneurons and at the neuromuscular junction, and with respect to altered physiology of the motor nerve terminal. To provide direct evidence for the primary role of humoral immunity, passive transfer with immunoglobulins from the two animal models and human ALS was carried out. Mice injected with serum or immunoglobulins from the animal disease models and human ALS but not controls demonstrated IgG in motoneurons and at the neuromuscular junction. The mice also demonstrated an increase in miniature end-plate potential (mepp) frequency, with normal amplitude and time course and normal resting membrane potential, indicating an increased resting quantal release of acetylcholine from the nerve terminal. The ability to transfer motoneuron dysfunction with serum immunoglobulins provides evidence for autoimmune mechanisms in the pathogenesis of both the animal models and human ALS.

  14. Transcriptional regulation of N-acetylaspartate metabolism in the 5xFAD model of Alzheimer's disease: evidence for neuron-glia communication during energetic crisis.

    Science.gov (United States)

    Zaroff, Samantha; Leone, Paola; Markov, Vladimir; Francis, Jeremy S

    2015-03-01

    N-acetylaspartate (NAA) provides a non-invasive clinical index of neuronal metabolic integrity across the entire neurodegenerative spectrum. While NAA function is not comprehensively defined, reductions in the brain are associated with compromised mitochondrial metabolism and are tightly linked to ATP. We have undertaken an analysis of abnormalities in NAA during early stage pathology in the 5xFAD mouse model of familial Alzheimer's disease and show here that dysregulated expression of the gene encoding for the rate-limiting NAA synthetic enzyme (Nat8L) is associated with deficits in mitochondrial oxidative phosphorylation in this model system. Downreguation of Nat8L is particularly pronounced in the 5xFAD hippocampus, and is preceded by a significant upregulation of oligodendrocytic aspartoacylase (aspa), which encodes for the sole known NAA-catabolizing enzyme in the brain. Reductions in 5xFAD NAA and Nat8L cannot be accounted for by discrepancies in either neuron content or activity of the substrate-providing malate-aspartate shuttle, thereby implicating transcriptional regulation in a coordinated response to pathological energetic crisis. A central role for ASPA in this response is supported by a parallel developmental analysis showing highly significant increases in Nat8L expression in an ASPA-null mouse model during a period of early postnatal development normally punctuated by the transcriptional upregulation of aspa. These results provide preliminary evidence of a signaling mechanism in Alzheimer's disease that involves cross talk between neurons and oligodendrocytes, and suggest that ASPA acts to negatively regulate Nat8L expression. This mechanism is proposed to be a fundamental means by which the brain conserves available substrate during energy crises. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Parvalbumin+ Neurons and Npas1+ Neurons Are Distinct Neuron Classes in the Mouse External Globus Pallidus.

    Science.gov (United States)

    Hernández, Vivian M; Hegeman, Daniel J; Cui, Qiaoling; Kelver, Daniel A; Fiske, Michael P; Glajch, Kelly E; Pitt, Jason E; Huang, Tina Y; Justice, Nicholas J; Chan, C Savio

    2015-08-26

    Compelling evidence suggests that pathological activity of the external globus pallidus (GPe), a nucleus in the basal ganglia, contributes to the motor symptoms of a variety of movement disorders such as Parkinson's disease. Recent studies have challenged the idea that the GPe comprises a single, homogenous population of neurons that serves as a simple relay in the indirect pathway. However, we still lack a full understanding of the diversity of the neurons that make up the GPe. Specifically, a more precise classification scheme is needed to better describe the fundamental biology and function of different GPe neuron classes. To this end, we generated a novel multicistronic BAC (bacterial artificial chromosome) transgenic mouse line under the regulatory elements of the Npas1 gene. Using a combinatorial transgenic and immunohistochemical approach, we discovered that parvalbumin-expressing neurons and Npas1-expressing neurons in the GPe represent two nonoverlapping cell classes, amounting to 55% and 27% of the total GPe neuron population, respectively. These two genetically identified cell classes projected primarily to the subthalamic nucleus and to the striatum, respectively. Additionally, parvalbumin-expressing neurons and Npas1-expressing neurons were distinct in their autonomous and driven firing characteristics, their expression of intrinsic ion conductances, and their responsiveness to chronic 6-hydroxydopamine lesion. In summary, our data argue that parvalbumin-expressing neurons and Npas1-expressing neurons are two distinct functional classes of GPe neurons. This work revises our understanding of the GPe, and provides the foundation for future studies of its function and dysfunction. Until recently, the heterogeneity of the constituent neurons within the external globus pallidus (GPe) was not fully appreciated. We addressed this knowledge gap by discovering two principal GPe neuron classes, which were identified by their nonoverlapping expression of the

  16. Mutant copper-zinc superoxide dismutase (SOD1) induces protein secretion pathway alterations and exosome release in astrocytes: implications for disease spreading and motor neuron pathology in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Basso, Manuela; Pozzi, Silvia; Tortarolo, Massimo; Fiordaliso, Fabio; Bisighini, Cinzia; Pasetto, Laura; Spaltro, Gabriella; Lidonnici, Dario; Gensano, Francesco; Battaglia, Elisa; Bendotti, Caterina; Bonetto, Valentina

    2013-05-31

    Amyotrophic lateral sclerosis is the most common motor neuron disease and is still incurable. The mechanisms leading to the selective motor neuron vulnerability are still not known. The interplay between motor neurons and astrocytes is crucial in the outcome of the disease. We show that mutant copper-zinc superoxide dismutase (SOD1) overexpression in primary astrocyte cultures is associated with decreased levels of proteins involved in secretory pathways. This is linked to a general reduction of total secreted proteins, except for specific enrichment in a number of proteins in the media, such as mutant SOD1 and valosin-containing protein (VCP)/p97. Because there was also an increase in exosome release, we can deduce that astrocytes expressing mutant SOD1 activate unconventional secretory pathways, possibly as a protective mechanism. This may help limit the formation of intracellular aggregates and overcome mutant SOD1 toxicity. We also found that astrocyte-derived exosomes efficiently transfer mutant SOD1 to spinal neurons and induce selective motor neuron death. We conclude that the expression of mutant SOD1 has a substantial impact on astrocyte protein secretion pathways, contributing to motor neuron pathology and disease spread.

  17. Do general radiographic examinations resemble a person-centred environment?

    International Nuclear Information System (INIS)

    Hayre, C.M.; Blackman, S.; Eyden, A.

    2016-01-01

    Aim and objective: It is argued whether general radiographic examinations adhere to a person-centred approach within the direct digital radiography (DDR) environment. General radiographic examinations continue to increase and constitute approximately 90% of all examinations undertaken in the clinical environment. This study explored the potential impact patients experience whilst undergoing general imaging examinations. Method: An ethnographic methodology provided insight of two general radiography environments in the United Kingdom (UK) using participant observation and semi-structured interviews. Findings: The findings highlighted an ‘in and out’ culture whereby patients are ‘hurried’ and ‘rushed’ out of X-ray rooms in response to increasing time pressures experienced by diagnostic radiographers. In addition, this study challenged that patients may begin to rank ‘speed’ and ‘waiting times’ above other elements of radiographic care thus presenting new challenges for radiographers within the clinical environment. Conclusion: It is asserted that radiographers should remain holistic healthcare professionals and not begin to resemble operators on the production line. Further, it challenges whether patients are beginning to rank aspects of radiographic care within contemporary practices. Advances in knowledge: Few studies have explored the radiographer–patient relationship within the DDR environment, yet this study provides insight of person-centred practices within contemporary practices. - Highlights: • Challenges whether the use of DDR conforms to a person-centred approach. • Challenges whether radiographers are ‘treating patients as persons’ using DDR. • Patients may begin to rank ‘speed’ and ‘waiting times’ above other aspects of radiographic care.

  18. Predator-Resembling Aversive Conditioning for Managing Habituated Wildlife

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    Elsabé Louise Kloppers

    2005-06-01

    Full Text Available Wildlife habituation near urban centers can disrupt natural ecological processes, destroy habitat, and threaten public safety. Consequently, management of habituated animals is typically invasive and often includes translocation of these animals to remote areas and sometimes even their destruction. Techniques to prevent or reverse habituation and other forms of in situ management are necessary to balance ecological and social requirements, but they have received very little experimental attention to date. This study compared the efficacy of two aversive conditioning treatments that used either humans or dogs to create sequences resembling chases by predators, which, along with a control category, were repeatedly and individually applied to 24 moderately habituated, radio-collared elk in Banff National Park during the winter of 2001-2002. Three response variables were measured before and after treatment. Relative to untreated animals, the distance at which elk fled from approaching humans, i.e., the flight response distance, increased following both human and dog treatments, but there was no difference between the two treatments. The proportion of time spent in vigilance postures decreased for all treatment groups, without differences among groups, suggesting that this behavior responded mainly to seasonal effects. The average distance between elk locations and the town boundary, measured once daily by telemetry, significantly increased for human-conditioned elk. One of the co-variates we measured, wolf activity, exerted counteracting effects on conditioning effects; flight response distances and proximity to the town site were both lower when wolf activity was high. This research demonstrates that it is possible to temporarily modify aspects of the behavior of moderately habituated elk using aversive conditioning, suggests a method for reducing habituation in the first place, and provides a solution for Banff and other jurisdictions to manage

  19. Msh2 acts in medium-spiny striatal neurons as an enhancer of CAG instability and mutant huntingtin phenotypes in Huntington's disease knock-in mice.

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    Marina Kovalenko

    Full Text Available The CAG trinucleotide repeat mutation in the Huntington's disease gene (HTT exhibits age-dependent tissue-specific expansion that correlates with disease onset in patients, implicating somatic expansion as a disease modifier and potential therapeutic target. Somatic HTT CAG expansion is critically dependent on proteins in the mismatch repair (MMR pathway. To gain further insight into mechanisms of somatic expansion and the relationship of somatic expansion to the disease process in selectively vulnerable MSNs we have crossed HTT CAG knock-in mice (HdhQ111 with mice carrying a conditional (floxed Msh2 allele and D9-Cre transgenic mice, in which Cre recombinase is expressed specifically in MSNs within the striatum. Deletion of Msh2 in MSNs eliminated Msh2 protein in those neurons. We demonstrate that MSN-specific deletion of Msh2 was sufficient to eliminate the vast majority of striatal HTT CAG expansions in HdhQ111 mice. Furthermore, MSN-specific deletion of Msh2 modified two mutant huntingtin phenotypes: the early nuclear localization of diffusely immunostaining mutant huntingtin was slowed; and the later development of intranuclear huntingtin inclusions was dramatically inhibited. Therefore, Msh2 acts within MSNs as a genetic enhancer both of somatic HTT CAG expansions and of HTT CAG-dependent phenotypes in mice. These data suggest that the selective vulnerability of MSNs may be at least in part contributed by the propensity for somatic expansion in these neurons, and imply that intervening in the expansion process is likely to have therapeutic benefit.

  20. Successful in vitro expansion and Characterization of Human Enteric Neuronal cells- A step towards Cell based therapies for Hirschsprung’s disease

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    Balamurugan M

    2010-01-01

    Full Text Available BACKGROUND: The Enteric Nervous system (ENS is a part of the Peripheral nervous system (PNS that controls the peristaltic activity of the gut wall which is essential for propulsion of food in the digestive tract. It is composed of a large number of neurons and glial cells, distributed throughout the length of the gut. These ganglion cells develop from the neural crest in the embryo. Failure of complete colonization of the gut by these enteric neural crest cells during early development of life results in absence of ganglia or neurons in a portion of the gut, usually the colon which leads to aperistaltis and severe intestinal obstruction. This is known as Hirschsprung’s disease (HSCR also known as congenital megacolon. HSCR affects 1 in 4500 newborns (1, 2. It appears either sporadically or has a familial basis and is often associated with other developmental defects. The main forms of treatment of HSCR are surgical resection of the aganglionic segment and pull through of the normal bowel. At present research is aimed at developing Cell based therapies for replacement of ganglion cells or enteric neuronal cells in the aganglionic portion of the gut thus aiming at restoring the function of the gut (1, 3, 5. In this study we have isolated, in vitro expanded and characterized the Enteric Neuronal cells derived from human gut full thickness biopsy samplesMATERIALS AND METHODS: The postnatal gut full thickness biopsy samples of size 2-4 mm were obtained using from 13 patients undergoing gut resection surgery after informed consent. The samples were washed in Phosphate Buffer saline and using forceps, the outer smooth muscle layers along with the myenteric plexus were peeled off from the underlying tissue as strips. The strips were washed in Phosphate Buffer saline (PBS and treated with 1mg/ml Collagenase/Dispase mixture in PBS for 30-45 min at 37°C. The digested cells were filtered with 70µm filter and the cell suspensions were centrifuged at 1800

  1. Neuronal Store-Operated Calcium Entry and Mushroom Spine Loss in Amyloid Precursor Protein Knock-In Mouse Model of Alzheimer's Disease.

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    Zhang, Hua; Wu, Lili; Pchitskaya, Ekaterina; Zakharova, Olga; Saito, Takashi; Saido, Takaomi; Bezprozvanny, Ilya

    2015-09-30

    Alzheimer's disease (AD) is the most common reason for elderly dementia in the world. We proposed that memory loss in AD is related to destabilization of mushroom postsynaptic spines involved in long-term memory storage. We demonstrated previously that stromal interaction molecule 2 (STIM2)-regulated neuronal store-operated calcium entry (nSOC) in postsynaptic spines play a key role in stability of mushroom spines by maintaining activity of synaptic Ca(2+)/calmodulin kinase II (CaMKII). Furthermore, we demonstrated previously that the STIM2-nSOC-CaMKII pathway is downregulated in presenilin 1 M146V knock-in (PS1-M146V KI) mouse model of AD, leading to loss of hippocampal mushroom spines in this model. In the present study, we demonstrate that hippocampal mushroom postsynaptic spines are also lost in amyloid precursor protein knock-in (APPKI) mouse model of AD. We demonstrated that loss of mushroom spines occurs as a result of accumulation of extracellular β-amyloid 42 in APPKI culture media. Our results indicate that extracellular Aβ42 acts by overactivating mGluR5 receptor in APPKI neurons, leading to elevated Ca(2+) levels in endoplasmic reticulum, compensatory downregulation of STIM2 expression, impaired synaptic nSOC, and reduced CaMKII activity. Pharmacological inhibition of mGluR5 or overexpression of STIM2 rescued synaptic nSOC and prevented mushroom spine loss in APPKI hippocampal neurons. Our results indicate that downregulation of synaptic STIM2-nSOC-CaMKII pathway causes loss of mushroom synaptic spines in both presenilin and APPKI mouse models of AD. We propose that modulators/activators of this pathway may have a potential therapeutic value for treatment of memory loss in AD. Significance statement: A direct connection between amyloid-induced synaptic mushroom spine loss and neuronal store-operated calcium entry pathway is shown. These results provide strong support for the calcium hypothesis of neurodegeneration and further validate the synaptic

  2. Molecular Programming of Mesodiencephalic Dopaminergic Neuronal Subsets

    NARCIS (Netherlands)

    Smidt, M.P.

    Dopamine neurons of the substantia nigra compacta (SNc) and ventral tegmental area (VTA) are critical components of the neuronal machinery to control emotion and movement in mammals. The slow and gradual death of these neurons as seen in Parkinson's disease has triggered a large investment in

  3. The spectrum of lower motor neuron syndromes

    NARCIS (Netherlands)

    van den Berg-Vos, R. M.; van den Berg, L. H.; Visser, J.; de Visser, M.; Franssen, H.; Wokke, J. H. J.

    2003-01-01

    This review discusses the most important lower motor neuron syndromes. This relatively rare group of syndromes has not been well described clinically. Two subgroups can be distinguished: patients in whom motor neurons (lower motor neuron disease (LMND)) are primarily affected or motor axons and

  4. Frequency and risk factor analysis of cognitive and anxiety-depressive disorders in patients with amyotrophic lateral sclerosis/motor neuron disease.

    Science.gov (United States)

    Cui, Fang; Zhu, Wenjia; Zhou, Zhibin; Ren, Yuting; Li, Yifan; Li, Mao; Huo, Yunyun; Huang, Xusheng

    2015-01-01

    To examine the frequency and risk factors of cognitive and anxiety-depressive disorders in patients with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). This was an observational study of 100 ALS/MND patients treated at our hospital outpatient and inpatient departments between January 2009 and April 2010 and 100 matched healthy controls. Subjects were surveyed using Mini Mental State Examination (MMSE), Zung Self-Rating Anxiety Scale (SAS), and Zung Self-Rating Depression Scale (SDS). Patient neurological status was graded by the ALS Functional Rating Scale (ALSFRS). Multivariate linear regression was used to identify factors associated with the MMSE, SAS, SDS, and ALSFRS scores. Patients had significantly lower MMSE scores than controls (P0.05). Patients with higher educational level (college and above), shorter disease course (disease course, and lower ALSFRS score were independent predictors of better cognitive function (higher MMSE score). Patients had significantly higher mean SAS and SDS total scores than controls (both Pdisease duration, and disease awareness did not influence SAS or SDS scores. Multivariate analysis indicated that lower education and lower ALSFRS were protective factors against anxiety and depression. The frequency of anxiety-depressive disorders was high among patients with ALS/MND. High educational level, short course of disease, and lower ALSFRS were associated with preserved cognitive function. Female sex, higher education, and lower ALSFRS score conferred a greater risk of anxiety and depression. Tailored pharmacotherapy and psychological interventions may help in reducing anxiety and depression in these patients.

  5. Neuroprotective Effect and Mechanism of Thiazolidinedione on Dopaminergic Neurons In Vivo and In Vitro in Parkinson’s Disease

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    Yanqin Wang

    2017-01-01

    Full Text Available The aim of the present study was to gain insight into the neuroprotection effects and mechanism of thiazolidinedione pioglitazone in both in vitro and in vivo MPP+/MPTP induced PD models. In vivo experimental results showed that oral treatment of pioglitazone resulted in significant improvements in behavior symptoms damaged by MPTP and increase in the survival of TH positive neurons in the pioglitazone intervention groups. In addition, oral treatment of pioglitazone increased the expression of peroxisome proliferator-activated receptor-γ coactivator of 1α (PGC-1α and increased the number of mitochondria, along with an observed improvement in mitochondrial ultrastructure. From in vitro studies, 2,4-thiazolidinedione resulted in increased levels of molecules regulated function of mitochondria, including PGC-1α, nuclear respiratory factor 1 (NRF1, NRF2, and mitochondria fusion 2 (Mfn2, and inhibited mitochondria fission 1 (Fis1. We show that protein levels of Bcl-2 and ERK were reduced in the MPP+-treated group compared with the control group. This effect was observed to be reversed upon treatment with 2,4-thiazolidinedione, as Bcl-2 and ERK expression levels were increased. We also observed that levels of the apoptotic protein Bax showed opposite changes compared to Bcl-2 and ERK levels. The results from this study confirm that pioglitazone/2,4-thiazolidinedione is able to activate PGC-1α and prevent damage of dopaminergic neurons and restore mitochondria ultrastructure through the regulation of mitochondria function.

  6. Ca2+ Handling in Isolated Brain Mitochondria and Cultured Neurons Derived from the YAC128 Mouse Model of Huntington’s Disease

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    Pellman, Jessica J.; Hamilton, James; Brustovetsky, Tatiana; Brustovetsky, Nickolay

    2015-01-01

    We investigated Ca2+ handling in isolated brain synaptic and nonsynaptic mitochondria and in cultured striatal neurons from the YAC128 mouse model of Huntington’s disease (HD). Both synaptic and nonsynaptic mitochondria from 2- and 12-month-old YAC128 mice had larger Ca2+ uptake capacity than mitochondria from YAC18 and wild-type FVB/NJ mice. Synaptic mitochondria from 12-month-old YAC128 mice had further augmented Ca2+ capacity compared with mitochondria from 2-month-old YAC128 mice and age-matched YAC18 and FVB/NJ mice. This increase in Ca2+ uptake capacity correlated with an increase in the amount of mutant huntingtin protein (mHtt) associated with mitochondria from 12-month-old YAC128 mice. We speculate that this may happen due to mHtt-mediated sequestration of free fatty acids thereby increasing resistance of mitochondria to Ca2+-induced damage. In experiments with striatal neurons from YAC128 and FVB/NJ mice, brief exposure to 25 or 100μM glutamate produced transient elevations in cytosolic Ca2+ followed by recovery to near resting levels. Following recovery of cytosolic Ca2+, mitochondrial depolarization with FCCP produced comparable elevations in cytosolic Ca2+, suggesting similar Ca2+ release and, consequently, Ca2+ loads in neuronal mitochondria from YAC128 and FVB/NJ mice. Together, our data argue against a detrimental effect of mHtt on Ca2+ handling in brain mitochondria of YAC128 mice. PMID:25963273

  7. Early post-treatment with 9-cis retinoic acid reduces neurodegeneration of dopaminergic neurons in a rat model of Parkinson’s disease

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    Yin Lian-Hu

    2012-10-01

    Full Text Available Abstract Background Retinoic acid (RA is a biologically active derivative of vitamin A. Previous studies have demonstrated that RA has protective effects against damage caused by H2O2 or oxygen-glucose deprivation in mesangial and PC12 cells. Pretreatment with 9-cis-retinoic acid (9cRA reduced infarction and TUNEL labeling in cerebral cortex as well as attenuated neurological deficits after distal middle cerebral artery occlusion in rats. The purpose of this study was to examine a protective role of 9cRA in dopaminergic (DA neurons in a typical rodent model of Parkinson’s disease (PD. Results The protective role of 9cRA was first examined in rat primary ventromesencephalic culture. Treatment with 9cRA significantly reduced 6-hydroxydopamine (6-OHDA-mediated cell death and TUNEL labeling in cultured dopaminergic neurons. The protective effect was also examined in adult male rats. Animals received unilateral 6-OHDA lesioning at the left medial forebrain bundle on day 0. Methamphetamine -induced rotational behavior was examined on days 6, 20 and 30 after lesioning. Animals were separated into 2 groups to balance rotational behavior and lesion extent on day 6 and were treated with either 9cRA or vehicle (i.c.v. on day 7 + intra-nasal from day 8 to day 14. Post-treatment with 9cRA significantly reduced methamphetamine –mediated ipislateral rotation at 20 and 30 days after lesioning. In vivo voltammetry was used to examine DA overflow in striatum. Treatment with 9cRA significantly increased KCl -evoked DA release in the lesioned striatum. 9cRA also increased tyrosine hydroxylase (+ cell number in the lesioned nigra as determined by unbiased stereology. Conclusion Our data suggests that early post-treatment with 9cRA has a protective effect against neurodegeneration in nigrostriatal DA neurons in an animal model of PD.

  8. Human neural stem cells improve cognition and promote synaptic growth in two complementary transgenic models of Alzheimer's disease and neuronal loss.

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    Ager, Rahasson R; Davis, Joy L; Agazaryan, Andy; Benavente, Francisca; Poon, Wayne W; LaFerla, Frank M; Blurton-Jones, Mathew

    2015-07-01

    Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder, affecting over 35 million people worldwide. Pathologically, AD is characterized by the progressive accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles within the brain. Together, these pathologies lead to marked neuronal and synaptic loss and corresponding impairments in cognition. Current treatments, and recent clinical trials, have failed to modify the clinical course of AD; thus, the development of novel and innovative therapies is urgently needed. Over the last decade, the potential use of stem cells to treat cognitive impairment has received growing attention. Specifically, neural stem cell transplantation as a treatment for AD offers a novel approach with tremendous therapeutic potential. We previously reported that intrahippocampal transplantation of murine neural stem cells (mNSCs) can enhance synaptogenesis and improve cognition in 3xTg-AD mice and the CaM/Tet-DT(A) model of hippocampal neuronal loss. These promising findings prompted us to examine a human neural stem cell population, HuCNS-SC, which has already been clinically tested for other neurodegenerative disorders. In this study, we provide the first evidence that transplantation of research grade HuCNS-SCs can improve cognition in two complementary models of neurodegeneration. We also demonstrate that HuCNS-SC cells can migrate and differentiate into immature neurons and glia and significantly increase synaptic and growth-associated markers in both 3xTg-AD and CaM/Tet-DTA mice. Interestingly, improvements in aged 3xTg-AD mice were not associated with altered Aβ or tau pathology. Rather, our findings suggest that human NSC transplantation improves cognition by enhancing endogenous synaptogenesis. Taken together, our data provide the first preclinical evidence that human NSC transplantation could be a safe and effective therapeutic approach for treating AD. © 2014 The Authors. Hippocampus

  9. Frequency and risk factor analysis of cognitive and anxiety-depressive disorders in patients with amyotrophic lateral sclerosis/motor neuron disease

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    Cui F

    2015-11-01

    Full Text Available Fang Cui, Wenjia Zhu, Zhibin Zhou, Yuting Ren, Yifan Li, Mao Li, Yunyun Huo, Xusheng Huang Department of Neurology, Chinese PLA General Hospital, Beijing, People’s Republic of China Objectives: To examine the frequency and risk factors of cognitive and anxiety-depressive disorders in patients with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND. Methods: This was an observational study of 100 ALS/MND patients treated at our hospital outpatient and inpatient departments between January 2009 and April 2010 and 100 matched healthy controls. Subjects were surveyed using Mini Mental State Examination (MMSE, Zung Self-Rating Anxiety Scale (SAS, and Zung Self-Rating Depression Scale (SDS. Patient neurological status was graded by the ALS Functional Rating Scale (ALSFRS. Multivariate linear regression was used to identify factors associated with the MMSE, SAS, SDS, and ALSFRS scores. Results: Patients had significantly lower MMSE scores than controls (P<0.05. MMSE score did not differ by sex or age (<50/≥50 years (P>0.05. Patients with higher educational level (college and above, shorter disease course (<2 years, and lower ALSFRS score (<20 had significantly higher MMSE scores (all P<0.05. Multivariate analysis revealed that higher education, shorter disease course, and lower ALSFRS score were independent predictors of better cognitive function (higher MMSE score. Patients had significantly higher mean SAS and SDS total scores than controls (both P<0.05, indicating higher subjective anxiety and depression. Female patients, patients with higher education, and those with higher ALSFRS scores had significantly higher SAS and SDS scores (all P<0.05. Age, occupation, diagnostic classification, disease duration, and disease awareness did not influence SAS or SDS scores. Multivariate analysis indicated that lower education and lower ALSFRS were protective factors against anxiety and depression. Conclusion: The frequency of anxiety

  10. Improved cell therapy protocols for Parkinson's disease based on differentiation efficiency and safety of hESC-, hiPSC-, and non-human primate iPSC-derived dopaminergic neurons

    DEFF Research Database (Denmark)

    Sundberg, Maria; Bogetofte, Helle; Lawson, Tristan

    2013-01-01

    of safety and efficacy of stem cell-derived DA neurons. The aim of this study was to improve the safety of human- and non-human primate iPSC (PiPSC)-derived DA neurons. According to our results, NCAM(+) /CD29(low) sorting enriched VM DA neurons from pluripotent stem cell-derived neural cell populations....... NCAM(+) /CD29(low) DA neurons were positive for FOXA2/TH and EN1/TH and this cell population had increased expression levels of FOXA2, LMX1A, TH, GIRK2, PITX3, EN1, NURR1 mRNA compared to unsorted neural cell populations. PiPSC-derived NCAM(+) /CD29(low) DA neurons were able to restore motor function......The main motor symptoms of Parkinson's disease are due to the loss of dopaminergic (DA) neurons in the ventral midbrain (VM). For the future treatment of Parkinson's disease with cell transplantation it is important to develop efficient differentiation methods for production of human iPSCs and h...

  11. The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson's disease.

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    Luis F Razgado-Hernandez

    Full Text Available The progressive degeneration of the dopamine neurons of the pars compacta of substantia nigra and the consequent loss of the dopamine innervation of the striatum leads to the impairment of motor behavior in Parkinson's disease. Accordingly, an efficient therapy of the disease should protect and regenerate the dopamine neurons of the substantia nigra and the dopamine innervation of the striatum. Nigral neurons express Brain Derived Neurotropic Factor (BDNF and dopamine D3 receptors, both of which protect the dopamine neurons. The chronic activation of dopamine D3 receptors by their agonists, in addition, restores, in part, the dopamine innervation of the striatum. Here we explored whether the over-expression of BDNF by dopamine neurons potentiates the effect of the activation of D3 receptors restoring nigrostriatal innervation. Twelve-month old Wistar rats were unilaterally injected with 6-hydroxydopamine into the striatum. Five months later, rats were treated with the D3 agonist 7-hydroxy-N,N-di-n-propy1-2-aminotetralin (7-OH-DPAT administered i.p. during 4½ months via osmotic pumps and the BDNF gene transfection into nigral cells using the neurotensin-polyplex nanovector (a non-viral transfection that selectively transfect the dopamine neurons via the high-affinity neurotensin receptor expressed by these neurons. Two months after the withdrawal of 7-OH-DPAT when rats were aged (24 months old, immunohistochemistry assays were made. The over-expression of BDNF in rats receiving the D3 agonist normalized gait and motor coordination; in addition, it eliminated the muscle rigidity produced by the loss of dopamine. The recovery of motor behavior was associated with the recovery of the nigral neurons, the dopamine innervation of the striatum and of the number of dendritic spines of the striatal neurons. Thus, the over-expression of BDNF in dopamine neurons associated with the chronic activation of the D3 receptors appears to be a promising strategy

  12. Interleukin-18 alters protein expressions of neurodegenerative diseases-linked proteins in human SH-SY5Y neuron-like cells

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    Elina M Sutinen

    2014-08-01

    Full Text Available Chronic inflammation and oxidative stress (OS are present in Alzheimer´s disease (AD brains in addition to neuronal loss, Amyloid-β (Aβ plaques and hyperphosphorylated tau-protein neurofibrillary tangles. Previously we showed that levels of the pro-inflammatory cytokine, interleukin-18 (IL-18, are elevated in post-mortem AD brains. IL-18 can modulate the tau kinases, Cdk5 and GSK3β, as well as Aβ-production. IL-18 levels are also increased in AD risk diseases, including type-2 diabetes and obesity. Here, we explored other IL-18 regulated proteins in neuron-like SH-SY5Y cells. Differentiated SH-SY5Y cells, incubated with IL-18 for 24, 48 or 72h, were analyzed by two-dimensional gel electrophoresis (2D-DIGE. Specific altered protein spots were chosen and identified with mass spectrometry and verified by western immunoblotting. IL-18 had time-dependent effects on the SH-SY5Y proteome, modulating numerous protein levels/modifications. We concentrated on those related to OS (DDAH2, peroxiredoxins 2, 3 and 6, DJ-1, BLVRA, Aβ-degradation (MMP14, TIMP2, Aβ-aggregation (Septin-2 and modifications of axon growth and guidance associated, collapsing response mediator protein 2 (CRMP2. IL-18 significantly increased antioxidative enzymes, indicative of OS, and altered levels of glycolytic α- and γ-enolase and multifunctional 14-3-3γ and -ε, commonly affected in neurodegenerative diseases. MMP14, TIMP2, α-enolase and 14-3-3ε, indirectly involved in Aβ metabolism, as well as Septin-2 showed changes that increase Aβ levels. Increased 14-3-3γ may contribute to GSK3β driven tau hyperphosphorylation and CRMP2 Thr514 and Ser522 phosphorylation with the Thr555-site, a target for Rho kinase, showing time-dependent changes. IL-18 also increased caspase-1 levels and vacuolization of the cells. Although our SH-SY5Y cells were not aged, as neurons in AD, our work suggests that heightened or prolonged IL-18 levels can drive protein changes of known

  13. Increased expression of the receptor for advanced glycation end products in neurons and astrocytes in a triple transgenic mouse model of Alzheimer's disease.

    Science.gov (United States)

    Choi, Bo-Ryoung; Cho, Woo-Hyun; Kim, Jiyoung; Lee, Hyong Joo; Chung, ChiHye; Jeon, Won Kyung; Han, Jung-Soo

    2014-02-07

    The receptor for advanced glycation end products (RAGE) has been reported to have a pivotal role in the pathogenesis of Alzheimer's disease (AD). This study investigated RAGE levels in the hippocampus and cortex of a triple transgenic mouse model of AD (3xTg-AD) using western blotting and immunohistochemical double-labeling to assess cellular localization. Analysis of western blots showed that there were no differences in the hippocampal and cortical RAGE levels in 10-month-old adult 3xTg-AD mice, but significant increases in RAGE expression were found in the 22- to 24-month-old aged 3xTg-AD mice compared with those of age-matched controls. RAGE-positive immunoreactivity was observed primarily in neurons of aged 3xTg-AD mice with very little labeling in non-neuronal cells, with the notable exception of RAGE presence in astrocytes in the hippocampal area CA1. In addition, RAGE signals were co-localized with the intracellular amyloid precursor protein (APP)/amyloid beta (Aβ) but not with the extracellular APP/Aβ. In aged 3xTg-AD mice, expression of human tau was observed in the hippocampal area CA1 and co-localized with RAGE signals. The increased presence of RAGE in the 3xTg-AD animal model showing critical aspects of AD neuropathology indicates that RAGE may contribute to cellular dysfunction in the AD brain.

  14. Curcumin inhibition of JNKs prevents dopaminergic neuronal loss in a mouse model of Parkinson’s disease through suppressing mitochondria dysfunction

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    Pan Jing

    2012-08-01

    Full Text Available Abstract Curcumin,a natural polyphenol obtained from turmeric,has been implicated to be neuroprotective in a variety of neurodegenerative disorders although the mechanism remains poorly understood. The results of our recent experiments indicated that curcumin could protect dopaminergic neurons from apoptosis in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP mouse model of Parkinson’s disease (PD. The death of dopaminergic neurons and the loss of dopaminergic axon in the striatum were significantly suppressed by curcumin in MPTP mouse model. Further studies showed that curcumin inhibited JNKs hyperphosphorylation induced by MPTP treatment. JNKs phosphorylation can cause translocation of Bax to mitochondria and the release of cytochrome c which both ultimately contribute to mitochondria-mediated apoptosis. These pro-apoptosis effect can be diminished by curcumin. Our experiments demonstrated that curcumin can prevent nigrostriatal degeneration by inhibiting the dysfunction of mitochondrial through suppressing hyperphosphorylation of JNKs induced by MPTP. Our results suggested that JNKs/mitochondria pathway may be a novel target in the treatment of PD patients.

  15. Secreted calmodulin-like skin protein inhibits neuronal death in cell-based Alzheimer's disease models via the heterotrimeric Humanin receptor.

    Science.gov (United States)

    Hashimoto, Y; Nawa, M; Kurita, M; Tokizawa, M; Iwamatsu, A; Matsuoka, M

    2013-03-21

    Humanin is a secreted bioactive peptide that is protective in a variety of death models, including cell-based neuronal death models related to Alzheimer's disease (AD). To mediate the protective effect in AD-related death models, Humanin signals via a cell-surface receptor that is generally composed of three subunits: ciliary neurotrophic factor receptor α, WSX-1 and gp130 (heterotrimeric Humanin receptor; htHNR). However, the protective effect of Humanin via the htHNR is weak (EC50=1-10 μM); therefore, it is possible that another physiological agonist for this receptor exists in vivo. In the current study, calmodulin-like skin protein (CLSP), a calmodulin relative with an undefined function, was shown to be secreted and inhibit neuronal death via the htHNR with an EC50 of 10-100 pM. CLSP was highly expressed in the skin, and the concentration in circulating normal human blood was ~5 nM. When administered intraperitoneally in mice, recombinant CLSP was transported across the blood-cerebrospinal fluid (CSF)-barrier and its concentration in the CSF reaches 1/100 of its serum concentration at 1 h after injection. These findings suggest that CLSP is a physiological htHNR agonist.

  16. Protective effects of a polysaccharide from Spirulina platensis on dopaminergic neurons in an MPTP-induced Parkinson's disease model in C57BL/6J mice.

    Science.gov (United States)

    Zhang, Fang; Lu, Jian; Zhang, Ji-Guo; Xie, Jun-Xia

    2015-02-01

    The present study aimed to determine whether a polysaccharide obtained from Spirulina platensis shows protective effects on dopaminergic neurons. A Parkinson's disease model was established through the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57BL/6J mice. Prior to the MPTP injection, some mice were pretreated with intraperitoneal injections of a polysaccharide derived from Spirulina platensis once daily for 10 days. The results showed that the immunoreactive staining and mRNA expression of the dopamine transporter and tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, in the substantia nigra, were significantly increased in mice pretreated with 800 mg/kg of the polysaccharide compared with those in MPTP-treated mice. The activities of superoxide dismutase and glutathione peroxidase in the serum and midbrain were also increased significantly in mice injected with MPTP after pretreatment with the polysaccharide from Spirulina platensis. By contrast, the activity of monoamine oxidase B in serum and midbrain maintained unchanged. These experimental findings indicate that the polysaccharide obtained from Spirulina platensis plays a protective role against the MPTP-induced loss of dopaminergic neurons in C57BL/6J mice, and that the antioxidative properties of this polysaccharide likely underlie its neuroprotective effect.

  17. Protective effects of a polysaccharide from Spirulina platensis on dopaminergic neurons in an MPTP-induced Parkinson′s disease model in C57BL/6J mice

    Directory of Open Access Journals (Sweden)

    Fang Zhang

    2015-01-01

    Full Text Available The present study aimed to determine whether a polysaccharide obtained from Spirulina platensis shows protective effects on dopaminergic neurons. A Parkinson′s disease model was established through the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP in C57BL/6J mice. Prior to the MPTP injection, some mice were pretreated with intraperitoneal injections of a polysaccharide derived from Spirulina platensis once daily for 10 days. The results showed that the immunoreactive staining and mRNA expression of the dopamine transporter and tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, in the substantia nigra, were significantly increased in mice pretreated with 800 mg/kg of the polysaccharide compared with those in MPTP-treated mice. The activities of superoxide dismutase and glutathione peroxidase in the serum and midbrain were also increased significantly in mice injected with MPTP after pretreatment with the polysaccharide from Spirulina platensis. By contrast, the activity of monoamine oxidase B in serum and midbrain maintained unchanged. These experimental findings indicate that the polysaccharide obtained from Spirulina platensis plays a protective role against the MPTP-induced loss of dopaminergic neurons in C57BL/6J mice, and that the antioxidative properties of this polysaccharide likely underlie its neuroprotective effect.

  18. The Origin of Spousal Resemblance for Alcohol Use Disorder.

    Science.gov (United States)

    Kendler, Kenneth S; Lönn, Sara Larsson; Salvatore, Jessica; Sundquist, Jan; Sundquist, Kristina

    2018-03-01

    Although spouses strongly resemble one another in their risk for alcohol use disorder (AUD), the causes of this association remain unclear. To examine longitudinally, in first marriages, the association of a first registration for AUD in one spouse with risk of registration in his or her partner and to explore changes in the risk for AUD registration in individuals with multiple marriages as they transition from a spouse with AUD to one without or vice versa. Population-wide Swedish registries were used to identify individuals born in Sweden between 1960 and 1990 who were married before the end of study follow-up on December 31, 2013. The study included 8562 marital pairs with no history of AUD registration prior to their first marriage and an AUD registration in 1 spouse during marriage and 4891 individuals with multiple marriages whose first spouse had no AUD registration and second spouse did or vice versa. Final statistical analyses were conducted from August 15 to September 1, 2017. A spousal onset or history of AUD registration. Alcohol use disorder registration in national medical, criminal, or pharmacy registries. Among the 8562 marital pairs (5883 female probands and 2679 male probands; mean [SD] age at marriage, 29.2 [5.7] years) in first marriages, the hazard ratio of AUD registration in wives immediately after the first AUD registration in their husbands was 13.82, which decreased 2 years later to 3.75. The hazard ratio of AUD registration in husbands after the first AUD registration in their wives was 9.21, which decreased 2 years later to 3.09. Among the 4891 individuals with multiple marriages (1439 women and 3452 men; mean [SD] age at first marriage, 25.5 [4.2] years), when individuals transitioned from a first marriage to a spouse with AUD to a second marriage to a spouse without AUD, the hazard ratio for AUD registration was 0.50 (95% CI, 0.42-0.59) in women and 0.51 (95% CI, 0.44-0.59) in men. After a first marriage to a spouse without AUD, the

  19. Postinhibitory rebound neurons and networks are disrupted in retrovirus-induced spongiform neurodegeneration.

    Science.gov (United States)

    Li, Ying; Davey, Robert A; Sivaramakrishnan, Shobhana; Lynch, William P

    2014-08-01

    Certain retroviruses induce progressive spongiform motor neuron disease with features resembling prion diseases and amyotrophic lateral sclerosis. With the neurovirulent murine leukemia virus (MLV) FrCasE, Env protein expression within glia leads to postsynaptic vacuolation, cellular effacement, and neuronal loss in the absence of neuroinflammation. To understand the physiological changes associated with MLV-induced spongiosis, and its neuronal specificity, we employed patch-clamp recordings and voltage-sensitive dye imaging in brain slices of the mouse inferior colliculus (IC), a midbrain nucleus that undergoes extensive spongiosis. IC neurons characterized by postinhibitory rebound firing (PIR) were selectively affected in FrCasE-infected mice. Coincident with Env expression in microglia and in glia characterized by NG2 proteoglycan expression (NG2 cells), rebound neurons (RNs) lost PIR, became hyperexcitable, and were reduced in number. PIR loss and hyperexcitability were reversed by raising internal calcium buffer concentrations in RNs. PIR-initiated rhythmic circuits were disrupted, and spontaneous synchronized bursting and prolonged depolarizations were widespread. Other IC neuron cell types and circuits within the same degenerative environment were unaffected. Antagonists of NMDA and/or AMPA receptors reduced burst firing in the IC but did not affect prolonged depolarizations. Antagonists of L-type calcium channels abolished both bursts and slow depolarizations. IC infection by the nonneurovirulent isogenic virus Friend 57E (Fr57E), whose Env protein is structurally similar to FrCasE, showed no RN hyperactivity or cell loss; however, PIR latency increased. These findings suggest that spongiform neurodegeneration arises from the unique excitability of RNs, their local regulation by glia, and the disruption of this relationship by glial expression of abnormal protein. Copyright © 2014 the American Physiological Society.

  20. [Mirror neurons].

    Science.gov (United States)

    Rubia Vila, Francisco José

    2011-01-01

    Mirror neurons were recently discovered in frontal brain areas of the monkey. They are activated when the animal makes a specific movement, but also when the animal observes the same movement in another animal. Some of them also respond to the emotional expression of other animals of the same species. These mirror neurons have also been found in humans. They respond to or "reflect" actions of other individuals in the brain and are thought to represent the basis for imitation and empathy and hence the neurobiological substrate for "theory of mind", the potential origin of language and the so-called moral instinct.

  1. Lung irradiation induces pulmonary vascular remodelling resembling pulmonary arterial hypertension

    NARCIS (Netherlands)

    Ghobadi, G.; Bartelds, B.; van der Veen, S. J.; Dickinson, M. G.; Brandenburg, S.; Berger, R. M. F.; Langendijk, J. A.; Coppes, R. P.; van Luijk, P.

    Background Pulmonary arterial hypertension (PAH) is a commonly fatal pulmonary vascular disease that is often diagnosed late and is characterised by a progressive rise in pulmonary vascular resistance resulting from typical vascular remodelling. Recent data suggest that vascular damage plays an

  2. Cardiac sarcoidosis resembling panic disorder: a case report.

    Science.gov (United States)

    Tokumitsu, Keita; Demachi, Jun; Yamanoi, Yukichi; Oyama, Shigeto; Takeuchi, Junko; Yachimori, Koji; Yasui-Furukori, Norio

    2017-01-13

    Sarcoidosis is a systemic disease of unknown etiology, in which granulomas develop in various organs, including the skin, lungs, eyes, or heart. It has been reported that patients with sarcoidosis are more likely to develop panic disorder than members of the general population. However, there are many unknown factors concerning the causal relationship between these conditions. We present the case of a 57-year-old woman who appeared to have panic disorder, as she experienced repeated panic attacks induced by transient complete atrioventricular block, associated with cardiac sarcoidosis. Psychotherapy and pharmacotherapy were not effective in the treatment of her panic attacks. However, when we implanted a permanent pacemaker and initiated steroid treatment for cardiac sarcoidosis, panic attacks were ameliorated. Based on these findings, we diagnosed the patient's symptoms as an anxiety disorder associated with cardiac sarcoidosis, rather than panic disorder. This report highlights the importance of considering cardiac sarcoidosis in the differential diagnosis of panic disorder. This cardiac disease should be considered especially in patients have a history of cardiac disease (e.g., arrhythmia) and atypical presentations of panic symptoms. Panic disorder is a psychiatric condition that is typically diagnosed after other medical conditions have been excluded. Because the diagnosis of sarcoidosis is difficult in some patients, caution is required. The palpitations and symptoms of heart failure associated with cardiac sarcoidosis can be misdiagnosed as psychiatric symptoms of panic disorder. The condition described in the current case study appears to constitute a physical disease, the diagnosis of which requires significant consideration and caution.

  3. Expression of the neuronal adaptor protein X11alpha protects against memory dysfunction in a transgenic mouse model of Alzheimer's disease.

    LENUS (Irish Health Repository)

    Mitchell, Jacqueline C

    2010-01-01

    X11alpha is a neuronal-specific adaptor protein that binds to the amyloid-beta protein precursor (AbetaPP). Overexpression of X11alpha reduces Abeta production but whether X11alpha also protects against Abeta-related memory dysfunction is not known. To test this possibility, we crossed X11alpha transgenic mice with AbetaPP-Tg2576 mice. AbetaPP-Tg2576 mice produce high levels of brain Abeta and develop age-related defects in memory function that correlate with increasing Abeta load. Overexpression of X11alpha alone had no detectable adverse effect upon behavior. However, X11alpha reduced brain Abeta levels and corrected spatial reference memory defects in aged X11alpha\\/AbetaPP double transgenics. Thus, X11alpha may be a therapeutic target for Alzheimer\\'s disease.

  4. Gender-related changes in increase of dopaminergic neurons in the olfactory bulb of Parkinson's disease patients

    NARCIS (Netherlands)

    Huisman, E.; Uylings, H.B.M.; Hoogland, P.V.J.M.

    2008-01-01

    Gender differences in dopaminergic related neurodegenerative diseases have hardly been studied until now. It is generally accepted that more men than women suffer from Parkinson's disease. One of the most prevalent symptoms in Parkinson's patients, hyposmia, does not show gender differences, while

  5. Fast progressive lower motor neuron disease is an ALS variant: A two-centre tract of interest-based MRI data analysis.

    Science.gov (United States)

    Müller, Hans-Peter; Agosta, Federica; Riva, Nilo; Spinelli, Edoardo G; Comi, Giancarlo; Ludolph, Albert C; Filippi, Massimo; Kassubek, Jan

    2018-01-01

    The criteria for assessing upper motor neuron pathology in pure lower motor neuron disease (LMND) still remain a major issue of debate with respect to the clinical classification as an amyotrophic lateral sclerosis (ALS) variant. The study was designed to investigate white matter damage by a hypothesis-guided tract-of-interest-based approach in patients with LMND compared with healthy controls and ´classical´ ALS patients in order to identify in vivo brain structural changes according to the neuropathologically defined ALS affectation pattern. Data were pooled from two previous studies at two different study sites (Ulm, Germany and Milano, Italy). DTI-based white matter integrity mapping was performed by voxelwise statistical comparison and by a tractwise analysis of fractional anisotropy (FA) maps according to the ALS-staging pattern for 65 LMND patients (clinically differentiated in fast and slow progressors) vs. 92 matched controls and 101 ALS patients with a 'classical' phenotype to identify white matter structural alterations. The analysis of white matter structural connectivity by regional FA reductions demonstrated the characteristic alteration patterns along the CST and also in frontal and prefrontal brain areas in LMND patients compared to controls and ALS. Fast progressing LMND showed substantial involvement, like in ALS, while slow progressors showed less severe alterations. In the tract-specific analysis according to the ALS-staging pattern, fast progressing LMND showed significant alterations of ALS-related tract systems as compared to slow progressors and controls. This study showed an affectation pattern for corticoefferent fibers in LMND with fast disease progression as defined for ALS, that way confirming the hypothesis that fast progressing LMND is a phenotypical variant of ALS.

  6. Neurotensin-Conjugated Reduced Graphene Oxide with Multi-Stage Near-Infrared-Triggered Synergic Targeted Neuron Gene Transfection In Vitro and In Vivo for Neurodegenerative Disease Therapy.

    Science.gov (United States)

    Hsieh, Tsung-Ying; Huang, Wei-Chen; Kang, Yi-Da; Chu, Chao-Yi; Liao, Wen-Lin; Chen, You-Yin; Chen, San-Yuan

    2016-12-01

    Delivery efficiency with gene transfection is a pivotal point in achieving maximized therapeutic efficacy and has been an important challenge with central nervous system (CNS) diseases. In this study, neurotensin (NT, a neuro-specific peptide)-conjugated polyethylenimine (PEI)-modified reduced graphene oxide (rGO) nanoparticles with precisely controlled two-stage near-infrared (NIR)-laser photothermal treatment to enhance the ability to target neurons and achieve high gene transfection in neurons. First-stage NIR laser irradiation on the cells with nanoparticles attached on the surface can increase the permeability of the cell membrane, resulting in an apparent increase in cellular uptake compared to untreated cells. In addition, second-stage NIR laser irradiation on the cells with nanoparticles inside can further induce endo/lysosomal cavitation, which not only helps nanoparticles escape from endo/lysosomes but also prevents plasmid DNA (pDNA) from being digested by DNase I. At least double pDNA amount can be released from rGO-PEI-NT/pDNA under NIR laser trigger release compared to natural release. Moreover, in vitro differentiated PC-12 cell and in vivo mice (C57BL/6) brain transfection experiments have demonstrated the highest transfection efficiency occurring when NT modification is combined with external multi-stage stimuli-responsive NIR laser treatment. The combination of neuro-specific targeting peptide and external NIR-laser-triggered aid provides a nanoplatform for gene therapy in CNS diseases. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  7. ER Stress Induced by Tunicamycin Triggers α-Synuclein Oligomerization, Dopaminergic Neurons Death and Locomotor Impairment: a New Model of Parkinson's Disease.

    Science.gov (United States)

    Cóppola-Segovia, Valentín; Cavarsan, Clarissa; Maia, Flavia G; Ferraz, Anete C; Nakao, Lia S; Lima, Marcelo Ms; Zanata, Silvio M

    2017-10-01

    Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive death of dopaminergic neurons of the substantia nigra pars compacta (SNpc), leading to the major clinical abnormalities that characterize this disease. Although PD's etiology is unknown, α-synuclein aggregation plays a pivotal role in PD pathogenesis, which could be associated to some pathological processes such as oxidative stress, endoplasmic reticulum (ER) stress, impaired protein degradation, and mitochondrial dysfunction. Increasing experimental evidence indicates that ER stress is involved in PD, however most of the described results employed cultured cell lines and genetically modified animal models. In this study, we developed a new ER stress rat model employing the well-known ER stressor tunicamycin (Tm). To evaluate if ER stress was able to induce PD features, we performed an intranigral injection of Tm (0.1 μg/cerebral hemisphere) and animals (male Wistar rats) were analyzed 7 days post injection. The classical 6-OHDA neurotoxin model (1 μg/cerebral hemisphere) was used as an established positive control for PD. We show that Tm injection induced locomotor impairment, dopaminergic neurons death, and activation of astroglia. In addition, we observed an extensive α-synuclein oligomerization in SNpc of Tm-injected animals when compared with DMSO-injected controls. Finally, both Tm and 6-OHDA treated animals presented increased levels of ER stress markers. Taken together, these findings show for the first time that the ER stressor Tm recapitulates some of the phenotypic characteristics observed in rodent models of PD, reinforcing the concept that ER stress could be an important contributor to the pathophysiology of PD. Therefore, we propose the intranigral Tm injection as a new ER stress-based model for the study of PD in vivo.

  8. Is dignity therapy feasible to enhance the end of life experience for people with motor neurone disease and their family carers?

    Directory of Open Access Journals (Sweden)

    Bentley Brenda

    2012-09-01

    Full Text Available Abstract Background Development of interventions that address psychosocial and existential distress in people with motor neurone disease (MND or that alleviate caregiver burden in MND family carers have often been suggested in the research literature. Dignity therapy, which was developed to reduce psychosocial and existential distress at the end of life, has been shown to benefit people dying of cancer and their families. These results may not be transferable to people with MND. The objectives of this study are to assess the feasibility, acceptability and potential effectiveness of dignity therapy to enhance the end of life experience for people with motor neurone disease and their family carers. Methods/design This is a cross-sectional study utilizing a single treatment group and a pre/post test design. The study population will comprise fifty people diagnosed with MND and their nominated family carers. Primarily quantitative outcomes will be gathered through measures assessed at baseline and at approximately one week after the intervention. Outcomes for participants include hopefulness, spirituality and dignity. Outcomes for family carers include perceived caregiver burden, hopefulness and anxiety/depression. Feedback and satisfaction with the intervention will be gathered through a questionnaire. Discussion This detailed research will explore if dignity therapy has the potential to enhance the end of life experience for people with MND and their family carers, and fill a gap for professionals who are called on to address the spiritual, existential and psychosocial needs of their MND patients and families. Trial registration ACTRN Trial Number: ACTRN12611000410954

  9. Dopamine D2 receptor and β-arrestin 2 mediate Amyloid-β elevation induced by anti-parkinson's disease drugs, levodopa and piribedil, in neuronal cells.

    Directory of Open Access Journals (Sweden)

    Jing Lu

    Full Text Available Although levodopa is the first-line medication for the treatment of Parkinson's disease (PD showing unsurpassable efficiency, its chronic use causes dyskinesia. Accordingly, dopamine agonists are increasingly employed as monotherapy or in combination with levodopa to reduce the risk of motor complications. It is well recognized that patients with PD often exhibit cognitive deficits. However, clinical and animal studies assessing the effects of dopaminergic medications on cognition are controversial. Amyloid-β (Aβ is one of the major hallmarks of Alzheimer's disease (AD, leading to progressive memory loss and cognitive deficit. Interestingly, the abnormal accumulation of Aβ is also detected in PD patients with cognitive deficits. Evidence indicated that levodopa induced a mild increase of Aβ plaque number and size in the brain of AD mouse. However,