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Sample records for neurodegenerative lysosomal storage

  1. Lysosomal dysfunction in neurodegenerative diseases

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    Klaudia Tomala

    2017-05-01

    Full Text Available Recent data advocate for the implication of lysosomes in the development of programmed cell death. Lysosomal dysfunction decreased the efficiency of autophagosome/lysosome fusion that leads to vacuolation of cells. Autophagic vacuoles containing damaged organelles and altered proteins are hallmarks in most neurodegenerative disorders. These aggregates consequently disrupt cellular homeostasis causing neuronal cell death due apoptosis or necrosis. Moreover calpain mediated or mutation inducted lysosomal rupture result in release of lysosomal cathepsins into the cytoplasm and inducing neuronal cell death. In this review we emphasize the pathophysiological mechanism connecting disrupting autophagy – lysosomal pathway and lysosomal dysfunction in neuronal cell death called lysosomal cell death.

  2. Mutation Frequency of Three Neurodegenerative Lysosomal Storage Diseases: From Screening to Treatment?

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    Duarte, Ana Joana; Ribeiro, Diogo; Oliveira, Pedro; Amaral, Olga

    2017-04-01

    The ascertainment of mutation frequencies in the general population may have impact on the population's wellbeing and respective healthcare services. Furthermore, it may help define which approaches will be more effective for certain patients based on the genetic cause of disease. Determine the frequency of three mutations, known to be a major cause of three distinct Lysosomal Storage Diseases (LSDs). The following pre-requisites were met: each mutation accounted for over 55% of the disease alleles among previously reported unrelated patients, all three diseases were among the most prevalent LSDs in the population under study, they all involved devastating deterioration of the nervous system, lacked curative treatment and may be fatal in childhood or adolescence. The anonymous samples used in this study were representative of the whole population; mutations were tested by PCR based methods, positive results were further confirmed. The diseases studied were Mucopolysaccharidosis type I (Hurler, MIM 607014), Tay Sachs disease variant B1 (TS, MIM 272800) and Metachromatic Leukodystrophy (MLD, MIM 250100); the mutations were, respectively, p.W402X, p.R178C and c.465+1G>A. Increased carrier frequencies were found for Tay Sachs disease variant B1 HEXA p.R178C mutation (1:340) and for the infantile MLD ARSA c.465+1G> A mutation (1:350) denoting higher risk for these sub-types of disease in Portugal and possibly in individuals of Iberian ancestry. Carrier screening in target populations may provide the foundations for more effective approaches to precision medicine. Copyright © 2017 IMSS. Published by Elsevier Inc. All rights reserved.

  3. The cell biology of lysosomal storage disorders

    NARCIS (Netherlands)

    Futerman, A.H.; van Meer, G.|info:eu-repo/dai/nl/068570368

    2004-01-01

    Lysosomal storage disorders, of which more than 40 are known, are caused by the defective activity of lysosomal proteins, which results in the intra-lysosomal accumulation of undegraded metabolites. Despite years of study of the genetic and molecular bases of lysosomal storage disorders, little is

  4. Genetic convergence of Parkinson's disease and lysosomal storage disorders.

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    Deng, Hao; Xiu, Xiaofei; Jankovic, Joseph

    2015-01-01

    Parkinson's disease is a common progressive neurodegenerative disorder characterized by predominant degeneration of the dopaminergic neurons in the substantia nigra pars compacta and the presence of intracellular inclusions enriched in α-synuclein, resulting in a variety motor and nonmotor symptoms. Lysosomal storage disorders are a group of disorders including Gaucher disease, Niemann-Pick disease, and neuronal ceroid lipofuscinoses caused by the defective activity of lysosomal and nonlysosomal proteins. In addition to an overlap in some clinical features between lysosomal storage disorders and Parkinson's disease, the two disorders may be also linked pathogenically. There is growing support for the notion that mutations in genes causing lysosomal storage disorders including the glucocerebrosidase gene, the sphingomyelin phosphodiesterase 1 gene, and the NPC1 gene may increase risk for developing Parkinson's disease. In this review, we discuss the recent advances in the genetic convergence of Parkinson's disease and lysosomal storage disorders, shedding new light on the understanding of shared pathogenic pathways.

  5. Biomarkers in Lysosomal Storage Diseases

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    Joaquin Bobillo Lobato

    2016-12-01

    Full Text Available A biomarker is generally an analyte that indicates the presence and/or extent of a biological process, which is in itself usually directly linked to the clinical manifestations and outcome of a particular disease. The biomarkers in the field of lysosomal storage diseases (LSDs have particular relevance where spectacular therapeutic initiatives have been achieved, most notably with the introduction of enzyme replacement therapy (ERT. There are two main types of biomarkers. The first group is comprised of those molecules whose accumulation is directly enhanced as a result of defective lysosomal function. These molecules represent the storage of the principal macro-molecular substrate(s of a specific enzyme or protein, whose function is deficient in the given disease. In the second group of biomarkers, the relationship between the lysosomal defect and the biomarker is indirect. In this group, the biomarker reflects the effects of the primary lysosomal defect on cell, tissue, or organ functions. There is no “gold standard” among biomarkers used to diagnosis and/or monitor LSDs, but there are a number that exist that can be used to reasonably assess and monitor the state of certain organs or functions. A number of biomarkers have been proposed for the analysis of the most important LSDs. In this review, we will summarize the most promising biomarkers in major LSDs and discuss why these are the most promising candidates for screening systems.

  6. Lysosomal exocytosis and lipid storage disorders

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    Samie, Mohammad Ali; Xu, Haoxing

    2014-01-01

    Lysosomes are acidic compartments in mammalian cells that are primarily responsible for the breakdown of endocytic and autophagic substrates such as membranes, proteins, and lipids into their basic building blocks. Lysosomal storage diseases (LSDs) are a group of metabolic disorders caused by genetic mutations in lysosomal hydrolases required for catabolic degradation, mutations in lysosomal membrane proteins important for catabolite export or membrane trafficking, or mutations in nonlysosomal proteins indirectly affecting these lysosomal functions. A hallmark feature of LSDs is the primary and secondary excessive accumulation of undigested lipids in the lysosome, which causes lysosomal dysfunction and cell death, and subsequently pathological symptoms in various tissues and organs. There are more than 60 types of LSDs, but an effective therapeutic strategy is still lacking for most of them. Several recent in vitro and in vivo studies suggest that induction of lysosomal exocytosis could effectively reduce the accumulation of the storage materials. Meanwhile, the molecular machinery and regulatory mechanisms for lysosomal exocytosis are beginning to be revealed. In this paper, we first discuss these recent developments with the focus on the functional interactions between lipid storage and lysosomal exocytosis. We then discuss whether lysosomal exocytosis can be manipulated to correct lysosomal and cellular dysfunction caused by excessive lipid storage, providing a potentially general therapeutic approach for LSDs. PMID:24668941

  7. The Link Between Lysosomal Storage Disorders and More Common Diseases

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    Michael Beck MD

    2016-12-01

    Full Text Available In the last decades, it has become more and more evident that lysosomal storage disorders and common neurodegenerative diseases such as Alzheimer and Parkinson diseases have clinical, neuropathological, and genetic features in common, including lysosomal dysfunction and impaired autophagy. Patients with Gaucher and even carriers of Gaucher disease have an increased risk to develop Parkinson disease. Likewise, individuals who are heterozygous for a mutation of a gene that causes an adult form of neuronal ceroid lipofuscinosis are more likely to be affected by a form of frontotemporal dementia in their later life. A further example is the gene NAGLU encoding the enzyme α- N -acetylglucosaminidase, which is deficient in patients with mucopolysaccharidosis type IIIB. Mutations of the NAGLU gene have been observed in patients affected by an axonal neuropathy. An interesting unexpected finding was the link between stuttering and genes that are essential for the function of all lysosomal enzymes. This review will present some example of the association of lysosomal storage disorders and neurodegenerative disease and discuss possible pathogenic mechanisms that are common to both conditions. The understanding of the pathophysiology of the endosomal–lysosomal–autophagic system may help to develop drugs, which might provide benefit not only for patients with rare lysosomal storage disorders but also for individuals affected by more common diseases.

  8. Lysosomal Storage Disorders and Malignancy

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    Gregory M. Pastores

    2017-02-01

    Full Text Available Lysosomal storage disorders (LSDs are infrequent to rare conditions caused by mutations that lead to a disruption in the usual sequential degradation of macromolecules or their transit within the cell. Gaucher disease (GD, a lipidosis, is among the most common LSD, with an estimated incidence of 1 in 40,000 among the Caucasian, non-Jewish population. Studies have indicated an increased frequency of polyclonal and monoclonal gammopathy among patients with GD. It has been shown that two major sphingolipids that accumulate in GD, namely, β-glucosylceramide 22:0 (βGL1-22 and glucosylsphingosine (LGL1, can be recognized by a distinct subset of CD1d-restricted human and murine type II natural killer T (NKT cells. Investigations undertaken in an affected mouse model revealed βGL1-22- and LGL1-specific NKT cells were present and constitutively promoted the expression of a T-follicular helper (TFH phenotype; injection of these lipids led to downstream induction of germinal center B cells, hypergammaglobulinemia, and the production of antilipid antibodies. Subsequent studies have found clonal immunoglobulin in 33% of sporadic human monoclonal gammopathies is also specific for the lysolipids LGL1 and lysophosphatidylcholine (LPC. Furthermore, substrate reduction ameliorated GD-associated gammopathy in mice. It had been hypothesized that chronic antigenic stimulation by the abnormal lipid storage and associated immune dysregulation may be the underlying mechanism for the increased incidence of monoclonal and polyclonal gammopathies, as well as an increased incidence of multiple myeloma in patients with GD. Current observations support this proposition and illustrate the value of investigations into rare diseases, which as ‘experiments of nature’ may provide insights into conditions found in the general population that continue to remain incompletely understood.

  9. Lysosomal Storage Disorders and Malignancy.

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    Pastores, Gregory M; Hughes, Derralynn A

    2017-02-27

    Lysosomal storage disorders (LSDs) are infrequent to rare conditions caused by mutations that lead to a disruption in the usual sequential degradation of macromolecules or their transit within the cell. Gaucher disease (GD), a lipidosis, is among the most common LSD, with an estimated incidence of 1 in 40,000 among the Caucasian, non-Jewish population. Studies have indicated an increased frequency of polyclonal and monoclonal gammopathy among patients with GD. It has been shown that two major sphingolipids that accumulate in GD, namely, β-glucosylceramide 22:0 (βGL1-22) and glucosylsphingosine (LGL1), can be recognized by a distinct subset of CD1d-restricted human and murine type II natural killer T (NKT) cells. Investigations undertaken in an affected mouse model revealed βGL1-22- and LGL1-specific NKT cells were present and constitutively promoted the expression of a T-follicular helper (TFH) phenotype; injection of these lipids led to downstream induction of germinal center B cells, hypergammaglobulinemia, and the production of antilipid antibodies. Subsequent studies have found clonal immunoglobulin in 33% of sporadic human monoclonal gammopathies is also specific for the lysolipids LGL1 and lysophosphatidylcholine (LPC). Furthermore, substrate reduction ameliorated GD-associated gammopathy in mice. It had been hypothesized that chronic antigenic stimulation by the abnormal lipid storage and associated immune dysregulation may be the underlying mechanism for the increased incidence of monoclonal and polyclonal gammopathies, as well as an increased incidence of multiple myeloma in patients with GD. Current observations support this proposition and illustrate the value of investigations into rare diseases, which as 'experiments of nature' may provide insights into conditions found in the general population that continue to remain incompletely understood.

  10. Lysosomal storage disease 2 - Pompe's disease

    NARCIS (Netherlands)

    van der Ploeg, Ans T.; Reuser, Arnold J. J.

    2008-01-01

    Pompe's disease, glycogen-storage disease type II, and acid maltase deficiency are alternative names for the same metabolic disorder. It is a pan-ethnic autosomal recessive trait characterised by acid alpha-glucosidase deficiency leading to lysosomal glycogen storage. Pompe's disease is also

  11. Induced pluripotent stem cell models of lysosomal storage disorders

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    Borger, Daniel K.; McMahon, Benjamin; Roshan Lal, Tamanna; Serra-Vinardell, Jenny; Aflaki, Elma

    2017-01-01

    ABSTRACT Induced pluripotent stem cells (iPSCs) have provided new opportunities to explore the cell biology and pathophysiology of human diseases, and the lysosomal storage disorder research community has been quick to adopt this technology. Patient-derived iPSC models have been generated for a number of lysosomal storage disorders, including Gaucher disease, Pompe disease, Fabry disease, metachromatic leukodystrophy, the neuronal ceroid lipofuscinoses, Niemann-Pick types A and C1, and several of the mucopolysaccharidoses. Here, we review the strategies employed for reprogramming and differentiation, as well as insights into disease etiology gleaned from the currently available models. Examples are provided to illustrate how iPSC-derived models can be employed to develop new therapeutic strategies for these disorders. We also discuss how models of these rare diseases could contribute to an enhanced understanding of more common neurodegenerative disorders such as Parkinson’s disease, and discuss key challenges and opportunities in this area of research. PMID:28592657

  12. Induced pluripotent stem cell models of lysosomal storage disorders

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    Daniel K. Borger

    2017-06-01

    Full Text Available Induced pluripotent stem cells (iPSCs have provided new opportunities to explore the cell biology and pathophysiology of human diseases, and the lysosomal storage disorder research community has been quick to adopt this technology. Patient-derived iPSC models have been generated for a number of lysosomal storage disorders, including Gaucher disease, Pompe disease, Fabry disease, metachromatic leukodystrophy, the neuronal ceroid lipofuscinoses, Niemann-Pick types A and C1, and several of the mucopolysaccharidoses. Here, we review the strategies employed for reprogramming and differentiation, as well as insights into disease etiology gleaned from the currently available models. Examples are provided to illustrate how iPSC-derived models can be employed to develop new therapeutic strategies for these disorders. We also discuss how models of these rare diseases could contribute to an enhanced understanding of more common neurodegenerative disorders such as Parkinson’s disease, and discuss key challenges and opportunities in this area of research.

  13. Astrocyte dysfunction triggers neurodegeneration in a lysosomal storage disorder.

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    Di Malta, Chiara; Fryer, John D; Settembre, Carmine; Ballabio, Andrea

    2012-08-28

    The role of astrocytes in neurodegenerative processes is increasingly appreciated. Here we investigated the contribution of astrocytes to neurodegeneration in multiple sulfatase deficiency (MSD), a severe lysosomal storage disorder caused by mutations in the sulfatase modifying factor 1 (SUMF1) gene. Using Cre/Lox mouse models, we found that astrocyte-specific deletion of Sumf1 in vivo induced severe lysosomal storage and autophagy dysfunction with consequential cytoplasmic accumulation of autophagic substrates. Lysosomal storage in astrocytes was sufficient to induce degeneration of cortical neurons in vivo. Furthermore, in an ex vivo coculture assay, we observed that Sumf1(-/-) astrocytes failed to support the survival and function of wild-type cortical neurons, suggesting a non-cell autonomous mechanism for neurodegeneration. Compared with the astrocyte-specific deletion of Sumf1, the concomitant removal of Sumf1 in both neurons and glia in vivo induced a widespread neuronal loss and robust neuroinflammation. Finally, behavioral analysis of mice with astrocyte-specific deletion of Sumf1 compared with mice with Sumf1 deletion in both astrocytes and neurons allowed us to link a subset of neurological manifestations of MSD to astrocyte dysfunction. This study indicates that astrocytes are integral components of the neuropathology in MSD and that modulation of astrocyte function may impact disease course.

  14. Mitochondrial Dysfunction in Lysosomal Storage Disorders.

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    de la Mata, Mario; Cotán, David; Villanueva-Paz, Marina; de Lavera, Isabel; Álvarez-Córdoba, Mónica; Luzón-Hidalgo, Raquel; Suárez-Rivero, Juan M; Tiscornia, Gustavo; Oropesa-Ávila, Manuel

    2016-10-11

    Lysosomal storage diseases (LSDs) describe a heterogeneous group of rare inherited metabolic disorders that result from the absence or loss of function of lysosomal hydrolases or transporters, resulting in the progressive accumulation of undigested material in lysosomes. The accumulation of substances affects the function of lysosomes and other organelles, resulting in secondary alterations such as impairment of autophagy, mitochondrial dysfunction, inflammation and apoptosis. LSDs frequently involve the central nervous system (CNS), where neuronal dysfunction or loss results in progressive neurodegeneration and premature death. Many LSDs exhibit signs of mitochondrial dysfunction, which include mitochondrial morphological changes, decreased mitochondrial membrane potential (ΔΨm), diminished ATP production and increased generation of reactive oxygen species (ROS). Furthermore, reduced autophagic flux may lead to the persistence of dysfunctional mitochondria. Gaucher disease (GD), the LSD with the highest prevalence, is caused by mutations in the GBA1 gene that results in defective and insufficient activity of the enzyme β-glucocerebrosidase (GCase). Decreased catalytic activity and/or instability of GCase leads to accumulation of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph) in the lysosomes of macrophage cells and visceral organs. Mitochondrial dysfunction has been reported to occur in numerous cellular and mouse models of GD. The aim of this manuscript is to review the current knowledge and implications of mitochondrial dysfunction in LSDs.

  15. Mitochondrial Dysfunction in Lysosomal Storage Disorders

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    Mario de la Mata

    2016-10-01

    Full Text Available Lysosomal storage diseases (LSDs describe a heterogeneous group of rare inherited metabolic disorders that result from the absence or loss of function of lysosomal hydrolases or transporters, resulting in the progressive accumulation of undigested material in lysosomes. The accumulation of substances affects the function of lysosomes and other organelles, resulting in secondary alterations such as impairment of autophagy, mitochondrial dysfunction, inflammation and apoptosis. LSDs frequently involve the central nervous system (CNS, where neuronal dysfunction or loss results in progressive neurodegeneration and premature death. Many LSDs exhibit signs of mitochondrial dysfunction, which include mitochondrial morphological changes, decreased mitochondrial membrane potential (ΔΨm, diminished ATP production and increased generation of reactive oxygen species (ROS. Furthermore, reduced autophagic flux may lead to the persistence of dysfunctional mitochondria. Gaucher disease (GD, the LSD with the highest prevalence, is caused by mutations in the GBA1 gene that results in defective and insufficient activity of the enzyme β-glucocerebrosidase (GCase. Decreased catalytic activity and/or instability of GCase leads to accumulation of glucosylceramide (GlcCer and glucosylsphingosine (GlcSph in the lysosomes of macrophage cells and visceral organs. Mitochondrial dysfunction has been reported to occur in numerous cellular and mouse models of GD. The aim of this manuscript is to review the current knowledge and implications of mitochondrial dysfunction in LSDs.

  16. Neuroinflammatory paradigms in lysosomal storage diseases

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    Megan Elizabeth Bosch

    2015-10-01

    Full Text Available Lysosomal storage diseases (LSDs include approximately 70 distinct disorders that collectively account for 14% of all inherited metabolic diseases. LSDs are caused by mutations in various enzymes/proteins that disrupt lysosomal function, which impairs macromolecule degradation following endosome-lysosome and phagosome-lysosome fusion and autophagy, ultimately disrupting cellular homeostasis. LSDs are pathologically typified by lysosomal inclusions composed of a heterogeneous mixture of various proteins and lipids that can be found throughout the body. However, in many cases the CNS is dramatically affected, which may result from heightened neuronal vulnerability based on their post-mitotic state. Besides intrinsic neuronal defects, another emerging factor common to many LSDs is neuroinflammation, which may negatively impact neuronal survival and contribute to neurodegeneration. Microglial and astrocyte activation is a hallmark of many LSDs that affect the CNS, which often precedes and predicts regions where eventual neuron loss will occur. However, the timing, intensity, and duration of neuroinflammation may ultimately dictate the impact on CNS homeostasis. For example, a transient inflammatory response following CNS insult/injury can be neuroprotective, as glial cells attempt to remove the insult and provide trophic support to neurons. However, chronic inflammation, as seen in several LSDs, can promote neurodegeneration by creating a neurotoxic environment due to elevated levels of cytokines, chemokines, and pro-apoptotic molecules. Although neuroinflammation has been reported in several LSDs, the cellular basis and mechanisms responsible for eliciting neuroinflammatory pathways are just beginning to be defined. This review highlights the role of neuroinflammation in select LSDs and its potential contribution to neuron loss.

  17. Prenatal diagnosis of lysosomal storage diseases using fetal blood

    NARCIS (Netherlands)

    Groener, J. E.; de Graaf, F. L.; Poorthuis, B. J.; Kanhai, H. H.

    1999-01-01

    Lysosomal storage diseases are a rare but significant cause of non-immune hydrops fetalis (NIHF). In 17 cases of NIHF detected by ultrasound, the activity of five lysosomal enzymes was measured in leukocytes or plasma of 1 ml of fetal blood obtained by cordocentesis. By this approach seven lysosomal

  18. Lysosome

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    Ursula Matte BSc, PhD

    2016-12-01

    Full Text Available Since Christian de Duve first described the lysosome in the 1950s, it has been generally presented as a membrane-bound compartment containing acid hydrolases that enables the cell to degrade molecules without being digested by autolysis. For those working on the field of lysosomal storage disorders, the lack of one such hydrolase would lead to undegraded or partially degraded substrate storage inside engorged organelles disturbing cellular function by yet poorly explored mechanisms. However, in recent years, a much more complex scenario of lysosomal function has emerged, beyond and above the cellular “digestive” system. Knowledge on how the impairment of this organelle affects cell functioning may shed light on signs and symptoms of lysosomal disorders and open new roads for therapy.

  19. Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release.

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    Shen, Dongbiao; Wang, Xiang; Li, Xinran; Zhang, Xiaoli; Yao, Zepeng; Dibble, Shannon; Dong, Xian-ping; Yu, Ting; Lieberman, Andrew P; Showalter, Hollis D; Xu, Haoxing

    2012-03-13

    Lysosomal lipid accumulation, defects in membrane trafficking and altered Ca(2+) homoeostasis are common features in many lysosomal storage diseases. Mucolipin transient receptor potential channel 1 (TRPML1) is the principle Ca(2+) channel in the lysosome. Here we show that TRPML1-mediated lysosomal Ca(2+) release, measured using a genetically encoded Ca(2+) indicator (GCaMP3) attached directly to TRPML1 and elicited by a potent membrane-permeable synthetic agonist, is dramatically reduced in Niemann-Pick (NP) disease cells. Sphingomyelins (SMs) are plasma membrane lipids that undergo sphingomyelinase (SMase)-mediated hydrolysis in the lysosomes of normal cells, but accumulate distinctively in lysosomes of NP cells. Patch-clamp analyses revealed that TRPML1 channel activity is inhibited by SMs, but potentiated by SMases. In NP-type C cells, increasing TRPML1's expression or activity was sufficient to correct the trafficking defects and reduce lysosome storage and cholesterol accumulation. We propose that abnormal accumulation of luminal lipids causes secondary lysosome storage by blocking TRPML1- and Ca(2+)-dependent lysosomal trafficking.

  20. Subcellular Nanorheology Reveals Lysosomal Viscosity as a Reporter for Lysosomal Storage Diseases.

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    Devany, John; Chakraborty, Kasturi; Krishnan, Yamuna

    2018-02-14

    We describe a new method to measure viscosity within subcellular organelles of a living cell using nanorheology. We demonstrate proof of concept by measuring viscosity in lysosomes in multiple cell types and disease models. The lysosome is an organelle responsible for the breakdown of complex biomolecules. When different lysosomal proteins are defective, they are unable to break down specific biological substrates, which get stored within the lysosome, causing about 70 fatal diseases called lysosomal storage disorders (LSDs). Although the buildup of storage material is critical to the pathology of these diseases, methods to monitor cargo accumulation in the lysosome are lacking for most LSDs. Using passive particle tracking nanorheology and fluorescence recovery after photobleaching, we report that viscosity in the lysosome increases significantly during cargo accumulation in several LSD models. In a mammalian cell culture model of Niemann Pick C, lysosomal viscosity directly correlates with the levels of accumulated cholesterol. We also observed increased viscosity in diverse LSD models in Caenorhabditis elegans, revealing that lysosomal viscosity is a powerful reporter with which to monitor substrate accumulation in LSDs for new diagnostics or to assay therapeutic efficacy.

  1. Epidemiology of lysosomal storage diseases in Sweden.

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    Hult, Malin; Darin, Niklas; von Döbeln, Ulrika; Månsson, Jan-Eric

    2014-12-01

    There are more than 50 inherited lysosomal storage diseases (LSDs), and this study examined the incidence of clinically diagnosed LSDs in Sweden. The number of patients diagnosed during 1980-2009 was compiled from the registries of the two Swedish diagnostic laboratories that cover the whole country. We identified 433 patients during the 30-year period, with a total incidence of one in every 6100 births and identified fairly constant annual diagnoses during the last 20 years. Krabbe disease was the most common (one in 39 000) followed by Gaucher disease (one in 47 000), metachromatic leukodystrophy and Salla disease. Gaucher disease was more frequent in Sweden than other European countries, due to a founder effect of the mutation (p.L444P) in northern Sweden. Metachromatic leukodystrophy was one of the most common LSDs, in common with other countries. Salla disease, which is very rare elsewhere, was the fourth most common, stemming from a founder mutation in the Salla region of northern Finland brought to Sweden by immigration. The collective incidence of LSDs in Sweden was essentially equal to other European countries, but with a somewhat different disease pattern. Our findings have implications for diagnostic algorithms and treatment strategies. ©2014 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.

  2. Lysosomal storage disorders: A review of the musculoskeletal features.

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    James, Rebecca A; Singh-Grewal, Davinder; Lee, Senq-J; McGill, Jim; Adib, Navid

    2016-03-01

    The lysosomal storage disorders are a collection of progressive, multisystem disorders that frequently present in childhood. Their timely diagnosis is paramount as they are becoming increasingly treatable. Musculoskeletal manifestations often occur early in the disease course, hence are useful as diagnostics clues. Non-inflammatory joint stiffness or pain, carpal tunnel syndrome, trigger fingers, unexplained pain crises and short stature should all prompt consideration of a lysosomal storage disorder. Recurrent ENT infections, hepatosplenomegaly, recurrent hernias and visual/hearing impairment - especially when clustered together - are important extra-skeletal features. As diagnostic and therapeutic options continue to evolve, children with lysosomal storage disorders and their families are facing more sophisticated options for screening and treatment. The aim of this article is to highlight the paediatric presentations of lysosomal storage disorders, with an emphasis on the musculoskeletal features. © 2016 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).

  3. Low-dose, continuous enzyme replacement therapy ameliorates brain pathology in the neurodegenerative lysosomal disorder mucopolysaccharidosis type IIIA.

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    King, Barbara; Hassiotis, Sofia; Rozaklis, Tina; Beard, Helen; Trim, Paul J; Snel, Marten F; Hopwood, John J; Hemsley, Kim M

    2016-05-01

    Repeated replacement of sulphamidase via cerebrospinal fluid injection is an effective treatment for pathological changes in the brain in mice and dogs with the lysosomal storage disorder, mucopolysaccharidosis type IIIA (MPS IIIA). Investigational trials of this approach are underway in children with this condition, however, infusions require attendance at a specialist medical facility. We sought to comprehensively evaluate the effectiveness of sustained-release (osmotic pump-delivered) enzyme replacement therapy in murine MPS IIIA as this method, if applied to humans, would require only subcutaneous administration of enzyme once the pump was installed. Six-week-old MPS IIIA and unaffected mice were implanted with subcutaneous mini-osmotic pumps connected to an infusion cannula directed at the right lateral ventricle. Either recombinant human sulphamidase or vehicle were infused over the course of 7 weeks, with pumps replaced part-way through the experimental period. We observed near-normalisation of primarily stored substrate (heparan sulphate) in both hemispheres of the MPS IIIA brain and cervical spinal cord, as determined using tandem mass spectrometry. Immunohistochemistry indicated a reduction in secondarily stored GM 3 ganglioside and neuroinflammatory markers. A bias towards the infusion side was seen in some, but not all outcomes. The recombinant enzyme appears stable under pump-like conditions for at least 1 month. Given that infusion pumps are in clinical use in other nervous system disorders, e.g. for treatment of spasticity or brain tumours, this treatment method warrants consideration for testing in large animal models of MPS IIIA and other lysosomal storage disorders that affect the brain. Clinical trials of repeated injection of replacement enzyme into CSF are underway in patients with the inherited neurodegenerative disorder mucopolysaccharidosis type IIIA. In this pre-clinical study, we examined an alternative approach - slow, continual infusion

  4. Autophagy in astrocytes: a novel culprit in lysosomal storage disorders.

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    Di Malta, Chiara; Fryer, John D; Settembre, Carmine; Ballabio, Andrea

    2012-12-01

    Neurodegeneration is a prominent feature of lysosomal storage disorders (LSDs). Emerging data identify autophagy dysfunction in neurons as a major component of the phenotype. However, the autophagy pathway in the CNS has been studied predominantly in neurons, whereas in other cell types it has been largely unexplored. We studied the lysosome-autophagic pathway in astrocytes from a murine model of multiple sulfatase deficiency (MSD), a severe form of LSD. Similar to what was observed in neurons, we found that lysosomal storage in astrocytes impairs autophagosome maturation and this, in turn, has an impact upon the survival of cortical neurons and accounts for some of the neurological features found in MSD. Thus, our data indicate that lysosomal/autophagic dysfunction in astrocytes is an important component of neurodegeneration in LSDs.

  5. Disease pathogenesis explained by basic science: lysosomal storage diseases as autophagocytic disorders.

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    Ballabio, A

    2009-01-01

    Lysosomal storage diseases (LSDs) are characterized by intra-lysosomal accumulation of undegraded metabolites due to the defective activity of lysosomal enzymes. There is a paucity of data, however, relating to the mechanisms that link this accumulation with disease pathology. Several LSDs can be attributed to deficiencies in the activity of sulfatase enzymes. The gene responsible for the post-translational modification that activates sulfatases, sulfatase modifying factor 1 (SUMF1), is defective in the rare autosomal recessive disorder multiple sulfatase deficiency (MSD). A mouse model of MSD (Sumf1 knockout mouse) exhibits a similar phenotype to patients with MSD, with marked lysosomal storage of undegraded metabolites, and increased expression of inflammatory markers and apoptotic markers. Investigation of disease pathology in mouse models of two LSDs (MSD and mucopolysaccharidosis (MPS) Type IIIA) has revealed an increased number of autophagosomes in these animals compared with wild-type mice. This appears to result from impaired autophagosome-lysosome fusion, which may in turn lead to an absence of autophagy. The suggestion that LSDs can be defined as disorders of autophagy implies that there may be some overlap between pathological mechanisms of LSDs and more common neurodegenerative diseases, and this may help provide direction for future therapeutic strategies.

  6. Frontotemporal dementia caused by CHMP2B mutation is characterised by neuronal lysosomal storage pathology

    DEFF Research Database (Denmark)

    Clayton, Emma L.; Mizielinska, Sarah; Edgar, James R.

    2015-01-01

    in human CHMP2B mutation brain than in neurodegenerative disease or age-matched control brains. These data suggest that lysosomal storage pathology is the major neuronal pathology in FTD caused by CHMP2B mutation. Recent evidence suggests that two other genes associated with FTD, GRN and TMEM106B......Mutations in the charged multivesicular body protein 2B (CHMP2B) cause frontotemporal dementia (FTD). We report that mice which express FTD-causative mutant CHMP2B at physiological levels develop a novel lysosomal storage pathology characterised by large neuronal autofluorescent aggregates....... The aggregates are an early and progressive pathology that occur at 3 months of age and increase in both size and number over time. These autofluorescent aggregates are not observed in mice expressing wild-type CHMP2B, or in non-transgenic controls, indicating that they are a specific pathology caused by mutant...

  7. The frequency of lysosomal storage diseases in The Netherlands

    NARCIS (Netherlands)

    Poorthuis, BJHM; Wevers, RA; Kleijer, WJ; Groener, JEM; de Jong, JGN; van Weely, S; Niezen-Koning, KE; van Diggelen, OP

    1999-01-01

    We have calculated the relative frequency and the birth prevalence of lysosomal storage diseases (LSDs) in The Netherlands based on all 963 enzymatically confirmed cases diagnosed during the period 1970-1996. The combined birth prevalence for all LSDs is 14 per 100,000 live births. Glycogenosis type

  8. Newborn Screening for Lysosomal Storage Disorders in Belgium

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    Francois Eyskens MD, PhD

    2017-11-01

    Full Text Available Lysosomal storage disorders (LSDs are a group of metabolic disorders with various clinical presentations, which complicate diagnosis. A pilot study was performed to test the appropriateness and effectiveness of the newborn screening method for Pompe disease, Fabry disease and mucopolysaccharidosis (MPS I in dried blood spots using liquid chromatography–tandem mass spectrometry. Around 20 000 newborn samples were analyzed for 3 lysosomal enzyme activities: α-glucosidase (deficient in Pompe disease, α-galactosidase (deficient in Fabry disease and α-iduronidase (IDUA, deficient in MPS I. Data were used for statistical analysis and to establish sex- and age-dependent reference ranges. Statistically significant higher α-glucosidase, α-galactosidase, and IDUA enzyme activities were observed in female newborns compared to male newborns. Newborns with a higher gestational age have a statistically significant lower α-glucosidase, α-galactosidase, and IDUA enzyme activities compared to newborns with a lower gestational age. For the first time, the data of a large-scale LSD study were used to assess statistical differences in enzyme activity in the newborn population, and these data highlight the importance of using reference intervals for lysosomal enzyme activities in function of sex and gestational age.

  9. Inherited lysosomal storage disease in an English springer spaniel.

    Science.gov (United States)

    Keller, C B; Lamarre, J

    1992-01-15

    Alpha-L-fucosidosis was diagnosed in a 17-month-old English Springer Spaniel with a history of slow development and progressive visual impairment. Lymphocytes and mononuclear cells with vacuolated cytoplasm were seen in a blood smear and in CSF, respectively. A severe deficiency of alpha-L-fucosidase activities in plasma and leukocytes was determined. Histologic examination revealed vacuolation of neurons, macrophages, and epithelial cells in most organ tissues. Canine fucosidosis is a progressive and fatal lysosomal storage disease in English Springer Spaniels. Affected dogs develop a neurologic disorder characterized by progressive motor and mental deterioration. Visual impairment is an unusual primary sign in a dog with alpha-L-fucosidosis.

  10. Biochemical and molecular characterization of novel mutations in GLB1 and NEU1 in patient cells with lysosomal storage disorders.

    Science.gov (United States)

    Kwak, Jae Eun; Son, Mi-Young; Son, Ye Seul; Son, Myung Jin; Cho, Yee Sook

    2015-02-20

    Lysosomes are cytoplasmic compartments that contain many acid hydrolases and play critical roles in the metabolism of a wide range of macromolecules. Deficiencies in lysosomal enzyme activities cause genetic diseases, called lysosomal storage disorders (LSDs). Many mutations have been identified in the genes responsible for LSDs, and the identification of mutations is required for the accurate molecular diagnoses. Here, we analyzed cell lines that were derived from two different LSDs, GM1 gangliosidosis and sialidosis. GM1 gangliosidosis is caused by mutations in the GLB1 gene that encodes β-galactosidase. A lack of β-galactosidase activity leads to the massive accumulation of GM1 ganglioside, which results in neurodegenerative pathology. Mutations in the NEU1 gene that encodes lysosomal sialidase cause sialidosis. Insufficient activity of lysosomal sialidase progressively increases the accumulation of sialylated molecules, and various clinical symptoms, including mental retardation, appear. We sequenced the entire coding regions of GLB1 and NEU1 in GM1 gangliosidosis and sialidosis patient cells, respectively. We found the novel mutations p.E186A in GLB1 and p.R347Q in NEU1, as well as many other mutations that have been previously reported. We also demonstrated that patient cells containing the novel mutations showed the molecular phenotypes of the corresponding disease. Further structural analysis suggested that these novel mutation sites are highly conserved and important for enzyme activity. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. From Lysosomal Storage Diseases to NKT Cell Activation and Back.

    Science.gov (United States)

    Pereira, Cátia S; Ribeiro, Helena; Macedo, M Fatima

    2017-02-25

    Lysosomal storage diseases (LSDs) are inherited metabolic disorders characterized by the accumulation of different types of substrates in the lysosome. With a multisystemic involvement, LSDs often present a very broad clinical spectrum. In many LSDs, alterations of the immune system were described. Special emphasis was given to Natural Killer T (NKT) cells, a population of lipid-specific T cells that is activated by lipid antigens bound to CD1d (cluster of differentiation 1 d) molecules at the surface of antigen-presenting cells. These cells have important functions in cancer, infection, and autoimmunity and were altered in a variety of LSDs' mouse models. In some cases, the observed decrease was attributed to defects in either lipid antigen availability, trafficking, processing, or loading in CD1d. Here, we review the current knowledge about NKT cells in the context of LSDs, including the alterations detected, the proposed mechanisms to explain these defects, and the relevance of these findings for disease pathology. Furthermore, the effect of enzyme replacement therapy on NKT cells is also discussed.

  12. From Lysosomal Storage Diseases to NKT Cell Activation and Back

    Directory of Open Access Journals (Sweden)

    Cátia S. Pereira

    2017-02-01

    Full Text Available Lysosomal storage diseases (LSDs are inherited metabolic disorders characterized by the accumulation of different types of substrates in the lysosome. With a multisystemic involvement, LSDs often present a very broad clinical spectrum. In many LSDs, alterations of the immune system were described. Special emphasis was given to Natural Killer T (NKT cells, a population of lipid-specific T cells that is activated by lipid antigens bound to CD1d (cluster of differentiation 1 d molecules at the surface of antigen-presenting cells. These cells have important functions in cancer, infection, and autoimmunity and were altered in a variety of LSDs’ mouse models. In some cases, the observed decrease was attributed to defects in either lipid antigen availability, trafficking, processing, or loading in CD1d. Here, we review the current knowledge about NKT cells in the context of LSDs, including the alterations detected, the proposed mechanisms to explain these defects, and the relevance of these findings for disease pathology. Furthermore, the effect of enzyme replacement therapy on NKT cells is also discussed.

  13. mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases

    Science.gov (United States)

    Palmieri, Michela; Pal, Rituraj; Nelvagal, Hemanth R.; Lotfi, Parisa; Stinnett, Gary R.; Seymour, Michelle L.; Chaudhury, Arindam; Bajaj, Lakshya; Bondar, Vitaliy V.; Bremner, Laura; Saleem, Usama; Tse, Dennis Y.; Sanagasetti, Deepthi; Wu, Samuel M.; Neilson, Joel R.; Pereira, Fred A.; Pautler, Robia G.; Rodney, George G.; Cooper, Jonathan D.; Sardiello, Marco

    2017-01-01

    Neurodegenerative diseases characterized by aberrant accumulation of undigested cellular components represent unmet medical conditions for which the identification of actionable targets is urgently needed. Here we identify a pharmacologically actionable pathway that controls cellular clearance via Akt modulation of transcription factor EB (TFEB), a master regulator of lysosomal pathways. We show that Akt phosphorylates TFEB at Ser467 and represses TFEB nuclear translocation independently of mechanistic target of rapamycin complex 1 (mTORC1), a known TFEB inhibitor. The autophagy enhancer trehalose activates TFEB by diminishing Akt activity. Administration of trehalose to a mouse model of Batten disease, a prototypical neurodegenerative disease presenting with intralysosomal storage, enhances clearance of proteolipid aggregates, reduces neuropathology and prolongs survival of diseased mice. Pharmacological inhibition of Akt promotes cellular clearance in cells from patients with a variety of lysosomal diseases, thus suggesting broad applicability of this approach. These findings open new perspectives for the clinical translation of TFEB-mediated enhancement of cellular clearance in neurodegenerative storage diseases. PMID:28165011

  14. Less Is More: Substrate Reduction Therapy for Lysosomal Storage Disorders

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    Maria Francisca Coutinho

    2016-07-01

    Full Text Available Lysosomal storage diseases (LSDs are a group of rare, life-threatening genetic disorders, usually caused by a dysfunction in one of the many enzymes responsible for intralysosomal digestion. Even though no cure is available for any LSD, a few treatment strategies do exist. Traditionally, efforts have been mainly targeting the functional loss of the enzyme, by injection of a recombinant formulation, in a process called enzyme replacement therapy (ERT, with no impact on neuropathology. This ineffectiveness, together with its high cost and lifelong dependence is amongst the main reasons why additional therapeutic approaches are being (and have to be investigated: chaperone therapy; gene enhancement; gene therapy; and, alternatively, substrate reduction therapy (SRT, whose aim is to prevent storage not by correcting the original enzymatic defect but, instead, by decreasing the levels of biosynthesis of the accumulating substrate(s. Here we review the concept of substrate reduction, highlighting the major breakthroughs in the field and discussing the future of SRT, not only as a monotherapy but also, especially, as complementary approach for LSDs.

  15. A non-conserved miRNA regulates lysosomal function and impacts on a human lysosomal storage disorder

    DEFF Research Database (Denmark)

    Frankel, Lisa B; Di Malta, Chiara; Wen, Jiayu

    2014-01-01

    Sulfatases are key enzymatic regulators of sulfate homeostasis with several biological functions including degradation of glycosaminoglycans (GAGs) and other macromolecules in lysosomes. In a severe lysosomal storage disorder, multiple sulfatase deficiency (MSD), global sulfatase activity...... is deficient due to mutations in the sulfatase-modifying factor 1 (SUMF1) gene, encoding the essential activator of all sulfatases. We identify a novel regulatory layer of sulfate metabolism mediated by a microRNA. miR-95 depletes SUMF1 protein levels and suppresses sulfatase activity, causing the disruption...... of proteoglycan catabolism and lysosomal function. This blocks autophagy-mediated degradation, causing cytoplasmic accumulation of autophagosomes and autophagic substrates. By targeting miR-95 in cells from MSD patients, we can effectively increase residual SUMF1 expression, allowing for reactivation of sulfatase...

  16. Lipid Storage Disorders Block Lysosomal Trafficking By Inhibiting TRP Channel and Calcium Release

    Science.gov (United States)

    Shen, Dongbiao; Wang, Xiang; Li, Xinran; Zhang, Xiaoli; Yao, Zepeng; Dibble, Shannon; Dong, Xian-ping; Yu, Ting; Lieberman, Andrew P.; Showalter, Hollis D.; Xu, Haoxing

    2012-01-01

    Lysosomal lipid accumulation, defects in membrane trafficking, and altered Ca2+ homeostasis are common features in many lysosomal storage diseases. Mucolipin TRP channel 1 (TRPML1) is the principle Ca2+ channel in the lysosome. Here we show that TRPML1-mediated lysosomal Ca2+ release, measured using a genetically-encoded Ca2+ indicator (GCaMP3) attached directly to TRPML1 and elicited by a potent membrane-permeable synthetic agonist, is dramatically reduced in Niemann-Pick (NP) disease cells. Sphingomyelins (SMs) are plasma membrane lipids that undergo Sphingomyelinase (SMase)-mediated hydrolysis in the lysosomes of normal cells, but accumulate distinctively in NP cell lysosomes. Patch-clamp analyses revealed that TRPML1 channel activity is inhibited by SMs, but potentiated by SMases. In NP type C (NPC) cells, increasing TRPML1’s expression/activity was sufficient to correct the trafficking defects and reduce lysosome storage and cholesterol accumulation. We propose that abnormal accumulation of luminal lipids causes secondary lysosome storage by blocking TRPML1- and Ca2+-dependent lysosomal trafficking. PMID:22415822

  17. Lipid Storage Disorders Block Lysosomal Trafficking By Inhibiting TRP Channel and Calcium Release

    OpenAIRE

    Shen, Dongbiao; Wang, Xiang; Li, Xinran; Zhang, Xiaoli; Yao, Zepeng; Dibble, Shannon; Dong, Xian-Ping; Yu, Ting; Lieberman, Andrew P.; Showalter, Hollis D.; Xu, Haoxing

    2012-01-01

    Lysosomal lipid accumulation, defects in membrane trafficking, and altered Ca2+ homeostasis are common features in many lysosomal storage diseases. Mucolipin TRP channel 1 (TRPML1) is the principle Ca2+ channel in the lysosome. Here we show that TRPML1-mediated lysosomal Ca2+ release, measured using a genetically-encoded Ca2+ indicator (GCaMP3) attached directly to TRPML1 and elicited by a potent membrane-permeable synthetic agonist, is dramatically reduced in Niemann-Pick (NP) disease cells....

  18. Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders

    NARCIS (Netherlands)

    Ferraz, Maria J.; Marques, André R. A.; Gaspar, Paulo; Mirzaian, Mina; van Roomen, Cindy; Ottenhoff, Roelof; Alfonso, Pilar; Irún, Pilar; Giraldo, Pilar; Wisse, Patrick; Sá Miranda, Clara; Overkleeft, Herman S.; Aerts, Johannes M.

    2016-01-01

    In lysosomal glycosphingolipid storage disorders, marked elevations in corresponding glycosphingoid bases (lyso-glycosphingolipids) have been reported, such as galactosylsphingosine in Krabbe disease, glucosylsphingosine in Gaucher disease and globotriaosylsphingosine in Fabry disease. Using

  19. Fusion of lysosomes with secretory organelles leads to uncontrolled exocytosis in the lysosomal storage disease mucolipidosis type IV.

    Science.gov (United States)

    Park, Soonhong; Ahuja, Malini; Kim, Min Seuk; Brailoiu, G Cristina; Jha, Archana; Zeng, Mei; Baydyuk, Maryna; Wu, Ling-Gang; Wassif, Christopher A; Porter, Forbes D; Zerfas, Patricia M; Eckhaus, Michael A; Brailoiu, Eugen; Shin, Dong Min; Muallem, Shmuel

    2016-02-01

    Mutations in TRPML1 cause the lysosomal storage disease mucolipidosis type IV (MLIV). The role of TRPML1 in cell function and how the mutations cause the disease are not well understood. Most studies focus on the role of TRPML1 in constitutive membrane trafficking to and from the lysosomes. However, this cannot explain impaired neuromuscular and secretory cells' functions that mediate regulated exocytosis. Here, we analyzed several forms of regulated exocytosis in a mouse model of MLIV and, opposite to expectations, we found enhanced exocytosis in secretory glands due to enlargement of secretory granules in part due to fusion with lysosomes. Preliminary exploration of synaptic vesicle size, spontaneous mEPSCs, and glutamate secretion in neurons provided further evidence for enhanced exocytosis that was rescued by re-expression of TRPML1 in neurons. These features were not observed in Niemann-Pick type C1. These findings suggest that TRPML1 may guard against pathological fusion of lysosomes with secretory organelles and suggest a new approach toward developing treatment for MLIV. © 2015 The Authors.

  20. Characterization of Drosophila Saposin-related mutants as a model for lysosomal sphingolipid storage diseases

    Directory of Open Access Journals (Sweden)

    Julia Sellin

    2017-06-01

    Full Text Available Sphingolipidoses are inherited diseases belonging to the class of lysosomal storage diseases (LSDs, which are characterized by the accumulation of indigestible material in the lysosome caused by specific defects in the lysosomal degradation machinery. While some LSDs can be efficiently treated by enzyme replacement therapy (ERT, this is not possible if the nervous system is affected due to the presence of the blood-brain barrier. Sphingolipidoses in particular often present as severe, untreatable forms of LSDs with massive sphingolipid and membrane accumulation in lysosomes, neurodegeneration and very short life expectancy. The digestion of intralumenal membranes within lysosomes is facilitated by lysosomal sphingolipid activator proteins (saposins, which are cleaved from a prosaposin precursor. Prosaposin mutations cause some of the severest forms of sphingolipidoses, and are associated with perinatal lethality in mice, hampering studies on disease progression. We identify the Drosophila prosaposin orthologue Saposin-related (Sap-r as a key regulator of lysosomal lipid homeostasis in the fly. Its mutation leads to a typical spingolipidosis phenotype with an enlarged endolysosomal compartment and sphingolipid accumulation as shown by mass spectrometry and thin layer chromatography. Sap-r mutants show reduced viability with ∼50% survival to adulthood, allowing us to study progressive neurodegeneration and analyze their lipid profile in young and aged flies. Additionally, we observe a defect in sterol homeostasis with local sterol depletion at the plasma membrane. Furthermore, we find that autophagy is increased, resulting in the accumulation of mitochondria in lysosomes, concomitant with increased oxidative stress. Together, we establish Drosophila Sap-r mutants as a lysosomal storage disease model suitable for studying the age-dependent progression of lysosomal dysfunction associated with lipid accumulation and the resulting pathological

  1. A non-conserved miRNA regulates lysosomal function and impacts on a human lysosomal storage disorder.

    Science.gov (United States)

    Frankel, Lisa B; Di Malta, Chiara; Wen, Jiayu; Eskelinen, Eeva-Liisa; Ballabio, Andrea; Lund, Anders H

    2014-12-19

    Sulfatases are key enzymatic regulators of sulfate homeostasis with several biological functions including degradation of glycosaminoglycans (GAGs) and other macromolecules in lysosomes. In a severe lysosomal storage disorder, multiple sulfatase deficiency (MSD), global sulfatase activity is deficient due to mutations in the sulfatase-modifying factor 1 (SUMF1) gene, encoding the essential activator of all sulfatases. We identify a novel regulatory layer of sulfate metabolism mediated by a microRNA. miR-95 depletes SUMF1 protein levels and suppresses sulfatase activity, causing the disruption of proteoglycan catabolism and lysosomal function. This blocks autophagy-mediated degradation, causing cytoplasmic accumulation of autophagosomes and autophagic substrates. By targeting miR-95 in cells from MSD patients, we can effectively increase residual SUMF1 expression, allowing for reactivation of sulfatase activity and increased clearance of sulfated GAGs. The identification of this regulatory mechanism opens the opportunity for a unique therapeutic approach in MSD patients where the need for exogenous enzyme replacement is circumvented.

  2. Amyloidosis, synucleinopathy, and prion encephalopathy in a neuropathic lysosomal storage disease: the CNS-biomarker potential of peripheral blood.

    Directory of Open Access Journals (Sweden)

    Bartholomew J Naughton

    Full Text Available Mucopolysaccharidosis (MPS IIIB is a devastating neuropathic lysosomal storage disease with complex pathology. This study identifies molecular signatures in peripheral blood that may be relevant to MPS IIIB pathogenesis using a mouse model. Genome-wide gene expression microarrays on pooled RNAs showed dysregulation of 2,802 transcripts in blood from MPS IIIB mice, reflecting pathological complexity of MPS IIIB, encompassing virtually all previously reported and as yet unexplored disease aspects. Importantly, many of the dysregulated genes are reported to be tissue-specific. Further analyses of multiple genes linked to major pathways of neurodegeneration demonstrated a strong brain-blood correlation in amyloidosis and synucleinopathy in MPS IIIB. We also detected prion protein (Prnp deposition in the CNS and Prnp dysregulation in the blood in MPS IIIB mice, suggesting the involvement of Prnp aggregation in neuropathology. Systemic delivery of trans-BBB-neurotropic rAAV9-hNAGLU vector mediated not only efficient restoration of functional α-N-acetylglucosaminidase and clearance of lysosomal storage pathology in the central nervous system (CNS and periphery, but also the correction of impaired neurodegenerative molecular pathways in the brain and blood. Our data suggest that molecular changes in blood may reflect pathological status in the CNS and provide a useful tool for identifying potential CNS-specific biomarkers for MPS IIIB and possibly other neurological diseases.

  3. Cell microencapsulation: a potential tool for the treatment of neuronopathic lysosomal storage diseases.

    Science.gov (United States)

    Matte, Ursula; Lagranha, Valeska Lizzi; de Carvalho, Talita Giacomet; Mayer, Fabiana Quoos; Giugliani, Roberto

    2011-10-01

    Lysosomal storage disorders (LSD) are monogenic diseases caused by the deficiency of different lysosomal enzymes that degrade complex substrates such as glycosaminoglycans, sphingolipids, and others. As a consequence there is multisystemic storage of these substrates. Most treatments for these disorders are based in the fact that most of these enzymes are soluble and can be internalized by adjacent cells via mannose-6-phosphate receptor. In that sense, these disorders are good candidates to be treated by somatic gene therapy based on cell microencapsulation. Here, we review the existing data about this approach focused on the LSD treatments, the advantages and limitations faced by these studies.

  4. Excessive burden of lysosomal storage disorder gene variants in Parkinson's disease.

    Science.gov (United States)

    Robak, Laurie A; Jansen, Iris E; van Rooij, Jeroen; Uitterlinden, André G; Kraaij, Robert; Jankovic, Joseph; Heutink, Peter; Shulman, Joshua M

    2017-12-01

    Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson's disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson's disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson's disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson's disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson's disease susceptibility genes. In our discovery cohort, the majority of Parkinson's disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson's disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson's disease susceptibility. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  5. Novel patient cell-based HTS assay for identification of small molecules for a lysosomal storage disease.

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    Haifeng Geng

    Full Text Available Small molecules have been identified as potential therapeutic agents for lysosomal storage diseases (LSDs, inherited metabolic disorders caused by defects in proteins that result in lysosome dysfunctional. Some small molecules function assisting the folding of mutant misfolded lysosomal enzymes that are otherwise degraded in ER-associated degradation. The ultimate result is the enhancement of the residual enzymatic activity of the deficient enzyme. Most of the high throughput screening (HTS assays developed to identify these molecules are single-target biochemical assays. Here we describe a cell-based assay using patient cell lines to identify small molecules that enhance the residual arylsulfatase A (ASA activity found in patients with metachromatic leukodystrophy (MLD, a progressive neurodegenerative LSD. In order to generate sufficient cell lines for a large scale HTS, primary cultured fibroblasts from MLD patients were transformed using SV40 large T antigen. These SV40 transformed (SV40t cells showed to conserve biochemical characteristics of the primary cells. Using a specific colorimetric substrate para-nitrocatechol sulfate (pNCS, detectable ASA residual activity were observed in primary and SV40t fibroblasts from a MLD patient (ASA-I179S cultured in multi-well plates. A robust fluorescence ASA assay was developed in high-density 1,536-well plates using the traditional colorimetric pNCS substrate, whose product (pNC acts as "plate fluorescence quencher" in white solid-bottom plates. The quantitative cell-based HTS assay for ASA generated strong statistical parameters when tested against a diverse small molecule collection. This cell-based assay approach can be used for several other LSDs and genetic disorders, especially those that rely on colorimetric substrates which traditionally present low sensitivity for assay-miniaturization. In addition, the quantitative cell-based HTS assay here developed using patient cells creates an

  6. Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of non-lysosomal proteins.

    Science.gov (United States)

    Dierks, Thomas; Schlotawa, Lars; Frese, Marc-André; Radhakrishnan, Karthikeyan; von Figura, Kurt; Schmidt, Bernhard

    2009-04-01

    Multiple sulfatase deficiency (MSD), mucolipidosis (ML) II/III and Niemann-Pick type C1 (NPC1) disease are rare but fatal lysosomal storage disorders caused by the genetic defect of non-lysosomal proteins. The NPC1 protein mainly localizes to late endosomes and is essential for cholesterol redistribution from endocytosed LDL to cellular membranes. NPC1 deficiency leads to lysosomal accumulation of a broad range of lipids. The precise functional mechanism of this membrane protein, however, remains puzzling. ML II, also termed I cell disease, and the less severe ML III result from deficiencies of the Golgi enzyme N-acetylglucosamine 1-phosphotransferase leading to a global defect of lysosome biogenesis. In patient cells, newly synthesized lysosomal proteins are not equipped with the critical lysosomal trafficking marker mannose 6-phosphate, thus escaping from lysosomal sorting at the trans Golgi network. MSD affects the entire sulfatase family, at least seven members of which are lysosomal enzymes that are specifically involved in the degradation of sulfated glycosaminoglycans, sulfolipids or other sulfated molecules. The combined deficiencies of all sulfatases result from a defective post-translational modification by the ER-localized formylglycine-generating enzyme (FGE), which oxidizes a specific cysteine residue to formylglycine, the catalytic residue enabling a unique mechanism of sulfate ester hydrolysis. This review gives an update on the molecular bases of these enigmatic diseases, which have been challenging researchers since many decades and so far led to a number of surprising findings that give deeper insight into both the cell biology and the pathobiochemistry underlying these complex disorders. In case of MSD, considerable progress has been made in recent years towards an understanding of disease-causing FGE mutations. First approaches to link molecular parameters with clinical manifestation have been described and even therapeutical options have been

  7. Presumptive Spontaneous Lysosomal Storage-Like Disease in a Crl:CD1(ICR) Mouse.

    Science.gov (United States)

    Hernon, Krista M; Whitcomb, Tiffany L; Davis, Lori; Cooper, Timothy K

    2017-02-01

    A clinically unremarkable 4.5-mo-old female Crl:CD1(ICR) VAF/Elite mouse was euthanized for scheduled sentinel processing. Gross necropsy findings included significant hepatosplenomegaly and visceral lymphadenomegaly, resulting in a preliminary gross diagnosis of lymphoma. Histology revealed florid accumulations of large, 'foamy' macrophages present in the bone marrow, small intestines, and viscera including liver, spleen, lymph nodes, thymus, uterus, and ovaries. The cytoplasm of these cells was abundant, stained pale blue with Wright-Giemsa and was periodic acid-Schiff positive. Given these characteristic gross and histologic findings, a spontaneous lysosomal storage-like disease was diagnosed in this mouse. Cholesterol ester storage disease is likely, because of the visceral involvement with sparing of the CNS, but could not be diagnosed definitively. To our knowledge, this report is the first to describe a case of spontaneous lysosomal storage disease in an outbred mouse of the CD1(ICR) background.

  8. A lysosomal storage disease induced by Ipomoea carnea in goats in Mozambique.

    Science.gov (United States)

    de Balogh, K K; Dimande, A P; van der Lugt, J J; Molyneux, R J; Naudé, T W; Welman, W G

    1999-05-01

    A novel plant-induced lysosomal storage disease was observed in goats from a village in Mozambique. Affected animals were ataxic, with head tremors and nystagmus. Because of a lack of suitable feed, the animals consumed an exotic hedge plant growing in the village that was identified as Ipomoea carnea (shrubby morning glory, Convolvulaceae). The toxicosis was reproduced by feeding I. carnea plant material to goats. In acute cases, histologic changes in the brain and spinal cord comprised widespread cytoplasmic vacuolation of neurons and glial cells in association with axonal spheroid formation. Ultrastructurally, cytoplasmic storage vacuoles in neurons were membrane bound and consistent with lysosomes. Cytoplasmic vacuolation was also found in neurons in the submucosal and mesenteric plexuses in the small intestine, in renal tubular epithelial cells, and in macrophage-phagocytic cells in the spleen and lymph nodes in acute cases. Residual alterations in the brain in chronic cases revealed predominantly cerebellar lesions characterized by loss of Purkinje neurons and gliosis of the Purkinje cell layer. Analysis of I. carnea plant material by gas chromatography-mass spectrometry established the presence of the mannosidase inhibitor swainsonine and 2 glycosidase inhibitors, calystegine B2 and calystegine C1, consistent with a plant-induced alpha-mannosidosis in the goats. The described storage disorder is analogous to the lysosomal storage diseases induced by ingestion of locoweeds (Astragalus and Oxytropis) and poison peas (Swainsona).

  9. Lysosomal storage disease in two presumed-related springboks (Antidorcas marsupialis).

    Science.gov (United States)

    Laurent, Sébastien; Sabot, Anne-Sophie; Colle, Marie-Anne; Nicolier, Alexandra

    2010-03-01

    In April 2007, two newborn springboks (Antidorcas marsupialis) from a zoo of southern France were found dead. Necropsy was performed on the two animals and revealed arthrogryposis, mild facial structural abnormalities, and bilateral enlargement of the kidneys with concurrent hydronephrosis in both newborns. Histopathologically, extensive cytoplasmic vacuolation of neurons in the central nervous system, thyroid follicular epithelium, renal tubular epithelium, enterocytes, hepatocytes, and ruminal epithelial cells was the most remarkable lesion in both animals. By electron microscopy, the vacuoles were membrane bound and contained scattered membranous and granular material within a primarily electron-lucent background. Hence, a diagnosis of lysosomal storage disease was established, with gross, histological, and ultrastructural features suggestive of an inherited form of mannosidosis. This report documents the first case of lysosomal storage disease in springboks.

  10. Chronic intestinal pseudo-obstruction. Did you search for lysosomal storage diseases?

    OpenAIRE

    Politei, J.; Durand, C; Schenone, A.B.; Torres, A.; Mukdsi, J.; Thurberg, B.L.

    2017-01-01

    Chronic intestinal pseudo-obstruction results in clinical manifestations that resemble intestinal obstruction but in the absence of any physical obstructive process. Fabry disease is an X-linked lysosomal storage disease characterized by the dysfunction of multiple systems, including significant gastrointestinal involvement. We report the occurrence of chronic intestinal pseudo-obstruction in two unrelated patients with Fabry disease and the possible explanation of a direct relation of these ...

  11. Analysis of urinary oligosaccharides in lysosomal storage disorders by capillary high-performance anion-exchange chromatography-mass spectrometry

    NARCIS (Netherlands)

    Bruggink, Cees; Poorthuis, Ben J. H. M.; Deelder, André M.; Wuhrer, Manfred

    2012-01-01

    Many lysosomal storage diseases are characterized by an increased urinary excretion of glycoconjugates and oligosaccharides that are characteristic for the underlying enzymatic defect. Here, we have used capillary high-performance anion-exchange chromatography (HPAEC) hyphenated to mass spectrometry

  12. Lipid metabolic perturbation is an early-onset phenotype in adult spinster mutants: a Drosophila model for lysosomal storage disorders.

    Science.gov (United States)

    Hebbar, Sarita; Khandelwal, Avinash; Jayashree, R; Hindle, Samantha J; Chiang, Yin Ning; Yew, Joanne Y; Sweeney, Sean T; Schwudke, Dominik

    2017-12-15

    Intracellular accumulation of lipids and swollen dysfunctional lysosomes are linked to several neurodegenerative diseases, including lysosomal storage disorders (LSD). Detailed characterization of lipid metabolic changes in relation to the onset and progression of neurodegeneration is currently missing. We systematically analyzed lipid perturbations in spinster (spin) mutants, a Drosophila model of LSD-like neurodegeneration. Our results highlight an imbalance in brain ceramide and sphingosine in the early stages of neurodegeneration, preceding the accumulation of endomembranous structures, manifestation of altered behavior, and buildup of lipofuscin. Manipulating levels of ceramidase and altering these lipids in spin mutants allowed us to conclude that ceramide homeostasis is the driving force in disease progression and is integral to spin function in the adult nervous system. We identified 29 novel physical interaction partners of Spin and focused on the lipid carrier protein, Lipophorin (Lpp). A subset of Lpp and Spin colocalize in the brain and within organs specialized for lipid metabolism (fat bodies and oenocytes). Reduced Lpp protein was observed in spin mutant tissues. Finally, increased levels of lipid metabolites produced by oenocytes in spin mutants allude to a functional interaction between Spin and Lpp, underscoring the systemic nature of lipid perturbation in LSD. © 2017 Hebbar et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

  13. Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain.

    Science.gov (United States)

    Snyder, E Y; Taylor, R M; Wolfe, J H

    1995-03-23

    Many metabolic diseases affecting the central nervous system are refractory to treatment because the blood-brain barrier restricts entry of therapeutic molecules. It may be possible to deliver therapeutic gene products directly to the brain by transplantation of neural progenitor cells, which can integrate into the murine central nervous system in a cytoarchitecturally appropriate manner. We tested this approach in mucopolysaccharidosis VII (Sly disease), a lysosomal storage disorder of humans, dogs and mice caused by an inherited deficiency of beta-glucuronidase. Lysosomal accumulation of glycosaminoglycans occurs in the brain and other tissues, causing a fatal progressive degenerative disorder, including mental retardation. Treatments are designed to provide a source of normal enzyme for uptake by diseased cells. We report here that by transplanting beta-glucuronidase-expressing neural progenitors into the cerebral ventricles of newborn mice, donor cells engrafted throughout the neuraxis. At maturity, donor-derived cells were present as normal constituents of diverse brain regions. beta-Glucuronidase activity was expressed along the entire neuraxis, resulting in widespread correction of lysosomal storage in neurons and glia in affected mice.

  14. Neurologic abnormalities in mouse models of the lysosomal storage disorders mucolipidosis II and mucolipidosis III γ.

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    Rachel A Idol

    Full Text Available UDP-GlcNAc:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase is an α2β2γ2 hexameric enzyme that catalyzes the synthesis of the mannose 6-phosphate targeting signal on lysosomal hydrolases. Mutations in the α/β subunit precursor gene cause the severe lysosomal storage disorder mucolipidosis II (ML II or the more moderate mucolipidosis III alpha/beta (ML III α/β, while mutations in the γ subunit gene cause the mildest disorder, mucolipidosis III gamma (ML III γ. Here we report neurologic consequences of mouse models of ML II and ML III γ. The ML II mice have a total loss of acid hydrolase phosphorylation, which results in depletion of acid hydrolases in mesenchymal-derived cells. The ML III γ mice retain partial phosphorylation. However, in both cases, total brain extracts have normal or near normal activity of many acid hydrolases reflecting mannose 6-phosphate-independent lysosomal targeting pathways. While behavioral deficits occur in both models, the onset of these changes occurs sooner and the severity is greater in the ML II mice. The ML II mice undergo progressive neurodegeneration with neuronal loss, astrocytosis, microgliosis and Purkinje cell depletion which was evident at 4 months whereas ML III γ mice have only mild to moderate astrocytosis and microgliosis at 12 months. Both models accumulate the ganglioside GM2, but only ML II mice accumulate fucosylated glycans. We conclude that in spite of active mannose 6-phosphate-independent targeting pathways in the brain, there are cell types that require at least partial phosphorylation function to avoid lysosomal dysfunction and the associated neurodegeneration and behavioral impairments.

  15. AAV-Mediated Gene Delivery in a Feline Model of Sandhoff Disease Corrects Lysosomal Storage in the Central Nervous System

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    Hannah E. Rockwell

    2015-04-01

    Full Text Available Sandhoff disease (SD is an autosomal recessive neurodegenerative disease caused by a mutation in the gene for the β-subunit of β-N-acetylhexosaminidase (Hex, resulting in the inability to catabolize ganglioside GM2 within the lysosomes. SD presents with an accumulation of GM2 and its asialo derivative GA2, primarily in the central nervous system. Myelin-enriched glycolipids, cerebrosides and sulfatides, are also decreased in SD corresponding with dysmyelination. At present, no treatment exists for SD. Previous studies have shown the therapeutic benefit of adeno-associated virus (AAV vector-mediated gene therapy in the treatment of SD in murine and feline models. In this study, we treated presymptomatic SD cats with AAVrh8 vectors expressing feline Hex in the thalamus combined with intracerebroventricular (Thal/ICV injections. Treated animals showed clearly improved neurologic function and quality of life, manifested in part by prevention or attenuation of whole-body tremors characteristic of untreated animals. Hex activity was significantly elevated, whereas storage of GM2 and GA2 was significantly decreased in tissue samples taken from the cortex, cerebellum, thalamus, and cervical spinal cord. Treatment also increased levels of myelin-enriched cerebrosides and sulfatides in the cortex and thalamus. This study demonstrates the therapeutic potential of AAV for feline SD and suggests a similar potential for human SD patients.

  16. Oligosaccharide analysis in urine by maldi-tof mass spectrometry for the diagnosis of lysosomal storage diseases.

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    Xia, Baoyun; Asif, Ghazia; Arthur, Leonard; Pervaiz, Muhammad A; Li, Xueli; Liu, Renpeng; Cummings, Richard D; He, Miao

    2013-09-01

    There are 45 known genetic diseases that impair the lysosomal degradation of macromolecules. The loss of a single lysosomal hydrolase leads to the accumulation of its undegraded substrates in tissues and increases of related glycoconjugates in urine, some of which can be detected by screening of free oligosaccharides (FOS) in urine. Traditional 1-dimensional TLC for urine oligosaccharide analysis has limited analytical specificity and sensitivity. We developed fast and robust urinary FOS and glycoaminoacid analyses by MALDI-time-of-flight/time-of-flight (MALDI-TOF/TOF) mass spectrometry for the diagnosis of oligosaccharidoses and other lysosomal storage diseases. The FOS in urine equivalent to 0.09 mg creatinine were purified through sequential passage over a Sep-Pak C18 column and a carbograph column and were then permethylated. MALDI-TOF/TOF was used to analyze the permethylated FOS. We studied urine samples from individuals in 7 different age groups ranging from 0-1 months to ≥ 17 years as well as urine from known patients with different lysosomal storage diseases. We identified diagnostic urinary FOS patterns for α-mannosidosis, galactosialidosis, mucolipidosis type II/III, sialidosis, α-fucosidosis, aspartylglucosaminuria (AGU), Pompe disease, Gaucher disease, and GM1 and GM2 gangliosidosis. Interestingly, the increase in urinary FOS characteristic of lysosomal storage diseases relative to normal FOS appeared to correlate with the disease severity. The analysis of urinary FOS by MALDI-TOF/TOF is a powerful tool for first-tier screening of oligosaccharidoses and lysosomal storage diseases.

  17. Screening patients referred to a metabolic clinic for lysosomal storage disorders.

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    Fuller, Maria; Tucker, Justin N; Lang, Debbie L; Dean, Caroline J; Fietz, Michael J; Meikle, Peter J; Hopwood, John J

    2011-06-01

    Lysosomal protein profiling is being developed as a high throughput method to screen populations for lysosomal storage disorders (LSD). 1415 blood spots from patients referred to a metabolic clinic for LSD were screened using a single multiplex assay for 14 proteins in a dried blood spot. All patients with Pompe disease, metachromatic leukodystrophy, and mucopolysaccharidosis (MPS) type I, IIIA, IIIB and VI were identified by reduced lysosomal protein. Five samples were identified as possible pseudo-arylsulfatase A deficiency; four were confirmed. One multiple sulfatase deficiency patient was identified with multiple reduced sulfatase proteins. There were 10 MPS II patients identified with reduced iduronate 2-sulfatase, and one MPS II patient with iduronate 2-sulfatase in the unaffected range. For Fabry disease, 10 male patients were identified with reduced α-galactosidase and 2/6 female Fabry heterozygotes returned α-galactosidase concentrations in the male Fabry range. All 10 mucolipidosis II/III patients were identified with multiple raised proteins. For 79 blood spots with chitotriosidase >3.4mg/l, a follow-up one-plex chitotriosidase assay enabled identification of all nine Gaucher patients. This study demonstrates the sensitivity and specificity of this technology to accurately identify 99% of LSD patients, with the exception of one MPS II false negative.

  18. A somatic cell defect is associated with the onset of neurological symptoms in a lysosomal storage disease

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    Rodriguez-Gil, Jorge L.; Larson, Denise M.; Wassif, Christopher A.; Yanjanin, Nicole M.; Anderson, Stacie M.; Kirby, Martha R.; Trivedi, Niraj S.; Porter, Forbes D.; Pavan, William J.

    2013-01-01

    Mutations in individuals with the lysosomal storage disorder Niemann-Pick disease, type C1 (NPC1) are heterogeneous, not localized to specific protein domains, and not correlated to time of onset or disease severity. We demonstrate direct correlation of the time of neurological symptom onset with the severity of lysosomal defects in NPC1 patient-derived fibroblasts. This is a novel assay for NPC1 individuals that may be predictive of NPC1 disease progression and broadly applicable to other lysosomal disorders. PMID:23850077

  19. Differentiation of norm and pathology during selective biochemical skreening of lysosomal storage diseases with increased excretion of oligosaccharides

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    N. Y. Mytsyk

    2015-06-01

    Full Text Available Oligosaccharides are a class of polymeric carbohydrates, which are constituents of a glycoside portion of glycoprotein and glycolipid molecules. The lysosomal hydrolase dysfunction due to lysosomal storage disorders results in partial or complete failure of degradation of some glycoproteins and glycolipids, causing the accumulation of specific undegraded substrates in the lysosomes of cells, the formation of the great number of oligosaccharide chains and their increased excretion with urine. Our work was aimed at detailed study of the specificities of interpreting the results of thin-layer chromatography (TLC of urine oligosaccharides in healthy persons of different age groups with the purpose of further application of these data while differentiating the norm and pathology in the course of primary selective screening of lysosomal storage disorders. The results obtained demonstrated that TLC plates for the majority of healthy persons had insignificant excretion of a number of oligosaccharides (from monosaccharides to hexasaccharides with Rlac > 0.15, which can be characterized as physiological oligosacchariduria, conditioned by the metabolism specificities in lysosomes. Therefore while interpreting the urine samples of patients with the suspected lysosomal storage disorder it is diagnostically reasonable to examine the TLC plates for the presence of both oligosaccharide groups, absent in the samples of healthy persons, and all the fractions with Rlac < 0.15.

  20. Abnormalities in neural progenitor cells in a dog model of lysosomal storage disease.

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    Walton, Raquel M; Wolfe, John H

    2007-08-01

    Lysosomal storage disorders constitute a large group of genetic diseases, many of which are characterized by mental retardation and other neurologic symptoms. The mechanisms of neural dysfunction remain poorly understood. Because neural progenitor cells (NPCs) are fundamentally important to normal brain development and function, we investigated NPC properties in a canine model of mucopolysaccharidosis VII (MPS VII). MPS VII is a lysosomal storage disorder characterized by defects in the catabolism of glycosaminoglycans. NPCs were isolated from the olfactory bulb, cerebellum, and striatal subventricular zone of normal and MPS VII (beta-glucuronidase-deficient) postnatal dog brains. Canine NPCs (cNPCs) from normal and MPS VII brains had similar growth curves, but cerebellar-derived cNPCs grew significantly slower than those derived from other regions. In differentiation assays, MPS VII cNPCs from the striatal subventricular zone and cerebellum generated fewer mature neuronal and/or glial cells than normal, and MPS VII olfactory bulb-derived cNPCs retained significantly more phenotypically immature cells. These differences were only present at the earliest time point after isolation; at later passages, there were no differences attributable to genotype. The data suggest that MPS VII cNPCs respond differently to developmental cues in vivo, probably because of the diseased neural microenvironment rather than intrinsic cellular deficits.

  1. Lysosomal storage disease: gene therapy on both sides of the blood-brain barrier.

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    Aronovich, Elena L; Hackett, Perry B

    2015-02-01

    Most lysosomal storage disorders affect the nervous system as well as other tissues and organs of the body. Previously, the complexities of these diseases, particularly in treating neurologic abnormalities, were too great to surmount. However, based on recent developments there are realistic expectations that effective therapies are coming soon. Gene therapy offers the possibility of affordable, comprehensive treatment associated with these diseases currently not provided by standards of care. With a focus on correction of neurologic disease by systemic gene therapy of mucopolysaccharidoses types I and IIIA, we review some of the major recent advances in viral and non-viral vectors, methods of their delivery and strategies leading to correction of both the nervous and somatic tissues as well as evaluation of functional correction of neurologic manifestations in animal models. We discuss two questions: what systemic gene therapy strategies work best for correction of both somatic and neurologic abnormalities in a lysosomal storage disorder and is there evidence that targeting peripheral tissues (e.g., in the liver) has a future for ameliorating neurologic disease in patients? Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Mucopolysaccharidosis IIIB, a lysosomal storage disease, triggers a pathogenic CNS autoimmune response

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    Popovich Phillip G

    2010-07-01

    Full Text Available Abstract Background Recently, using a mouse model of mucopolysaccharidosis (MPS IIIB, a lysosomal storage disease with severe neurological deterioration, we showed that MPS IIIB neuropathology is accompanied by a robust neuroinflammatory response of unknown consequence. This study was to assess whether MPS IIIB lymphocytes are pathogenic. Methods Lymphocytes from MPS IIIB mice were adoptively transferred to naïve wild-type mice. The recipient animals were then evaluated for signs of disease and inflammation in the central nervous system. Results Our results show for the first time, that lymphocytes isolated from MPS IIIB mice caused a mild paralytic disease when they were injected systemically into naïve wild-type mice. This disease is characterized by mild tail and lower trunk weakness with delayed weight gain. The MPS IIIB lymphocytes also trigger neuroinflammation within the CNS of recipient mice characterized by an increase in transcripts of IL2, IL4, IL5, IL17, TNFα, IFNα and Ifi30, and intraparenchymal lymphocyte infiltration. Conclusions Our data suggest that an autoimmune response directed at CNS components contributes to MPS IIIB neuropathology independent of lysosomal storage pathology. Adoptive transfer of purified T-cells will be needed in future studies to identify specific effector T-cells in MPS IIIB neuroimmune pathogenesis.

  3. Glyco-engineering strategies for the development of therapeutic enzymes with improved efficacy for the treatment of lysosomal storage diseases.

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    Oh, Doo-Byoung

    2015-08-01

    Lysosomal storage diseases (LSDs) are a group of inherent diseases characterized by massive accumulation of undigested compounds in lysosomes, which is caused by genetic defects resulting in the deficiency of a lysosomal hydrolase. Currently, enzyme replacement therapy has been successfully used for treatment of 7 LSDs with 10 approved therapeutic enzymes whereas new approaches such as pharmacological chaperones and gene therapy still await evaluation in clinical trials. While therapeutic enzymes for Gaucher disease have N-glycans with terminal mannose residues for targeting to macrophages, the others require N-glycans containing mannose-6-phosphates that are recognized by mannose-6-phosphate receptors on the plasma membrane for cellular uptake and targeting to lysosomes. Due to the fact that efficient lysosomal delivery of therapeutic enzymes is essential for the clearance of accumulated compounds, the suitable glycan structure and its high content are key factors for efficient therapeutic efficacy. Therefore, glycan remodeling strategies to improve lysosomal targeting and tissue distribution have been highlighted. This review describes the glycan structures that are important for lysosomal targeting and provides information on recent glyco-engineering technologies for the development of therapeutic enzymes with improved efficacy.

  4. Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders.

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    Ferraz, Maria J; Marques, André R A; Gaspar, Paulo; Mirzaian, Mina; van Roomen, Cindy; Ottenhoff, Roelof; Alfonso, Pilar; Irún, Pilar; Giraldo, Pilar; Wisse, Patrick; Sá Miranda, Clara; Overkleeft, Herman S; Aerts, Johannes M

    2016-02-01

    In lysosomal glycosphingolipid storage disorders, marked elevations in corresponding glycosphingoid bases (lyso-glycosphingolipids) have been reported, such as galactosylsphingosine in Krabbe disease, glucosylsphingosine in Gaucher disease and globotriaosylsphingosine in Fabry disease. Using LC–MS/MS, we comparatively investigated the occurrence of abnormal lyso-glycosphingolipids in tissues and plasma of mice with deficiencies in lysosomal α-galactosidase A, glucocerebrosidase and galactocerebrosidase. The nature and specificity of lyso-glycosphingolipid abnormalities are reported and compared to that in correspondingly more abundant N-acylated glycosphingolipids. Specific elevations in tissue and plasma globotriaosylsphingosine were detected in α-galactosidase A-deficient mice; glucosylsphingosine in glucocerebrosidase-deficient mice and galactosylsphingosine in galactocerebrosidase-deficient animals. A similar investigation was conducted for two mouse models of Niemann Pick type C (Npc1nih and Npc1nmf164), revealing significant tissue elevation of several neutral glycosphingolipids and concomitant increased plasma glucosylsphingosine. This latter finding was recapitulated by analysis of plasma of NPC patients. The value of plasma glucosylsphingosine in biochemical confirmation of the diagnosis of NPC is discussed.

  5. The awesome lysosome

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    Ballabio, Andrea

    2016-01-01

    In the early 50s, Christian De Duve identified a new cellular structure, the lysosome, defined as the cell's ?suicide bag? (de Duve, 2005). Sixty years later, it is clear that the lysosome greatly exceeded the expectations of its discoverer. Over 50 different types of lysosomal storage diseases have been identified, each due to the deficiency or malfunction of a specific lysosomal protein. In addition, an important role of the lysosome has been unveiled in several common human diseases, such ...

  6. Exclusion of NEU1 and PPGB from candidate genes for a lysosomal storage disease in Japanese Black cattle.

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    Masoudi, Ali Akbar; Yamato, Osamu; Yoneda, Kazuhiro; Tsuji, Takehito; Mikami, Osamu; Kunieda, Tetsuo

    2009-10-01

    A case of lysosomal storage disease has been reported in a calf of Japanese Black cattle. Lysosomal storage diseases are hereditary diseases caused by deficiency of lysosomal hydrolases. The clinical and pathological features and accumulated substrates of the affected animal indicated a possibility of sialidosis or galactosialidosis caused by deficiency of neuraminidase (NEU1) or protective protein for beta-galactosidase (PPGB). In the present study, we investigated nucleotide sequences of the genes encoding these two proteins to evaluate whether mutation of these genes is involved in this disease. We determined cattle genomic sequences of these two genes by using bovine EST sequences and the nucleotide sequences of all exons of these genes were compared between affected and normal animals. The results showed several nucleotide substitutions, but none of them was a functional mutation or specific to the affected animal. Furthermore, genotyping of the microsatellite markers in the vicinity of these two genes revealed no homozygosity of the chromosomal regions including these genes in the affected animal. These findings indicated that neither NEU1 nor PPGB gene is responsible for the lysosomal storage disease of Japanese Black cattle and therefore the disease is neither sialidosis nor galactosialidosis.

  7. Targeted Polymeric Nanoparticles for Brain Delivery of High Molecular Weight Molecules in Lysosomal Storage Disorders.

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    Marika Salvalaio

    Full Text Available Lysosomal Storage Disorders (LSDs are a group of metabolic syndromes, each one due to the deficit of one lysosomal enzyme. Many LSDs affect most of the organ systems and overall about 75% of the patients present neurological impairment. Enzyme Replacement Therapy, although determining some systemic clinical improvements, is ineffective on the CNS disease, due to enzymes' inability to cross the blood-brain barrier (BBB. With the aim to deliver the therapeutic enzymes across the BBB, we here assayed biodegradable and biocompatible PLGA-nanoparticles (NPs in two murine models for LSDs, Mucopolysaccharidosis type I and II (MPS I and MPS II. PLGA-NPs were modified with a 7-aminoacid glycopeptide (g7, yet demonstrated to be able to deliver low molecular weight (MW molecules across the BBB in rodents. We specifically investigated, for the first time, the g7-NPs ability to transfer a model drug (FITC-albumin with a high MW, comparable to the enzymes to be delivered for LSDs brain therapy. In vivo experiments, conducted on wild-type mice and knockout mouse models for MPS I and II, also included a whole series of control injections to obtain a broad preliminary view of the procedure efficiency. Results clearly showed efficient BBB crossing of albumin in all injected mice, underlying the ability of NPs to deliver high MW molecules to the brain. These results encourage successful experiments with enzyme-loaded g7-NPs to deliver sufficient amounts of the drug to the brain district on LSDs, where exerting a corrective effect on the pathological phenotype.

  8. Chitotriosidase activity as additional biomarker in the diagnosis of lysosomal storage diseases

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    N. V. Olkhovych

    2016-02-01

    Full Text Available To date, several genetic variants that lead to a deficiency of chitotriosidase activity have been described. The duplication of 24 bp (dup24bp in exon 10 of the CHIT1 gene, which causes a complete loss of enzymatic activity of the gene product, is the most common among the European population. The aim of the study was to evaluate the possibility of using chitotriosidase activity as an additional biomarker in diagnosis of lysosomal storage diseases (LSDs in Ukraine, to determine this parameter in blood plasma of the patients with various lysosomal diseases and to assess the effect of the presence of dup24bp in the CHIT1 gene on this parameter. It has been shown that chitotriosidase activity in blood plasma is a convenient additional biochemical marker in the diagnosis of some LSDs, namely Gaucher disease, Niemann-Pick disease A, B, C and GM1-gangliosidosis. Reference ranges of the normal chitotriosidase activity were determined in blood plasma of Ukrainian population and found to be 8.0-53.1 nmol 4-methylumbelliferone/h·ml of plasma. The total allele frequency of the dup24bp in the CHIT1 gene in Ukrainian population was determined, which amounted to 0.26 (323/1244 that is higher than in European population. It was indicated that molecular-genetic screening of dup24bp in the CHIT1 gene is a necessary stage in a protocol for the laboratory diagnosis of Gaucher disease, Niemann-Pick disease A, B, C as well as GM1-gangliosidosis to avoid incorrect diagnosis.

  9. Lysosomal Membrane Permeability Stimulates Protein Aggregate Formation in Neurons of a Lysosomal Disease

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    Micsenyi, Matthew C.; Sikora, Jakub; Stephney, Gloria; Dobrenis, Kostantin

    2013-01-01

    Protein aggregates are a common pathological feature of neurodegenerative diseases and several lysosomal diseases, but it is currently unclear what aggregates represent for pathogenesis. Here we report the accumulation of intraneuronal aggregates containing the macroautophagy adapter proteins p62 and NBR1 in the neurodegenerative lysosomal disease late-infantile neuronal ceroid lipofuscinosis (CLN2 disease). CLN2 disease is caused by a deficiency in the lysosomal enzyme tripeptidyl peptidase I, which results in aberrant lysosomal storage of catabolites, including the subunit c of mitochondrial ATP synthase (SCMAS). In an effort to define the role of aggregates in CLN2, we evaluated p62 and NBR1 accumulation in the CNS of Cln2−/− mice. Although increases in p62 and NBR1 often suggest compromised degradative mechanisms, we found normal ubiquitin–proteasome system function and only modest inefficiency in macroautophagy late in disease. Importantly, we identified that SCMAS colocalizes with p62 in extra-lysosomal aggregates in Cln2−/− neurons in vivo. This finding is consistent with SCMAS being released from lysosomes, an event known as lysosomal membrane permeability (LMP). We predicted that LMP and storage release from lysosomes results in the sequestration of this material as cytosolic aggregates by p62 and NBR1. Notably, LMP induction in primary neuronal cultures generates p62-positive aggregates and promotes p62 localization to lysosomal membranes, supporting our in vivo findings. We conclude that LMP is a previously unrecognized pathogenic event in CLN2 disease that stimulates cytosolic aggregate formation. Furthermore, we offer a novel role for p62 in response to LMP that may be relevant for other diseases exhibiting p62 accumulation. PMID:23804102

  10. Ocular manifestations and management recommendations of lysosomal storage disorders I: mucopolysaccharidoses

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    Fenzl CR

    2015-09-01

    Full Text Available Carlton R Fenzl,1 Kyla Teramoto,2 Majid Moshirfar3 1John A Moran Eye Center, University of Utah, Salt Lake City, UT, USA; 2John A Burns School of Medicine, University of Hawai’i, Honolulu, HI, USA; 3Cornea and Refractive Surgery Division, Department of Ophthalmology, Francis I. Proctor Foundation, University of California, San Francisco, CA, USA Abstract: The mucopolysaccharidoses (MPS are a group of lysosomal storage disorders caused by inborn errors of glycosaminoglycan (GAG metabolism. These diseases are classified by enzyme deficiency into seven groups: type I, II, III, IV, VI, VII, and IX. GAG accumulation leads to characteristic clinical features. Some ophthalmic findings that are characteristic of MPS diseases include corneal clouding, retinal degeneration, decreased electroretinogram wave amplitude, optic atrophy, papilledema, and glaucoma. Current treatments such as hematopoietic stem cell transplantation and enzyme replacement therapy have increased the life span of many MPS patients and created the need to improve management of ocular symptoms. This article aims to provide a comprehensive review of ocular manifestations and treatment options for the various types of MPS. Keywords: MPS, glycosaminoglycan, corneal clouding

  11. The Role of Next-Generation Sequencing in the Diagnosis of Lysosomal Storage Disorders

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    Katalin Komlosi MD, PhD

    2016-10-01

    Full Text Available Next-generation sequencing (NGS panels are used widely in clinical diagnostics to identify genetic causes of various monogenic disease groups including neurometabolic disorders and, more recently, lysosomal storage disorders (LSDs. Many new challenges have been introduced through these new technologies, both at the laboratory level and at the bioinformatics level, with consequences including new requirements for interpretation of results, and for genetic counseling. We review some recent examples of the application of NGS technologies, with purely diagnostic and with both diagnostic and research aims, for establishing a rapid genetic diagnosis in LSDs. Given that NGS can be applied in a way that takes into account the many issues raised by international consensus guidelines, it can have a significant role even early in the course of the diagnostic process, in combination with biochemical and clinical data. Besides decreasing the delay in diagnosis for many patients, a precise molecular diagnosis is extremely important as new therapies are becoming available within the LSD spectrum for patients who share specific types of mutations. A genetic diagnosis is also the prerequisite for genetic counseling, family planning, and the individual choice of reproductive options in affected families.

  12. High proportion of mannosidosis and fucosidosis among lysosomal storage diseases in Cuba.

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    Menéndez-Sainz, C; González-Quevedo, A; González-García, S; Peña-Sánchez, M; Giugliani, R

    2012-08-13

    Although lysosomal storage disorders (LSDs) are considered individually rare, as a group they present a non-negligible frequency. Few studies have been made of populational occurrence of LSDs; they have been conducted predominantly on Caucasian populations. We studied the occurrence of LSDs in Cuba. Data from individuals who had been referred to the Institute of Neurology and Neurosurgery in Havana from hospitals all over the country between January 1990 and December 2005 were analyzed. This institute was the only laboratory to provide enzyme-based diagnostic testing for 19 LSDs in Cuba during this period. Occurrence rates were calculated by dividing the number of postnatal diagnoses by the number of births during the study period. The combined occurrence of LSDs in Cuba was 5.6 per 100,000, lower than that reported in other studies conducted on Caucasian populations. The most frequent individual LSDs were: mucopolysaccharidosis type I (1.01 per 100,000) and, surprisingly, alpha-mannosidosis (0.72 per 100,000) and fucosidosis (0.62 per 100,000). These findings may be related to specific genetic characteristics and admixture of the Cuban population. This is the first comprehensive study of the occurrence of LSDs in Cuba. We conclude that the epidemiology of these diseases can vary regionally, and we stress the need for similar surveys in other Latin American countries.

  13. Chronic intestinal pseudo-obstruction. Did you search for lysosomal storage diseases?

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    Politei, J; Durand, C; Schenone, A B; Torres, A; Mukdsi, J; Thurberg, B L

    2017-06-01

    Chronic intestinal pseudo-obstruction results in clinical manifestations that resemble intestinal obstruction but in the absence of any physical obstructive process. Fabry disease is an X-linked lysosomal storage disease characterized by the dysfunction of multiple systems, including significant gastrointestinal involvement. We report the occurrence of chronic intestinal pseudo-obstruction in two unrelated patients with Fabry disease and the possible explanation of a direct relation of these two disorders. In Fabry disease, gastrointestinal symptoms occur in approximately 70% of male patients, but the frequency ranges from 19% to 69% in different series. In some patients, colonic dysmotility due glycolipid deposition in autonomic plexus and ganglia can lead to the pseudo-obstruction syndrome, simulating intestinal necrosis. That is why up to this date colostomy has been performed in some cases, even for children with FD without cardiac, renal or cerebrovascular compromise. Early treatment with enzyme replacement therapy in asymptomatic or mildly symptomatic patients may be justified in order to prevent disease progression. Several studies have demonstrated that enzyme replacement therapy alleviates GI manifestations. Because of the non-specific nature of the gastrointestinal symptoms, diagnosis of Fabry disease is often delayed for several years. Gastrointestinal involvement is often misdiagnosed or under-reported. It is therefore very important to consider Fabry disease in the differential diagnosis of chronic intestinal pseudo-obstruction.

  14. Chronic intestinal pseudo-obstruction. Did you search for lysosomal storage diseases?

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    J. Politei

    2017-06-01

    Full Text Available Chronic intestinal pseudo-obstruction results in clinical manifestations that resemble intestinal obstruction but in the absence of any physical obstructive process. Fabry disease is an X-linked lysosomal storage disease characterized by the dysfunction of multiple systems, including significant gastrointestinal involvement. We report the occurrence of chronic intestinal pseudo-obstruction in two unrelated patients with Fabry disease and the possible explanation of a direct relation of these two disorders. In Fabry disease, gastrointestinal symptoms occur in approximately 70% of male patients, but the frequency ranges from 19% to 69% in different series. In some patients, colonic dysmotility due glycolipid deposition in autonomic plexus and ganglia can lead to the pseudo-obstruction syndrome, simulating intestinal necrosis. That is why up to this date colostomy has been performed in some cases, even for children with FD without cardiac, renal or cerebrovascular compromise. Early treatment with enzyme replacement therapy in asymptomatic or mildly symptomatic patients may be justified in order to prevent disease progression. Several studies have demonstrated that enzyme replacement therapy alleviates GI manifestations. Because of the non-specific nature of the gastrointestinal symptoms, diagnosis of Fabry disease is often delayed for several years. Gastrointestinal involvement is often misdiagnosed or under-reported. It is therefore very important to consider Fabry disease in the differential diagnosis of chronic intestinal pseudo-obstruction.

  15. Partial restoration of mutant enzyme homeostasis in three distinct lysosomal storage disease cell lines by altering calcium homeostasis.

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    Ting-Wei Mu

    2008-02-01

    Full Text Available A lysosomal storage disease (LSD results from deficient lysosomal enzyme activity, thus the substrate of the mutant enzyme accumulates in the lysosome, leading to pathology. In many but not all LSDs, the clinically most important mutations compromise the cellular folding of the enzyme, subjecting it to endoplasmic reticulum-associated degradation instead of proper folding and lysosomal trafficking. A small molecule that restores partial mutant enzyme folding, trafficking, and activity would be highly desirable, particularly if one molecule could ameliorate multiple distinct LSDs by virtue of its mechanism of action. Inhibition of L-type Ca2+ channels, using either diltiazem or verapamil-both US Food and Drug Administration-approved hypertension drugs-partially restores N370S and L444P glucocerebrosidase homeostasis in Gaucher patient-derived fibroblasts; the latter mutation is associated with refractory neuropathic disease. Diltiazem structure-activity studies suggest that it is its Ca2+ channel blocker activity that enhances the capacity of the endoplasmic reticulum to fold misfolding-prone proteins, likely by modest up-regulation of a subset of molecular chaperones, including BiP and Hsp40. Importantly, diltiazem and verapamil also partially restore mutant enzyme homeostasis in two other distinct LSDs involving enzymes essential for glycoprotein and heparan sulfate degradation, namely alpha-mannosidosis and type IIIA mucopolysaccharidosis, respectively. Manipulation of calcium homeostasis may represent a general strategy to restore protein homeostasis in multiple LSDs. However, further efforts are required to demonstrate clinical utility and safety.

  16. Self-eating in skeletal development: implications for lysosomal storage disorders.

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    Settembre, Carmine; Arteaga-Solis, Emilio; Ballabio, Andrea; Karsenty, Gerard

    2009-02-01

    Macroautophagy (a.k.a. autophagy) is a cellular process aimed at the recycling of proteins and organelles that is achieved when autophagosomes fuse with lysosomes. Accordingly, lysosomal dysfunctions are often associated with impaired autophagy. We demonstrated that inactivation of the sulfatase modifying factor 1 gene (Sumf1), a gene mutated in multiple sulfatase deficiency (MSD), causes glycosaminoglycans (GAGs) to accumulate in lysosomes, which in turn disrupts autophagy. We utilized a murine model of MSD to study how impairment of this process affects chondrocyte viability and thus skeletal development.

  17. Pressure for drug development in lysosomal storage disorders - a quantitative analysis thirty years beyond the US orphan drug act.

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    Mechler, Konstantin; Mountford, William K; Hoffmann, Georg F; Ries, Markus

    2015-04-18

    Lysosomal storage disorders are a heterogeneous group of approximately 50 monogenically inherited orphan conditions. A defect leads to the storage of complex molecules in the lysosome, and patients develop a complex multisystemic phenotype of high morbidity often associated with premature death. More than 30 years ago the Orphan Drug Act of 1983 passed the United States legislation intended to facilitate the development of drugs for rare disorders. We directed our efforts in assessing which lysosomal diseases had drug development pressure and what distinguished those with successful development and approvals from diseases not treated or without orphan drug designation. Analysis of the FDA database for orphan drug designations through descriptive and comparative statistics. Between 1983 and 2013, fourteen drugs for seven conditions received FDA approval. Overall, orphan drug status was designated 70 times for 20 conditions. Approved therapies were enzyme replacement therapies (N = 10), substrate reduction therapies (N = 1), small molecules facilitating lysosomal substrate transportation (N = 3). FDA approval was significantly associated with a disease prevalence higher than 0.5/100,000 (p = 0.00742) and clinical development programs that did not require a primary neurological endpoint (p = 0.00059). Orphan drug status was designated for enzymes, modified enzymes, fusion proteins, chemical chaperones, small molecules leading to substrate reduction, or facilitating subcellular substrate transport, stem cells as well as gene therapies. Drug development focused on more common diseases. Primarily neurological diseases were neglected. Small clinical trials with either somatic or biomarker endpoints were successful. Enzyme replacement therapy was the most successful technology. Four factors played a key role in successful orphan drug development or orphan drug designations: 1) prevalence of disease 2) endpoints 3) regulatory precedent, and 4) technology platform

  18. Pharmaceutical Chaperones and Proteostasis Regulators in the Therapy of Lysosomal Storage Disorders: Current Perspective and Future Promises

    Directory of Open Access Journals (Sweden)

    Fedah E. Mohamed

    2017-07-01

    Full Text Available Different approaches have been utilized or proposed for the treatment of lysosomal storage disorders (LSDs including enzyme replacement and hematopoietic stem cell transplant therapies, both aiming to compensate for the enzymatic loss of the underlying mutated lysosomal enzymes. However, these approaches have their own limitations and therefore the vast majority of LSDs are either still untreatable or their treatments are inadequate. Missense mutations affecting enzyme stability, folding and cellular trafficking are common in LSDs resulting often in low protein half-life, premature degradation, aggregation and retention of the mutant proteins in the endoplasmic reticulum. Small molecular weight compounds such as pharmaceutical chaperones (PCs and proteostasis regulators have been in recent years to be promising approaches for overcoming some of these protein processing defects. These compounds are thought to enhance lysosomal enzyme activity by specific binding to the mutated enzyme or by manipulating components of the proteostasis pathways promoting protein stability, folding and trafficking and thus enhancing and restoring some of the enzymatic activity of the mutated protein in lysosomes. Multiple compounds have already been approved for clinical use to treat multiple LSDs like migalastat in the treatment of Fabry disease and others are currently under research or in clinical trials such as Ambroxol hydrochloride and Pyrimethamine. In this review, we are presenting a general overview of LSDs, their molecular and cellular bases, and focusing on recent advances on targeting and manipulation proteostasis, including the use of PCs and proteostasis regulators, as therapeutic targets for some LSDs. In addition, we present the successes, limitations and future perspectives in this field.

  19. Decreased T2 signal in the thalami may be a sign of lysosomal storage disease

    Energy Technology Data Exchange (ETDEWEB)

    Autti, Taina [Helsinki University Central Hospital, Helsinki Medical Imaging Center, P.O. Box 340, Helsinki (Finland); Joensuu, Raimo [AstraZeneca R and D Molndal, Moelndal (Sweden); Aaberg, Laura [University of Helsinki, Department of Child Neurology, Hospital for Children and Adolescents, Helsinki (Finland)

    2007-07-15

    Lysosomal disorders are rare and are caused by genetically transmitted lysosomal enzyme deficiencies. A decreased T2 signal in the thalamus has occasionally been reported. Because the finding of bilateral abnormal signal intensity of the thalamus on T2-weighted images has not been systematically reviewed, and its value as a diagnostic tool critically evaluated, we carried out a systematic review of the literature. Articles in English with 30 trios of keywords were collected from PubMed. Exclusion criteria were lack of conventional T2-weighted images in the protocol and not being a human study. Finally, 111 articles were included. The thalamus was considered affected only if mentioned in the text or in the figure legends. Some 117 patients with various lysosomal diseases and five patients with ceruloplasmin deficiency were reported to have a bilateral decrease in T2 signal intensity. At least one article reported a bilateral decrease in signal intensity of the thalami on T2-weighted images in association with GM1 and GM2 gangliosidosis and with Krabbe's disease, aspartylglucosaminuria, mannosidosis, fucosidosis, and mucolipidosis IV. Furthermore, thalamic alteration was a consistent finding in several types of neuronal ceroid lipofuscinosis (NCL) including CLN1 (infantile NCL), CLN2 (classic late infantile NCL), CLN3 (juvenile NCL), CLN5 (Finnish variant late infantile NCL), and CLN7 (Turkish variant late infantile NCL). A decrease in T2 signal intensity in the thalami seems to be a sign of lysosomal disease. (orig.)

  20. Lysosomal storage disease in the brain: mutations of the β-mannosidase gene identified in autosomal dominant nystagmus.

    Science.gov (United States)

    Yu, Ping; Cui, Yun; Cai, Wanshi; Wu, Honghu; Xiao, Xiaoqiang; Shao, Qianzhi; Ma, Liang; Guo, Sen; Wu, Nana; Jin, Zi-Bing; Wang, Yongjin; Cai, Tao; Sun, Zhong Sheng; Qu, Jia

    2015-12-01

    Genetic etiology of congenital/infantile nystagmus remains largely unknown. This study aimed to identify genomic mutations in patients with infantile nystagmus and an associated disease network. Patients with inherited and sporadic infantile nystagmus were recruited for whole-exome and Sanger sequencing. β-Mannosidase activities were measured. Gene expression, protein-protein interaction, and nystagmus-associated lysosomal storage disease (LSD) genes were analyzed. A novel heterozygous mutation (c.2013G>A; p.R638H) of MANBA, which encodes lysosomal β-mannosidase, was identified in patients with autosomal-dominant nystagmus. An additional mutation (c.2346T>A; p.L749H) in MANBA was found by screening patients with sporadic nystagmus. MANBA was expressed in the pretectal nucleus of the developing midbrain, known to be involved in oculomotor and optokinetic nystagmus. Functional validation of these mutations demonstrated a significant decrease of β-mannosidase activities in the patients as well as in mutant-transfected HEK293T cells. Further analysis revealed that nystagmus is present in at least 24 different LSDs involving the brain. This is the first identification of MANBA mutations in patients with autosomal-dominant nystagmus, suggesting a new clinical entity. Because β-mannosidase activities are required for development of the oculomotor nervous system, our findings shed new light on the role of LSD-associated genes in the pathogenesis of infantile nystagmus.

  1. Swainsonine-induced lysosomal storage disease in goats caused by the ingestion of Turbina cordata in Northeastern Brazil.

    Science.gov (United States)

    Dantas, A F M; Riet-Correa, F; Gardner, D R; Medeiros, R M T; Barros, S S; Anjos, B L; Lucena, R B

    2007-01-01

    A disease of the central nervous system in goats was observed in the municipalities of Juazeiro, Casa Nova and Curaça, state of Bahia, and Petrolina, state of Pernambuco, Northeastern Brazil. The disease was produced experimentally in two goats by the administration of dry Turbina cordata mixed with grain. Clinical signs were observed after the ingestion of 62 and 106 g/kg body weight in 28 and 54 days, respectively. The concentration of swainsonine in the plant varied from less than 0.001% to 0.14% (dry weight). Clinical signs of natural and experimental cases included difficulties in standing, ataxia, hypermetria, wide-based stance, intention tremors, spastic paresis mainly in the hind legs, nystagmus, abnormal postural reactions, head tilting, and falling. Diffuse vacuolation of neurons, epithelial cells of pancreas, thyroids, and renal tubules were observed on the histology. From the electron microscopy of Purkinje cells the vacuoles represented dilated lysosomes. These findings demonstrated that T. cordata causes an acquired glycoprotein lysosomal storage disease. The intoxication occurs at least in an area of 27,000 km2 causing severe losses in goats, and some farmers report the disease also in cattle.

  2. Quantification of free sialic acid in urine by HPLC-electrospray tandem mass spectrometry: A tool for the diagnosis of sialic acid storage disease

    NARCIS (Netherlands)

    Valianpour, Fredoen; Abeling, Nicolaas G. G. M.; Duran, Marinus; Huijmans, Jan G. M.; Kulik, Willem

    2004-01-01

    Background: Sialic acid storage diseases (SSDs) are severe autosomal recessive neurodegenerative disorders caused by a transport defect across the lysosomal membrane, which leads to accumulation of sialic acid in tissues, fibroblasts, and urine. Defective free sialic acid transport can be

  3. Biotherapeutic target or sink: analysis of the macrophage mannose receptor tissue distribution in murine models of lysosomal storage diseases.

    Science.gov (United States)

    Zhang, Xin Sheen; Brondyk, William; Lydon, John T; Thurberg, Beth L; Piepenhagen, Peter A

    2011-06-01

    Lysosomal storage diseases (LSDs) are metabolic disorders caused by enzyme deficiencies that lead to lysosomal accumulation of undegraded substrates. Enzyme replacement therapies (ERT) have been developed as treatments for patients with Gaucher, Niemann-Pick, Fabry, and Pompe diseases. Depending on the disease, the corresponding therapeutic enzyme is designed to be internalized by diseased cells through receptor-mediated endocytosis via macrophage mannose receptors (MMR) or mannose-6-phosphate receptors (M6PR). Enzymes developed to treat Gaucher and Niemann-Pick diseases are meant to target MMR-expressing cells, and in the case of Cerezyme [recombinant human β-glucocerebrosidase (rhβGC)] for treating Gaucher disease, glycans on the enzyme are modified to increase specificity toward this receptor. Due to heterogeneity in glycosylation on enzymes intended to target the M6PR, however, there may also be some unintended targeting to MMR-expressing cells, which could act as unwanted sinks. Examples include Fabrazyme [recombinant human α-galactosidase A (rhαGal)] for treating Fabry disease and Myozyme [recombinant human acid α-glucosidase (rhGAA)] for treating Pompe disease. It is therefore of great interest to better understand the cell type and tissue distribution of MMR in murine LSD models used to evaluate ERT efficacy and mechanism of action. In this study, we generated affinity-purified polyclonal antibody against murine MMR and used it to carry out a systematic examination of MMR protein localization in murine models of Gaucher, Niemann-Pick, Fabry, and Pompe diseases. Using immunohistochemistry, immunofluorescence, and confocal microscopy, we examined MMR distribution in liver, spleen, lung, kidney, heart, diaphragm, quadriceps, and triceps in these animal models and compared them with MMR distribution in wild-type mice.

  4. Effect of collection, transport, processing and storage of blood specimens on the activity of lysosomal enzymes in plasma and leukocytes

    Directory of Open Access Journals (Sweden)

    M. Burin

    2000-09-01

    Full Text Available This study was designed to evaluate the effect of different conditions of collection, transport and storage on the quality of blood samples from normal individuals in terms of the activity of the enzymes ß-glucuronidase, total hexosaminidase, hexosaminidase A, arylsulfatase A and ß-galactosidase. The enzyme activities were not affected by the different materials used for collection (plastic syringes or vacuum glass tubes. In the evaluation of different heparin concentrations (10% heparin, 5% heparin, and heparinized syringe in the syringes, it was observed that higher doses resulted in an increase of at least 1-fold in the activities of ß-galactosidase, total hexosaminidase and hexosaminidase A in leukocytes, and ß-glucuronidase in plasma. When the effects of time and means of transportation were studied, samples that had been kept at room temperature showed higher deterioration with time (72 and 96 h before processing, and in this case it was impossible to isolate leukocytes from most samples. Comparison of heparin and acid citrate-dextrose (ACD as anticoagulants revealed that ß-glucuronidase and hexosaminidase activities in plasma reached levels near the lower normal limits when ACD was used. In conclusion, we observed that heparin should be used as the preferable anticoagulant when measuring these lysosomal enzyme activities, and we recommend that, when transport time is more than 24 h, samples should be shipped by air in a styrofoam box containing wet ice.

  5. Spontaneous lysosomal storage disease caused by Sida carpinifolia (Malvaceae) poisoning in cattle.

    Science.gov (United States)

    Furlan, F H; Lucioli, J; Veronezi, L O; Medeiros, A L; Barros, S S; Traverso, S D; Gava, A

    2009-03-01

    Clinical and pathologic findings for the spontaneous poisoning by Sida carpinifolia in cattle are described in this study. A survey on field cases of S. carpinifolia in cattle was carried out on farms of Alto Vale do Itajaí, State of Santa Catarina, southern Brazil. Sixteen affected animals were clinically evaluated and 9 were subjected to postmortem examination. The main clinical signs consisted of marching gait, alert gaze, head tremors, and poor growth. Histologic and ultrastructural lesions consisted of vacuolization and distension of neuronal perikarya, mainly from Purkinje cells, and of the cytoplasm of acinar pancreatic and thyroid follicular cells. Clinical signs and lesions varied from mild to severe. Improvement of the clinical signs was observed in cattle after a period of up to 90 days without consuming the plant; however, residual lesions, mainly characterized by axonal spheroids and absence of Purkinje neurons in some areas of the cerebellum, were observed in these cases. It is concluded that the natural chronic consumption of S. carpinifolia was the etiologic cause of storage disease in cattle in this study.

  6. Simultaneous Testing for 6 Lysosomal Storage Disorders and X-Adrenoleukodystrophy in Dried Blood Spots by Tandem Mass Spectrometry.

    Science.gov (United States)

    Tortorelli, Silvia; Turgeon, Coleman T; Gavrilov, Dimitar K; Oglesbee, Devin; Raymond, Kimiyo M; Rinaldo, Piero; Matern, Dietrich

    2016-09-01

    Newborn screening for lysosomal storage disorders (LSD) has revealed that late-onset variants of these conditions are unexpectedly frequent and therefore may evade diagnosis. We developed an efficient and cost-effective multiplex assay to diagnose six LSDs and several peroxisomal disorders in patients presenting with diverse phenotypes at any age. Three 3-mm dried blood spot (DBS) punches were placed into individual microtiter plates. One disc was treated with a cocktail containing acid sphingomyelinase-specific substrate and internal standard (IS). To the second DBS we added a cocktail containing substrate and IS for β-glucosidase, acid α-glucosidase, α-galactosidase A, galactocerebrosidase, and α-L-iduronidase. The third DBS was extracted with methanol containing d4-C26 lysophosphatidylcholine as IS and stored until the enzyme plates were combined and purified by liquid-liquid and solid-phase extraction. The extracts were evaporated, reconstituted with the extract from the lysophosphatidylcholine plate, and analyzed by flow injection tandem mass spectrometry. Reference intervals were determined by analysis of 550 samples from healthy controls. DBS from confirmed patients with 1 of the 6 LSDs (n = 33), X-adrenoleukodystrophy (n = 9), or a peroxisomal biogenesis disorder (n = 5), as well as carriers for Fabry disease (n = 17) and X-adrenoleukodystrophy (n = 5), were analyzed for assay validation. Prospective clinical testing of 578 samples revealed 25 patients affected with 1 of the detectable conditions. Our flow injection tandem mass spectrometry approach is amenable to high-throughput population screening for Hurler disease, Gaucher disease, Niemann-Pick A/B disease, Pompe disease, Krabbe disease, Fabry disease, X-adrenoleukodystrophy, and peroxisomal biogenesis disorder in DBS. © 2016 American Association for Clinical Chemistry.

  7. Loss of Mitochondrial Function Impairs Lysosomes.

    Science.gov (United States)

    Demers-Lamarche, Julie; Guillebaud, Gérald; Tlili, Mouna; Todkar, Kiran; Bélanger, Noémie; Grondin, Martine; Nguyen, Angela P; Michel, Jennifer; Germain, Marc

    2016-05-06

    Alterations in mitochondrial function, as observed in neurodegenerative diseases, lead to disrupted energy metabolism and production of damaging reactive oxygen species. Here, we demonstrate that mitochondrial dysfunction also disrupts the structure and function of lysosomes, the main degradation and recycling organelle. Specifically, inhibition of mitochondrial function, following deletion of the mitochondrial protein AIF, OPA1, or PINK1, as well as chemical inhibition of the electron transport chain, impaired lysosomal activity and caused the appearance of large lysosomal vacuoles. Importantly, our results show that lysosomal impairment is dependent on reactive oxygen species. Given that alterations in both mitochondrial function and lysosomal activity are key features of neurodegenerative diseases, this work provides important insights into the etiology of neurodegenerative diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  8. 'Doctor Google' ending the diagnostic odyssey in lysosomal storage disorders: parents using internet search engines as an efficient diagnostic strategy in rare diseases.

    Science.gov (United States)

    Bouwman, Machtelt G; Teunissen, Quirine G A; Wijburg, Frits A; Linthorst, Gabor E

    2010-08-01

    The expansion of the internet has resulted in widespread availability of medical information for both patients and physicians. People increasingly spend time on the internet searching for an explanation, diagnosis or treatment for their symptoms. Regarding rare diseases, the use of the internet may be an important tool in the diagnostic process. The authors present two cases in which concerned parents made a correct diagnosis of a lysosomal storage disorder in their child by searching the internet after a long doctor's delay. These cases illustrate the utility of publicly available internet search engines in diagnosing rare disorders and in addition illustrate the lengthy diagnostic odyssey which is common in these disorders.

  9. CNS penetration of intrathecal-lumbar idursulfase in the monkey, dog and mouse: implications for neurological outcomes of lysosomal storage disorder.

    Science.gov (United States)

    Calias, Pericles; Papisov, Mikhail; Pan, Jing; Savioli, Nancy; Belov, Vasily; Huang, Yan; Lotterhand, Jason; Alessandrini, Mary; Liu, Nan; Fischman, Alan J; Powell, Jan L; Heartlein, Michael W

    2012-01-01

    A major challenge for the treatment of many central nervous system (CNS) disorders is the lack of convenient and effective methods for delivering biological agents to the brain. Mucopolysaccharidosis II (Hunter syndrome) is a rare inherited lysosomal storage disorder resulting from a deficiency of iduronate-2-sulfatase (I2S). I2S is a large, highly glycosylated enzyme. Intravenous administration is not likely to be an effective therapy for disease-related neurological outcomes that require enzyme access to the brain cells, in particular neurons and oligodendrocytes. We demonstrate that intracerebroventricular and lumbar intrathecal administration of recombinant I2S in dogs and nonhuman primates resulted in widespread enzyme distribution in the brain parenchyma, including remarkable deposition in the lysosomes of both neurons and oligodendrocytes. Lumbar intrathecal administration also resulted in enzyme delivery to the spinal cord, whereas little enzyme was detected there after intraventricular administration. Mucopolysaccharidosis II model is available in mice. Lumbar administration of recombinant I2S to enzyme deficient animals reduced the storage of glycosaminoglycans in both superficial and deep brain tissues, with concurrent morphological improvements. The observed patterns of enzyme transport from cerebrospinal fluid to the CNS tissues and the resultant biological activity (a) warrant further investigation of intrathecal delivery of I2S via lumbar catheter as an experimental treatment for the neurological symptoms of Hunter syndrome and (b) may have broader implications for CNS treatment with biopharmaceuticals.

  10. CNS penetration of intrathecal-lumbar idursulfase in the monkey, dog and mouse: implications for neurological outcomes of lysosomal storage disorder.

    Directory of Open Access Journals (Sweden)

    Pericles Calias

    Full Text Available A major challenge for the treatment of many central nervous system (CNS disorders is the lack of convenient and effective methods for delivering biological agents to the brain. Mucopolysaccharidosis II (Hunter syndrome is a rare inherited lysosomal storage disorder resulting from a deficiency of iduronate-2-sulfatase (I2S. I2S is a large, highly glycosylated enzyme. Intravenous administration is not likely to be an effective therapy for disease-related neurological outcomes that require enzyme access to the brain cells, in particular neurons and oligodendrocytes. We demonstrate that intracerebroventricular and lumbar intrathecal administration of recombinant I2S in dogs and nonhuman primates resulted in widespread enzyme distribution in the brain parenchyma, including remarkable deposition in the lysosomes of both neurons and oligodendrocytes. Lumbar intrathecal administration also resulted in enzyme delivery to the spinal cord, whereas little enzyme was detected there after intraventricular administration. Mucopolysaccharidosis II model is available in mice. Lumbar administration of recombinant I2S to enzyme deficient animals reduced the storage of glycosaminoglycans in both superficial and deep brain tissues, with concurrent morphological improvements. The observed patterns of enzyme transport from cerebrospinal fluid to the CNS tissues and the resultant biological activity (a warrant further investigation of intrathecal delivery of I2S via lumbar catheter as an experimental treatment for the neurological symptoms of Hunter syndrome and (b may have broader implications for CNS treatment with biopharmaceuticals.

  11. Screening of lysosomal storage disorders: application of the online trapping-and-cleanup liquid chromatography/mass spectrometry method for mucopolysaccharidosis I.

    Science.gov (United States)

    Ombrone, Daniela; Malvagia, Sabrina; Funghini, Silvia; Giocaliere, Elisa; Della Bona, Maria Luisa; Forni, Giulia; De Luca, Alessio; Villanelli, Fabio; Casetta, Bruno; Guerrini, Renzo; la Marca, Giancarlo

    2013-01-01

    In recent years, new treatments have become available to treat some lysosomal storage disorders (LSDs) and many studies suggest that there is a benefit with starting therapy early. Newborn screening should detect diseases early enough for prompt treatment. Some countries include additional conditions, such as some LSDs, into their newborn screening panels. Mucopolysaccharidosis Type I (MPS I) is an autosomal recessive disorder caused by the deficiency of α-L-iduronidase (IDUA) activity. Currently, enzyme replacement therapy (ERT) or bone marrow transplantation is available and this has raised a growing interest for the development of a newborn screening test. In 2009, we reported a new fast and simplified tandem mass spectrometry-based method for quantifying five enzyme activities on dried blood spots. Here, we describe the inclusion of IDUA activity determination for the simultaneous detection of six lysosomal storage diseases. We have defined reference normal ranges by testing 680 healthy newborns and 240 adults. The assay was checked through three confirmed MPS I patients whose IDUA activity was below the normal range. Reproducibility of the assays has been established by assessing the intra-day and inter-day assay imprecisions. This quick assay has been devised to be implemented in newborn screening by liquid chromatography tandem mass spectrometry.

  12. Impact of lysosomal storage disorders on biology of mesenchymal stem cells: Evidences from in vitro silencing of glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes.

    Science.gov (United States)

    Squillaro, Tiziana; Antonucci, Ivana; Alessio, Nicola; Esposito, Anna; Cipollaro, Marilena; Melone, Mariarosa Anna Beatrice; Peluso, Gianfranco; Stuppia, Liborio; Galderisi, Umberto

    2017-12-01

    Lysosomal storage disorders (LDS) comprise a group of rare multisystemic diseases resulting from inherited gene mutations that impair lysosomal homeostasis. The most common LSDs, Gaucher disease (GD), and Fabry disease (FD) are caused by deficiencies in the lysosomal glucocerebrosidase (GBA) and alpha-galactosidase A (GLA) enzymes, respectively. Given the systemic nature of enzyme deficiency, we hypothesized that the stem cell compartment of GD and FD patients might be also affected. Among stem cells, mesenchymal stem cells (MSCs) are a commonly investigated population given their role in hematopoiesis and the homeostatic maintenance of many organs and tissues. Since the impairment of MSC functions could pose profound consequences on body physiology, we evaluated whether GBA and GLA silencing could affect the biology of MSCs isolated from bone marrow and amniotic fluid. Those cell populations were chosen given the former's key role in organ physiology and the latter's intriguing potential as an alternative stem cell model for human genetic disease. Our results revealed that GBA and GLA deficiencies prompted cell cycle arrest along with the impairment of autophagic flux and an increase of apoptotic and senescent cell percentages. Moreover, an increase in ataxia-telangiectasia-mutated staining 1 hr after oxidative stress induction and a return to basal level at 48 hr, along with persistent gamma-H2AX staining, indicated that MSCs properly activated DNA repair signaling, though some damages remained unrepaired. Our data therefore suggest that MSCs with reduced GBA or GLA activity are prone to apoptosis and senescence due to impaired autophagy and DNA repair capacity. © 2017 Wiley Periodicals, Inc.

  13. Newborn screening for six lysosomal storage disorders in a cohort of Mexican patients: Three-year findings from a screening program in a closed Mexican health system.

    Science.gov (United States)

    Navarrete-Martínez, Juana Inés; Limón-Rojas, Ana Elena; Gaytán-García, Maria de Jesús; Reyna-Figueroa, Jesús; Wakida-Kusunoki, Guillermo; Delgado-Calvillo, Ma Del Rocío; Cantú-Reyna, Consuelo; Cruz-Camino, Héctor; Cervantes-Barragán, David Eduardo

    2017-05-01

    To evaluate the results of a lysosomal newborn screening (NBS) program in a cohort of 20,018 Mexican patients over the course of 3years in a closed Mexican Health System (Petróleos Mexicanos [PEMEX] Health Services). Using dried blood spots (DBS), we performed a multiplex tandem mass spectrometry enzymatic assay for six lysosomal storage disorders (LSDs) including Pompe disease, Fabry disease, Gaucher disease, mucopolysaccharidosis type I (MPS-I), Niemann-Pick type A/B, and Krabbe disease. Screen-positive cases were confirmed using leukocyte enzymatic activity and DNA molecular analysis. From July 2012 to April 2016, 20,018 patients were screened; 20 patients were confirmed to have an LSD phenotype (99.9 in 100,000 newborns). Final distributions include 11 Pompe disease, five Fabry disease, two MPS-I, and two Niemann-Pick type A/B patients. We did not find any Gaucher or Krabbe patients. A final frequency of 1 in 1001 LSD newborn phenotypes was established. NBS is a major public health achievement that has decreased the morbidity and mortality of inborn errors of metabolism. The introduction of NBS for LSD presents new challenges. This is the first multiplex Latin-American study of six LSDs detected through NBS. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease.

    Directory of Open Access Journals (Sweden)

    Marcelina Malinowska

    Full Text Available BACKGROUND: Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments. We recently described significant reductions of accumulated heparan sulphate substrate in liver of a mouse model of MPSIIIB using the tyrosine kinase inhibitor genistein. METHODOLOGY/PRINCIPAL FINDINGS: We report here that high doses of genistein aglycone, given continuously over a 9 month period to MPSIIIB mice, significantly reduce lysosomal storage, heparan sulphate substrate and neuroinflammation in the cerebral cortex and hippocampus, resulting in correction of the behavioural defects observed. Improvements in synaptic vesicle protein expression and secondary storage in the cerebral cortex were also observed. CONCLUSIONS/SIGNIFICANCE: Genistein may prove useful as a substrate reduction agent to delay clinical onset of MPSIIIB and, due to its multimodal action, may provide a treatment adjunct for several other neurodegenerative metabolic diseases.

  15. Autophagic/lysosomal dysfunction in Alzheimer's disease.

    Science.gov (United States)

    Orr, Miranda E; Oddo, Salvatore

    2013-01-01

    Autophagy serves as the sole catabolic mechanism for degrading organelles and protein aggregates. Increasing evidence implicates autophagic dysfunction in Alzheimer's disease (AD) and other neurodegenerative diseases associated with protein misprocessing and accumulation. Under physiologic conditions, the autophagic/lysosomal system efficiently recycles organelles and substrate proteins. However, reduced autophagy function leads to the accumulation of proteins and autophagic and lysosomal vesicles. These vesicles contain toxic lysosomal hydrolases as well as the proper cellular machinery to generate amyloid-beta, the major component of AD plaques. Here, we provide an overview of current research focused on the relevance of autophagic/lysosomal dysfunction in AD pathogenesis as well as potential therapeutic targets aimed at restoring autophagic/lysosomal pathway function.

  16. Sialic acid deposition impairs the utility of AAV9, but not peptide-modified AAVs for brain gene therapy in a mouse model of lysosomal storage disease.

    Science.gov (United States)

    Chen, Yong Hong; Claflin, Kristin; Geoghegan, James C; Davidson, Beverly L

    2012-07-01

    Recombinant vector systems have been recently identified that when delivered systemically can transduce neurons, glia, and endothelia in the central nervous system (CNS), providing an opportunity to develop therapies for diseases affecting the brain without performing direct intracranial injections. Vector systems based on adeno-associated virus (AAV) include AAV serotype 9 (AAV9) and AAVs that have been re-engineered at the capsid level for CNS tropism. Here, we performed a head-to-head comparison of AAV9 and a capsid modified AAV for their abilities to rescue CNS and peripheral disease in an animal model of lysosomal storage disease (LSD), the mucopolysacharidoses (MPS) VII mouse. While the peptide-modified AAV reversed cognitive deficits, improved storage burden in the brain, and substantially prolonged survival, we were surprised to find that AAV9 provided no CNS benefit. Additional experiments demonstrated that sialic acid, a known inhibitor of AAV9, is elevated in the CNS of MPS VII mice. These studies highlight how disease manifestations can dramatically impact the known tropism of recombinant vectors, and raise awareness to assuming similar transduction profiles between normal and disease models.

  17. A missense change in the ATG4D gene links aberrant autophagy to a neurodegenerative vacuolar storage disease.

    Science.gov (United States)

    Kyöstilä, Kaisa; Syrjä, Pernilla; Jagannathan, Vidhya; Chandrasekar, Gayathri; Jokinen, Tarja S; Seppälä, Eija H; Becker, Doreen; Drögemüller, Michaela; Dietschi, Elisabeth; Drögemüller, Cord; Lang, Johann; Steffen, Frank; Rohdin, Cecilia; Jäderlund, Karin H; Lappalainen, Anu K; Hahn, Kerstin; Wohlsein, Peter; Baumgärtner, Wolfgang; Henke, Diana; Oevermann, Anna; Kere, Juha; Lohi, Hannes; Leeb, Tosso

    2015-04-01

    Inherited neurodegenerative disorders are debilitating diseases that occur across different species. We have performed clinical, pathological and genetic studies to characterize a novel canine neurodegenerative disease present in the Lagotto Romagnolo dog breed. Affected dogs suffer from progressive cerebellar ataxia, sometimes accompanied by episodic nystagmus and behavioral changes. Histological examination revealed unique pathological changes, including profound neuronal cytoplasmic vacuolization in the nervous system, as well as spheroid formation and cytoplasmic aggregation of vacuoles in secretory epithelial tissues and mesenchymal cells. Genetic analyses uncovered a missense change, c.1288G>A; p.A430T, in the autophagy-related ATG4D gene on canine chromosome 20 with a highly significant disease association (p = 3.8 x 10-136) in a cohort of more than 2300 Lagotto Romagnolo dogs. ATG4D encodes a poorly characterized cysteine protease belonging to the macroautophagy pathway. Accordingly, our histological analyses indicated altered autophagic flux in affected tissues. The knockdown of the zebrafish homologue atg4da resulted in a widespread developmental disturbance and neurodegeneration in the central nervous system. Our study describes a previously unknown canine neurological disease with particular pathological features and implicates the ATG4D protein as an important autophagy mediator in neuronal homeostasis. The canine phenotype serves as a model to delineate the disease-causing pathological mechanism(s) and ATG4D function, and can also be used to explore treatment options. Furthermore, our results reveal a novel candidate gene for human neurodegeneration and enable the development of a genetic test for veterinary diagnostic and breeding purposes.

  18. A Missense Change in the ATG4D Gene Links Aberrant Autophagy to a Neurodegenerative Vacuolar Storage Disease

    Science.gov (United States)

    Kyöstilä, Kaisa; Syrjä, Pernilla; Jagannathan, Vidhya; Chandrasekar, Gayathri; Jokinen, Tarja S.; Seppälä, Eija H.; Becker, Doreen; Drögemüller, Michaela; Dietschi, Elisabeth; Drögemüller, Cord; Lang, Johann; Steffen, Frank; Rohdin, Cecilia; Jäderlund, Karin H.; Lappalainen, Anu K.; Hahn, Kerstin; Wohlsein, Peter; Baumgärtner, Wolfgang; Henke, Diana; Oevermann, Anna; Kere, Juha; Lohi, Hannes; Leeb, Tosso

    2015-01-01

    Inherited neurodegenerative disorders are debilitating diseases that occur across different species. We have performed clinical, pathological and genetic studies to characterize a novel canine neurodegenerative disease present in the Lagotto Romagnolo dog breed. Affected dogs suffer from progressive cerebellar ataxia, sometimes accompanied by episodic nystagmus and behavioral changes. Histological examination revealed unique pathological changes, including profound neuronal cytoplasmic vacuolization in the nervous system, as well as spheroid formation and cytoplasmic aggregation of vacuoles in secretory epithelial tissues and mesenchymal cells. Genetic analyses uncovered a missense change, c.1288G>A; p.A430T, in the autophagy-related ATG4D gene on canine chromosome 20 with a highly significant disease association (p = 3.8 x 10-136) in a cohort of more than 2300 Lagotto Romagnolo dogs. ATG4D encodes a poorly characterized cysteine protease belonging to the macroautophagy pathway. Accordingly, our histological analyses indicated altered autophagic flux in affected tissues. The knockdown of the zebrafish homologue atg4da resulted in a widespread developmental disturbance and neurodegeneration in the central nervous system. Our study describes a previously unknown canine neurological disease with particular pathological features and implicates the ATG4D protein as an important autophagy mediator in neuronal homeostasis. The canine phenotype serves as a model to delineate the disease-causing pathological mechanism(s) and ATG4D function, and can also be used to explore treatment options. Furthermore, our results reveal a novel candidate gene for human neurodegeneration and enable the development of a genetic test for veterinary diagnostic and breeding purposes. PMID:25875846

  19. A missense change in the ATG4D gene links aberrant autophagy to a neurodegenerative vacuolar storage disease.

    Directory of Open Access Journals (Sweden)

    Kaisa Kyöstilä

    2015-04-01

    Full Text Available Inherited neurodegenerative disorders are debilitating diseases that occur across different species. We have performed clinical, pathological and genetic studies to characterize a novel canine neurodegenerative disease present in the Lagotto Romagnolo dog breed. Affected dogs suffer from progressive cerebellar ataxia, sometimes accompanied by episodic nystagmus and behavioral changes. Histological examination revealed unique pathological changes, including profound neuronal cytoplasmic vacuolization in the nervous system, as well as spheroid formation and cytoplasmic aggregation of vacuoles in secretory epithelial tissues and mesenchymal cells. Genetic analyses uncovered a missense change, c.1288G>A; p.A430T, in the autophagy-related ATG4D gene on canine chromosome 20 with a highly significant disease association (p = 3.8 x 10-136 in a cohort of more than 2300 Lagotto Romagnolo dogs. ATG4D encodes a poorly characterized cysteine protease belonging to the macroautophagy pathway. Accordingly, our histological analyses indicated altered autophagic flux in affected tissues. The knockdown of the zebrafish homologue atg4da resulted in a widespread developmental disturbance and neurodegeneration in the central nervous system. Our study describes a previously unknown canine neurological disease with particular pathological features and implicates the ATG4D protein as an important autophagy mediator in neuronal homeostasis. The canine phenotype serves as a model to delineate the disease-causing pathological mechanism(s and ATG4D function, and can also be used to explore treatment options. Furthermore, our results reveal a novel candidate gene for human neurodegeneration and enable the development of a genetic test for veterinary diagnostic and breeding purposes.

  20. The use of port-a-caths in adult patients with Lysosomal Storage Disorders receiving Enzyme Replacement Therapy-one centre experience

    Directory of Open Access Journals (Sweden)

    Mairead McLoughlin

    2017-12-01

    Full Text Available Port-a-cath is a widely used device in patients with long-term venous access demand such as frequent or continuous administration of medications such as Enzyme Replacement Therapy (ERT, chemotherapy delivery, blood transfusions, blood products, and fluids. Patients with Lysosomal Storage Diseases (LSDs often require recurrent courses of ERT. We reviewed our experience of using port-a-caths in patients with LSDs with the focus on challenges and complications associated with these catheters. Among 245 adult patients who were treated with ERT, twenty patients (8.2% had a port-a-cath inserted due to poor venous access. Six patients were using their first port whereas five other patients had their port-a-caths replaced at least once. The remaining six patients had inactive port-a-caths. The majority of patients with active port-a-caths never missed more than one consecutive infusion, although one patient missed 2 consecutive infusions whilst on holiday. We identified significant gaps in patients' and their families' understanding of the management of port-a-caths and risks associated with them. It resulted in producing a leaflet and designing an educational program for our LSD patients.

  1. A Prospective Treatment Option for Lysosomal Storage Diseases: CRISPR/Cas9 Gene Editing Technology for Mutation Correction in Induced Pluripotent Stem Cells

    Directory of Open Access Journals (Sweden)

    Chloe L. Christensen

    2017-02-01

    Full Text Available Ease of design, relatively low cost and a multitude of gene-altering capabilities have all led to the adoption of the sophisticated and yet simple gene editing system: clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9. The CRISPR/Cas9 system holds promise for the correction of deleterious mutations by taking advantage of the homology directed repair pathway and by supplying a correction template to the affected patient’s cells. Currently, this technique is being applied in vitro in human-induced pluripotent stem cells (iPSCs to correct a variety of severe genetic diseases, but has not as of yet been used in iPSCs derived from patients affected with a lysosomal storage disease (LSD. If adopted into clinical practice, corrected iPSCs derived from cells that originate from the patient themselves could be used for therapeutic amelioration of LSD symptoms without the risks associated with allogeneic stem cell transplantation. CRISPR/Cas9 editing in a patient’s cells would overcome the costly, lifelong process associated with currently available treatment methods, including enzyme replacement and substrate reduction therapies. In this review, the overall utility of the CRISPR/Cas9 gene editing technique for treatment of genetic diseases, the potential for the treatment of LSDs and methods currently employed to increase the efficiency of this re-engineered biological system will be discussed.

  2. Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology

    DEFF Research Database (Denmark)

    Kirkegaard, Thomas; Roth, Anke G; Petersen, Nikolaj H T

    2010-01-01

    inhibition of ASM, effectively revert the Hsp70-mediated stabilization of lysosomes. Notably, the reduced ASM activity in cells from patients with Niemann-Pick disease (NPD) A and B-severe lysosomal storage disorders caused by mutations in the sphingomyelin phosphodiesterase 1 gene (SMPD1) encoding for ASM...

  3. The Big Bluff of Amyotrophic Lateral Sclerosis Diagnosis: The Role of Neurodegenerative Disease Mimics.

    Science.gov (United States)

    Bicchi, Ilaria; Emiliani, Carla; Vescovi, Angelo; Martino, Sabata

    2015-01-01

    Neurodegenerative diseases include a significant number of pathologies affecting the nervous system. Generally, the primary cause of each disease is specific; however, recently, it was shown that they may be correlated at molecular level. This aspect, together with the exhibition of similar symptoms, renders the diagnosis of these disorders difficult. Amyotrophic lateral sclerosis is one of these pathologies. Herein, we report several cases of amyotrophic lateral sclerosis misdiagnosed as a consequence of features that are common to several neurodegenerative diseases, such as Parkinson's, Huntington's and Alzheimer's disease, spinal muscular atrophy, progressive bulbar palsy, spastic paraplegia and frontotemporal dementia, and mostly with the lysosomal storage disorder GM2 gangliosidosis. Overall reports highlight that the differential diagnosis for amyotrophic lateral sclerosis should include correlated mechanisms. © 2015 S. Karger AG, Basel.

  4. Action of polystyrene nanoparticles of different sizes on lysosomal function and integrity

    Directory of Open Access Journals (Sweden)

    Fröhlich Eleonore

    2012-07-01

    Full Text Available Abstract Background Data from environmental exposure to nanoparticles (NPs suggest that chronic exposure may increase the incidence of lung, cardiovascular and neurodegenerative diseases. Impairment of cell function by intracellular accumulation of NPs is also suspected. Many types of NPs have been detected in the endosomal-lysosomal system and, upon repeated exposure, alterations of the endosomal-lysosomal system may occur. To identify such effects we compared the effect of carboxyl polystyrene particles (CPS of different sizes (20-500 nm on lysosomes of the endothelial cell line EAhy926 after short (24h and long (72h-96h exposure times. Lysosomal localization of CPS, as well as lysosomal pH, lysosomal membrane integrity, morphology of the endosomal-lysosomal system and activities of the lysosomal enzymes,cathepsin B and sulfatases, upon exposure to CPS were recorded. Results CPS in sizes ≤100 nm showed high co-localization with lysosomes already after 4h, larger CPS after 24h. None of the particles at non-cytotoxic concentrations caused marked changes in lysosomal pH or destroyed lysosomal membrane integrity. At 24h of exposure, 20 nm CPS induced significant dilatation of the endosomal-lysosomal system and reduced activity of lysosomal sulfatases. After 72h, these alterations were less pronounced. Conclusions Despite accumulation in lysosomes CPS induced only small changes in lysosomes. Upon longer contact, these changes are even less pronounced. The presented panel of assays may serve to identify effects on lysosomes also for other NPs.

  5. Molecular Mechanisms of Pathogenesis in a Glycosphigolipid and a Glycoprotein Storage Disease

    Science.gov (United States)

    d’Azzo, Alessandra; Bonten, Erik

    2011-01-01

    The lysosomal system comprises a specialized network of organelles crucial for the sorting, digestion, recycling and secretion of cellular components. With their content of hydrolytic enzymes lysosomes regulate the degradation of a multitude of substrates that reach these organelles via the biosynthetic or the endocytic route. Gene defects that affect one or more of these hydrolases lead to lysosomal storage diseases (LSD). This underscores the apparent lack of redundancy of these enzymes and the importance of the lysosomal system in cell and tissue homeostasis. Some of the lysosomal enzymes may form multiprotein complexes, which usually work synergistically on substrates and in this configuration, may respond more efficiently to changes in substrate load and composition. A well-characterized lysosomal multienzyme complex is the one comprised of the glycosidases, β-galactosidase (β-GAL) and neuramidase-1 (NEU1), and of the serine carboxypeptidase protective protein/cathepsin A (PPCA). Three neurodegenerative LSDs are caused by either single or combined deficiency of these lysosomal enzymes. Sialidosis (NEU1 deficiency) and galactosialidosis (combined NEU1 and β-gal deficiency, secondary to a primary defect of PPCA) belong to the glycoprotein storage diseases, whereas GM1-gangliosidosis (β-GAL deficiency) is a glycosphingolipid storage disease. Identification of novel molecular pathways that are deregulated because of loss of enzyme activity and/or accumulation of specific metabolites in various cell types has shed light on mechanisms of disease pathogenesis and may pave the way for future development of new therapies for these LSDs. PMID:21118106

  6. Biphasic regulation of lysosomal exocytosis by oxidative stress.

    Science.gov (United States)

    Ravi, Sreeram; Peña, Karina A; Chu, Charleen T; Kiselyov, Kirill

    2016-11-01

    Oxidative stress drives cell death in a number of diseases including ischemic stroke and neurodegenerative diseases. A better understanding of how cells recover from oxidative stress is likely to lead to better treatments for stroke and other diseases. The recent evidence obtained in several models ties the process of lysosomal exocytosis to the clearance of protein aggregates and toxic metals. The mechanisms that regulate lysosomal exocytosis, under normal or pathological conditions, are only beginning to emerge. Here we provide evidence for the biphasic effect of oxidative stress on lysosomal exocytosis. Lysosomal exocytosis was measured using the extracellular levels of the lysosomal enzyme beta-hexosaminidase (ß-hex). Low levels or oxidative stress stimulated lysosomal exocytosis, but inhibited it at high levels. Deletion of the lysosomal ion channel TRPML1 eliminated the stimulatory effect of low levels of oxidative stress. The inhibitory effects of oxidative stress appear to target the component of lysosomal exocytosis that is driven by extracellular Ca 2+ . We propose that while moderate oxidative stress promotes cellular repair by stimulating lysosomal exocytosis, at high levels oxidative stress has a dual pathological effect: it directly causes cell damage and impairs damage repair by inhibiting lysosomal exocytosis. Harnessing these adaptive mechanisms may point to pharmacological interventions for diseases involving oxidative proteotoxicity or metal toxicity. Copyright © 2016 Elsevier Ltd. All rights reserved.

  7. Longitudinal Study of Neurodegenerative Disorders

    Science.gov (United States)

    2018-01-31

    MLD; Krabbe Disease; ALD; MPS I; MPS II; MPS III; Vanishing White Matter Disease; GM3 Gangliosidosis; PKAN; Tay-Sachs Disease; NP Deficiency; Osteopetrosis; Alpha-Mannosidosis; Sandhoff Disease; Niemann-Pick Diseases; MPS IV; Gaucher Disease; GAN; GM1 Gangliosidoses; Morquio Disease; S-Adenosylhomocysteine Hydrolase Deficiency; Batten Disease; Pelizaeus-Merzbacher Disease; Leukodystrophy; Lysosomal Storage Diseases; Purine Nucleoside Phosphorylase Deficiency; Multiple Sulfatase Deficiency Disease

  8. Lipids, lysosomes, and autophagy.

    Science.gov (United States)

    Jaishy, Bharat; Abel, E Dale

    2016-09-01

    Lipids are essential components of a cell providing energy substrates for cellular processes, signaling intermediates, and building blocks for biological membranes. Lipids are constantly recycled and redistributed within a cell. Lysosomes play an important role in this recycling process that involves the recruitment of lipids to lysosomes via autophagy or endocytosis for their degradation by lysosomal hydrolases. The catabolites produced are redistributed to various cellular compartments to support basic cellular function. Several studies demonstrated a bidirectional relationship between lipids and lysosomes that regulate autophagy. While lysosomal degradation pathways regulate cellular lipid metabolism, lipids also regulate lysosome function and autophagy. In this review, we focus on this bidirectional relationship in the context of dietary lipids and provide an overview of recent evidence of how lipid-overload lipotoxicity, as observed in obesity and metabolic syndrome, impairs lysosomal function and autophagy that may eventually lead to cellular dysfunction or cell death. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

  9. Endosome-lysosomes and neurodegeneration.

    Science.gov (United States)

    Mayer, R J; Tipler, C; Laszlo, L; Arnold, J; Lowe, J; Landon, M

    1994-01-01

    A number of the major human and animal neurodegenerative diseases, such as Alzheimer's disease and sheep scrapie, are characterised by deposits of amyloid, arising through incomplete breakdown of membrane proteins. Although our knowledge concerning these diseases is increasing, they remain largely untreatable. Recently, attention has focussed on the mechanisms of production of different types of amyloid and the likely involvement within cells of acid compartments called endosome-lysosomes. These organelles may be 'bioreactor' sites for the unfolding and partial degradation of membrane proteins to generate the amyloid materials. These subsequently become expelled from the cell, or are released from dead cells, and accumulate as pathological entities. Common features of the disease processes give new direction to therapeutic intervention.

  10. Sphingolipids and lysosomal pathologies.

    Science.gov (United States)

    Schulze, Heike; Sandhoff, Konrad

    2014-05-01

    Endocytosed (glyco)sphingolipids are degraded, together with other membrane lipids in a stepwise fashion by endolysosomal enzymes with the help of small lipid binding proteins, the sphingolipid activator proteins (SAPs), at the surface of intraluminal lysosomal vesicles. Inherited defects in a sphingolipid-degrading enzyme or SAP cause the accumulation of the corresponding lipid substrates, including cytotoxic lysosphingolipids, such as galactosylsphingosine and glucosylsphingosine, and lead to a sphingolipidosis. Analysis of patients with prosaposin deficiency revealed the accumulation of intra-endolysosmal vesicles and membrane structures (IM). Feeding of prosaposin reverses the storage, suggesting inner membrane structures as platforms of sphingolipid degradation. Water soluble enzymes can hardly attack sphingolipids embedded in the membrane of inner endolysosomal vesicles. The degradation of sphingolipids with few sugar residues therefore requires the help of the SAPs, and is strongly stimulated by anionic membrane lipids. IMs are rich in anionic bis(monoacylglycero)phosphate (BMP). This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology. © 2013.

  11. Expanding Newborn Screening for Lysosomal Disorders: Opportunities and Challenges

    Science.gov (United States)

    Waggoner, Darrel J.; Tan, Christopher A.

    2011-01-01

    Newborn screening (NBS), since its implementation in the 1960s, has traditionally been successful in reducing mortality and disability in children with a range of different conditions. Lysosomal storage disorders (LSD) are a heterogeneous group of inherited metabolic diseases that result from lysosomal dysfunction. Based on available treatment and…

  12. Systemic and neurologic abnormalities distinguish the lysosomal disorders sialidosis and galactosialidosis in mice.

    Science.gov (United States)

    de Geest, Natalie; Bonten, Erik; Mann, Linda; de Sousa-Hitzler, Jean; Hahn, Christopher; d'Azzo, Alessandra

    2002-06-01

    Neuraminidase initiates the hydrolysis of sialo-glycoconjugates by removing their terminal sialic acid residues. In humans, primary or secondary deficiency of this enzyme leads to two clinically similar neurodegenerative lysosomal storage disorders: sialidosis and galactosialidosis (GS). Mice nullizygous at the Neu1 locus develop clinical abnormalities reminiscent of early-onset sialidosis in children, including severe nephropathy, progressive edema, splenomegaly, kyphosis and urinary excretion of sialylated oligosaccharides. Although the sialidosis mouse model shares clinical and histopathological features with GS mice and GS patients, we have identified phenotypic abnormalities that seem specific for sialidosis mice. These include progressive deformity of the spine, high incidence of premature death, age-related extramedullary hematopoiesis, and lack of early degeneration of cerebellar Purkinje cells. The differences and similarities identified in these sialidosis and GS mice may help to better understand the pathophysiology of these diseases in children and to identify more targeted therapies for each of these diseases.

  13. Crosstalk between Lysosomes and Mitochondria in Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Nicoletta Plotegher

    2017-12-01

    Full Text Available Parkinson's disease (PD is the most common motor neurodegenerative disorder. In most cases the cause of the disease is unknown, while in about 10% of subjects, it is associated with mutations in a number of different genes. Several different mutations in 15 genes have been identified as causing familial forms of the disease, while many others have been identified as risk factors. A striking number of these genes are either involved in the regulation of mitochondrial function or of endo-lysosomal pathways. Mutations affecting one of these two pathways are often coupled with defects in the other pathway, suggesting a crosstalk between them. Moreover, PD-linked mutations in genes encoding proteins with other functions are frequently associated with defects in mitochondrial and/or autophagy/lysosomal function as a secondary effect. Even toxins that impair mitochondrial function and cause parkinsonian phenotypes, such as rotenone, also impair lysosomal function. In this review, we explore the reciprocal relationship between mitochondrial and lysosomal pathways in PD. We will discuss the impact of mitochondrial dysfunction on the lysosomal compartment and of endo-lysosomal defects on mitochondrial function, and explore the roles of both causative genes and genes that are risk factors for PD. Understanding the pathways that govern these interactions should help to define a framework to understand the roles and mechanisms of mitochondrial and lysosomal miscommunication in the pathophysiology of PD.

  14. Meditation and neurodegenerative diseases

    National Research Council Canada - National Science Library

    Newberg, Andrew B; Serruya, Mijail; Wintering, Nancy; Moss, Aleezé Sattar; Reibel, Diane; Monti, Daniel A

    2014-01-01

    .... Meditation techniques present an interesting potential adjuvant treatment for patients with neurodegenerative diseases and have the advantage of being inexpensive, and easy to teach and perform...

  15. Mitochondrial respiration controls lysosomal function during inflammatory T cell responses

    Science.gov (United States)

    Baixauli, Francesc; Acín-Pérez, Rebeca; Villarroya-Beltrí, Carolina; Mazzeo, Carla; Nuñez-Andrade, Norman; Gabandé-Rodriguez, Enrique; Dolores Ledesma, Maria; Blázquez, Alberto; Martin, Miguel Angel; Falcón-Pérez, Juan Manuel; Redondo, Juan Miguel; Enríquez, Jose Antonio; Mittelbrunn, Maria

    2016-01-01

    Summary The endolysosomal system is critical for the maintenance of cellular homeostasis. However, how endolysosomal compartment is regulated by mitochondrial function is largely unknown. We have generated a mouse model with defective mitochondrial function in CD4+ T lymphocytes by genetic deletion of the mitochondrial transcription factor A (Tfam). Mitochondrial respiration-deficiency impairs lysosome function, promotes p62 and sphingomyelin accumulation and disrupts endolysosomal trafficking pathways and autophagy, thus linking a primary mitochondrial dysfunction to a lysosomal storage disorder. The impaired lysosome function in Tfam-deficient cells subverts T cell differentiation toward pro-inflammatory subsets and exacerbates the in vivo inflammatory response. Restoration of NAD+ levels improves lysosome function and corrects the inflammatory defects in Tfam-deficient T cells. Our results uncover a mechanism by which mitochondria regulate lysosome function to preserve T cell differentiation and effector functions, and identify novel strategies for intervention in mitochondrial-related diseases. PMID:26299452

  16. [Sleep in neurodegenerative disorders].

    Science.gov (United States)

    Happe, S; Mayer, G

    2006-10-01

    Neurodegenerative disorders are a group of heterogeneous, progressive disorders of varying etiology that affect one or more systems. They occur predominantly at older age, during which the structure and amount of sleep undergo changes. Neurodegenerative processes cause structural changes of the sleep/wake generators in the brainstem which result in disorders such as daytime sleepiness, insomnia, sleep-related movement and breathing disturbances, and disorders of the circadian rhythms. Some sleep disorders manifest years before the onset of neurodegenerative disorders and may serve as predictors. Polysomnography shows sleep fragmentation, tonic or phasic movements of the extremities, alteration of respiratory muscles, reduced slow wave sleep, REM sleep absence or without muscle atonia, increased arousal or wake activity, epileptiform EEG activity, and changes in sleep-related breathing. Very frequently, REM sleep behaviour disorder is associated with neurodegenerative disorders. In this overview we present symptoms, pathophysiology, and polysomnographic findings of sleep disorders in prevalent neurodegenerative disorders.

  17. lysosome tethering and fusion

    Indian Academy of Sciences (India)

    AMIT TULI

    Conserved across evolution (skipped in budding yeast), similar localization and function reported for Drosophila and C. elegans homolog of Arl8 (Hofmann et al.,. JCS 2006, Nakae I et al., MBoC 2010); and. □ Arl8b regulates spatial distribution of lysosomes (Hofmann et al., JCS 2006). Arl8b-GFP. LAMP1. Merge ...

  18. Lysosomal and Mitochondrial Liaisons in Niemann-Pick Disease

    Directory of Open Access Journals (Sweden)

    Sandra Torres

    2017-11-01

    Full Text Available Lysosomal storage disorders (LSD are characterized by the accumulation of diverse lipid species in lysosomes. Niemann-Pick type A/B (NPA/B and type C diseases Niemann-Pick type C (NPC are progressive LSD caused by loss of function of distinct lysosomal-residing proteins, acid sphingomyelinase and NPC1, respectively. While the primary cause of these diseases differs, both share common biochemical features, including the accumulation of sphingolipids and cholesterol, predominantly in endolysosomes. Besides these alterations in lysosomal homeostasis and function due to accumulation of specific lipid species, the lysosomal functional defects can have far-reaching consequences, disrupting intracellular trafficking of sterols, lipids and calcium through membrane contact sites (MCS of apposed compartments. Although MCS between endoplasmic reticulum and mitochondria have been well studied and characterized in different contexts, emerging evidence indicates that lysosomes also exhibit close proximity with mitochondria, which translates in their mutual functional regulation. Indeed, as best illustrated in NPC disease, alterations in the lysosomal-mitochondrial liaisons underlie the secondary accumulation of specific lipids, such as cholesterol in mitochondria, resulting in mitochondrial dysfunction and defective antioxidant defense, which contribute to disease progression. Thus, a better understanding of the lysosomal and mitochondrial interactions and trafficking may identify novel targets for the treatment of Niemann-Pick disease.

  19. RBD and Neurodegenerative Diseases.

    Science.gov (United States)

    Jiang, Haiyang; Huang, Jinsha; Shen, Yan; Guo, Shiyi; Wang, Luxi; Han, Chao; Liu, Ling; Ma, Kai; Xia, Yun; Li, Jie; Xu, Xiaoyun; Xiong, Nian; Wang, Tao

    2017-05-01

    Rapid eye movement (REM) sleep behavior disorder (RBD) is a sleep disorder characterized by enacting one's dreams during the REM sleep, with most of the dreams being violent or aggressive, so that patients often come to see the doctor complaining hurting themselves or bed partners during sleep. Prevalence of RBD, based on population, is 0.38-2.01 %, but much higher in patients with neurodegenerative diseases, especially synucleinopathies. RBD may herald the emergence of synucleinopathies by decades, such that it may be used as an effective early marker of neurodegenerative diseases. Pharmaceutical treatment of RBD includes clonazepam, melatonin, pramipexole, and some newly reported medications. In this review, we summarized the clinical and PSG features of RBD, the pathophysiology and the therapy of it, focusing on the correlation between neurodegenerative diseases and RBD, in order to emphasize the significance of RBD as an early marker of neurodegenerative diseases.

  20. Niemann-Pick C disease gene mutations and age-related neurodegenerative disorders.

    Directory of Open Access Journals (Sweden)

    Michael Zech

    Full Text Available Niemann-Pick type C (NPC disease is a rare autosomal-recessively inherited lysosomal storage disorder caused by mutations in NPC1 (95% or NPC2. Given the highly variable phenotype, diagnosis is challenging and particularly late-onset forms with predominantly neuropsychiatric presentations are likely underdiagnosed. Pathophysiologically, genetic alterations compromising the endosomal/lysosomal system are linked with age-related neurodegenerative disorders. We sought to examine a possible association of rare sequence variants in NPC1 and NPC2 with Parkinson's disease (PD, frontotemporal lobar degeneration (FTLD and progressive supranuclear palsy (PSP, and to genetically determine the proportion of potentially misdiagnosed NPC patients in these neurodegenerative conditions. By means of high-resolution melting, we screened the coding regions of NPC1 and NPC2 for rare genetic variation in a homogenous German sample of patients clinically diagnosed with PD (n = 563, FTLD (n = 133 and PSP (n = 94, and 846 population-based controls. The frequencies of rare sequence variants in NPC1/2 did not differ significantly between patients and controls. Disease-associated NPC1/2 mutations were found in six PD patients (1.1% and seven control subjects (0.8%, but not in FTLD or PSP. All rare variation was detected in the heterozygous state and no compound heterozygotes were observed. Our data do not support the hypothesis that rare NPC1/2 variants confer susceptibility for PD, FTLD, or PSP in the German population. Misdiagnosed NPC patients were not present in our samples. However, further assessment of NPC disease genes in age-related neurodegeneration is warranted.

  1. Neuronal ceroid lipofuscinoses caused by defects in soluble lysosomal enzymes (CLN1 and CLN2).

    Science.gov (United States)

    Hofmann, Sandra L; Atashband, Armita; Cho, Steve K; Das, Amit K; Gupta, Praveena; Lu, Jui-Yun

    2002-08-01

    Infantile and classical late infantile neuronal ceroid lipofuscinoses (NCL) are two recent additions to the expanding spectrum of lysosomal storage disorders caused by deficiencies in lysosomal hydrolases. They are latecomers to the lysosomal storage disorders, probably because of the heterogeneous nature of the storage material, which precluded meaningful biochemical analysis. Infantile NCL is caused by deficiency in palmitoyl-protein thioesterase, an enzyme that hydrolyzes fatty acids from cysteine residues in lipid-modified proteins. Classical late-infantile NCL is caused by a deficiency in tripeptidyl amino peptidase-I, a lysosomal peptidase that removes three amino acids from the free amino terminus of peptides or small proteins. Late-onset forms of these disorders have been described. The clinical, biochemical, and molecular genetic aspects of these two latest lysosomal storage disorders are discussed in this review. In addition, approaches to treatment and future directions for research are examined.

  2. Sleep and neurodegenerative diseases.

    Science.gov (United States)

    Chokroverty, Sudhansu

    2009-09-01

    Sleep disturbances are common in neurodegenerative diseases. Disturbed sleep can result in fatigue, irritability, morning headaches, impaired motor and cognitive skills, depression, and daytime somnolence. The major sleep complaints include insomnia, hypersomnia, parasomnia, excessive nocturnal motor activity, circadian sleep-wake rhythm disturbance, and respiratory dysrhythmia. The pathogenetic mechanisms of sleep disturbances may be secondary to direct structural alteration of the sleep-wake generating neurons or from several other indirect mechanisms. At the biochemical level, neurodegenerative diseases may be largely classified as tauopathies, alpha-synucleinopathies, and other diseases. Overnight polysomnography (PSG), Multiple Sleep Latency Test, Maintenance of Wakefulness Test, and actigraphy are some important diagnostic laboratory tests in the evaluation of sleep disturbances. Management of sleep disturbances is complex and is based primarily on the nature of the sleep disturbance. The clinical profiles, pathogenetic mechanisms, PSG findings, and management issues are discussed here with reference to some common neurodegenerative diseases. Thieme Medical Publishers.

  3. Molecular Chaperone Dysfunction in Neurodegenerative Diseases and Effects of Curcumin

    Directory of Open Access Journals (Sweden)

    Panchanan Maiti

    2014-01-01

    Full Text Available The intra- and extracellular accumulation of misfolded and aggregated amyloid proteins is a common feature in several neurodegenerative diseases, which is thought to play a major role in disease severity and progression. The principal machineries maintaining proteostasis are the ubiquitin proteasomal and lysosomal autophagy systems, where heat shock proteins play a crucial role. Many protein aggregates are degraded by the lysosomes, depending on aggregate size, peptide sequence, and degree of misfolding, while others are selectively tagged for removal by heat shock proteins and degraded by either the proteasome or phagosomes. These systems are compromised in different neurodegenerative diseases. Therefore, developing novel targets and classes of therapeutic drugs, which can reduce aggregates and maintain proteostasis in the brains of neurodegenerative models, is vital. Natural products that can modulate heat shock proteins/proteosomal pathway are considered promising for treating neurodegenerative diseases. Here we discuss the current knowledge on the role of HSPs in protein misfolding diseases and knowledge gained from animal models of Alzheimer’s disease, tauopathies, and Huntington’s diseases. Further, we discuss the emerging treatment regimens for these diseases using natural products, like curcumin, which can augment expression or function of heat shock proteins in the cell.

  4. Lysosomal acid lipase deficiency--an under-recognized cause of dyslipidaemia and liver dysfunction

    NARCIS (Netherlands)

    Reiner, Željko; Guardamagna, Ornella; Nair, Devaki; Soran, Handrean; Hovingh, Kees; Bertolini, Stefano; Jones, Simon; Ćorić, Marijana; Calandra, Sebastiano; Hamilton, John; Eagleton, Terence; Ros, Emilio

    2014-01-01

    Lysosomal acid lipase deficiency (LAL-D) is a rare autosomal recessive lysosomal storage disease caused by deleterious mutations in the LIPA gene. The age at onset and rate of progression vary greatly and this may relate to the nature of the underlying mutations. Patients presenting in infancy have

  5. Intracellular sphingosine releases calcium from lysosomes

    Science.gov (United States)

    Höglinger, Doris; Haberkant, Per; Aguilera-Romero, Auxiliadora; Riezman, Howard; Porter, Forbes D; Platt, Frances M; Galione, Antony; Schultz, Carsten

    2015-01-01

    To elucidate new functions of sphingosine (Sph), we demonstrate that the spontaneous elevation of intracellular Sph levels via caged Sph leads to a significant and transient calcium release from acidic stores that is independent of sphingosine 1-phosphate, extracellular and ER calcium levels. This photo-induced Sph-driven calcium release requires the two-pore channel 1 (TPC1) residing on endosomes and lysosomes. Further, uncaging of Sph leads to the translocation of the autophagy-relevant transcription factor EB (TFEB) to the nucleus specifically after lysosomal calcium release. We confirm that Sph accumulates in late endosomes and lysosomes of cells derived from Niemann-Pick disease type C (NPC) patients and demonstrate a greatly reduced calcium release upon Sph uncaging. We conclude that sphingosine is a positive regulator of calcium release from acidic stores and that understanding the interplay between Sph homeostasis, calcium signaling and autophagy will be crucial in developing new therapies for lipid storage disorders such as NPC. DOI: http://dx.doi.org/10.7554/eLife.10616.001 PMID:26613410

  6. Endosome-lysosomes, ubiquitin and neurodegeneration.

    Science.gov (United States)

    Mayer, R J; Tipler, C; Arnold, J; Laszlo, L; Al-Khedhairy, A; Lowe, J; Landon, M

    1996-01-01

    Before the advent of ubiquitin immunochemistry and immunogold electron microscopy, there was no known intracellular molecular commonality between neurodegenerative diseases. The application of antibodies which primarily detect ubiquitin protein conjugates has shown that all of the human and animal idiopathic and transmissible chronic neurodegenerative diseases, (including Alzheimer's disease (AD), Lewy body disease (LBD), amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD) and scrapie) are related by some form of intraneuronal inclusion which contains ubiquitin protein conjugates. In addition, disorders such as Alzheimer's disease, CJD and sheep scrapie, are characterised by deposits of amyloid, arising through incomplete breakdown of membrane proteins which may be associated with cytoskeletal reorganisation. Although our knowledge about these diseases is increasing, they remain largely untreatable. Recently, attention has focused on the mechanisms of production of different types of amyloid and the likely involvement within cells of the endosome-lysosome system, organelles which are immuno-positive for ubiquitin protein conjugates. These organelles may be 'bioreactor' sites for the unfolding and partial degradation of membrane proteins to generate the amyloid materials or their precursors which subsequently become expelled from the cell, or are released from dead cells, and accumulate as pathological entities. Such common features of the disease processes give new direction to therapeutic intervention.

  7. Inhibition of Intermediate-Conductance Calcium-Activated K Channel (KCa3.1) and Fibroblast Mitogenesis by α-Linolenic Acid and Alterations of Channel Expression in the Lysosomal Storage Disorders, Fabry Disease, and Niemann Pick C.

    Science.gov (United States)

    Oliván-Viguera, Aida; Lozano-Gerona, Javier; López de Frutos, Laura; Cebolla, Jorge J; Irún, Pilar; Abarca-Lachen, Edgar; García-Malinis, Ana J; García-Otín, Ángel Luis; Gilaberte, Yolanda; Giraldo, Pilar; Köhler, Ralf

    2017-01-01

    The calcium/calmodulin-gated KCa3.1 channel regulates normal and abnormal mitogenesis by controlling K+-efflux, cell volume, and membrane hyperpolarization-driven calcium-entry. Recent studies suggest modulation of KCa3.1 by omega-3 fatty acids as negative modulators and impaired KCa3.1 functions in the inherited lysosomal storage disorder (LSD), Fabry disease (FD). In the first part of present study, we characterize KCa3.1 in murine and human fibroblasts and test the impact of omega-3 fatty acids on fibroblast proliferation. In the second, we study whether KCa3.1 is altered in the LSDs, FD, and Niemann-Pick disease type C (NPC). Our patch-clamp and mRNA-expression studies on murine and human fibroblasts show functional expression of KCa3.1. KCa currents display the typical pharmacological fingerprint of KCa3.1: Ca2+-activation, potentiation by the positive-gating modulators, SKA-31 and SKA-121, and inhibition by TRAM-34, Senicapoc (ICA-17043), and the negative-gating modulator, 13b. Considering modulation by omega-3 fatty acids we found that α-linolenic acid (α-LA) and docosahexanenoic acid (DHA) inhibit KCa3.1 currents and strongly reduce fibroblast growth. The α-LA-rich linseed oil and γ-LA-rich borage oil at 0.5% produce channel inhibition while α-LA/γ-LA-low oils has no anti-proliferative effect. Concerning KCa3.1 in LSD, mRNA expression studies, and patch-clamp on primary fibroblasts from FD and NPC patients reveal lower KCa3.1-gene expression and membrane expression than in control fibroblasts. In conclusion, the omega-3 fatty acid, α-LA, and α-LA/γ-LA-rich plant oils, inhibit fibroblast KCa3.1 channels and mitogenesis. Reduced fibroblast KCa3.1 functions are a feature and possible biomarker of cell dysfunction in FD and NPC and supports the concept that biased lipid metabolism is capable of negatively modulating KCa3.1 expression.

  8. Sleep in Neurodegenerative Diseases.

    Science.gov (United States)

    Iranzo, Alex

    2016-03-01

    Disorders of sleep are an integral part of neurodegenerative diseases and include insomnia, sleep-wake cycle disruption, excessive daytime sleepiness that may be manifested as persistent somnolence or sudden onset of sleep episodes, obstructive and central sleep apnea, rapid eye movement sleep behavior disorder, and restless legs syndrome. The origin of these sleep disorders is multifactorial including degeneration of the brain areas that modulate sleep, the symptoms of the disease, and the effect of medications. Treatment of sleep disorders in patients with neurodegenerative diseases should be individualized and includes behavioral therapy, sleep hygiene, bright light therapy, melatonin, hypnotics, waking-promoting agents, and continuous positive airway pressure. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Endo-lysosomal and autophagic dysfunction: a driving factor in Alzheimer's disease?

    Science.gov (United States)

    Whyte, Lauren S; Lau, Adeline A; Hemsley, Kim M; Hopwood, John J; Sargeant, Timothy J

    2017-03-01

    Alzheimer's disease (AD) is the most common cause of dementia, and its prevalence will increase significantly in the coming decades. Although important progress has been made, fundamental pathogenic mechanisms as well as most hereditary contributions to the sporadic form of the disease remain unknown. In this review, we examine the now substantial links between AD pathogenesis and lysosomal biology. The lysosome hydrolyses and processes cargo delivered by multiple pathways, including endocytosis and autophagy. The endo-lysosomal and autophagic networks are central to clearance of cellular macromolecules, which is important given there is a deficit in clearance of amyloid-β in AD. Numerous studies show prominent lysosomal dysfunction in AD, including perturbed trafficking of lysosomal enzymes and accumulation of the same substrates that accumulate in lysosomal storage disorders. Examination of the brain in lysosomal storage disorders shows the accumulation of amyloid precursor protein metabolites, which further links lysosomal dysfunction with AD. This and other evidence leads us to hypothesise that genetic variation in lysosomal genes modifies the disease course of sporadic AD. © 2016 International Society for Neurochemistry.

  10. Lysosomal multienzyme complex: pros and cons of working together.

    Science.gov (United States)

    Bonten, Erik J; Annunziata, Ida; d'Azzo, Alessandra

    2014-06-01

    The ubiquitous distribution of lysosomes and their heterogeneous protein composition reflects the versatility of these organelles in maintaining cell homeostasis and their importance in tissue differentiation and remodeling. In lysosomes, the degradation of complex, macromolecular substrates requires the synergistic action of multiple hydrolases that usually work in a stepwise fashion. This catalytic machinery explains the existence of lysosomal enzyme complexes that can be dynamically assembled and disassembled to efficiently and quickly adapt to the pool of substrates to be processed or degraded, adding extra tiers to the regulation of the individual protein components. An example of such a complex is the one composed of three hydrolases that are ubiquitously but differentially expressed: the serine carboxypeptidase, protective protein/cathepsin A (PPCA), the sialidase, neuraminidase-1 (NEU1), and the glycosidase β-galactosidase (β-GAL). Next to this 'core' complex, the existence of sub-complexes, which may contain additional components, and function at the cell surface or extracellularly, suggests as yet unexplored functions of these enzymes. Here we review how studies of basic biological processes in the mouse models of three lysosomal storage disorders, galactosialidosis, sialidosis, and GM1-gangliosidosis, revealed new and unexpected roles for the three respective affected enzymes, Ppca, Neu1, and β-Gal, that go beyond their canonical degradative activities. These findings have broadened our perspective on their functions and may pave the way for the development of new therapies for these lysosomal storage disorders.

  11. Lysosomal glycosphingolipid catabolism by acid ceramidase: formation of glycosphingoid bases during deficiency of glycosidases

    NARCIS (Netherlands)

    Ferraz, Maria J.; Marques, André R. A.; Appelman, Monique D.; Verhoek, Marri; Strijland, Anneke; Mirzaian, Mina; Scheij, Saskia; Ouairy, Cécile M.; Lahav, Daniel; Wisse, Patrick; Overkleeft, Herman S.; Boot, Rolf G.; Aerts, Johannes M.

    2016-01-01

    Glycosphingoid bases are elevated in inherited lysosomal storage disorders with deficient activity of glycosphingolipid catabolizing glycosidases. We investigated the molecular basis of the formation of glucosylsphingosine and globotriaosylsphingosine during deficiency of glucocerebrosidase (Gaucher

  12. Protecting cells by protecting their vulnerable lysosomes: Identification of a new mechanism for preserving lysosomal functional integrity upon oxidative stress.

    Directory of Open Access Journals (Sweden)

    Raquel Pascua-Maestro

    2017-02-01

    many cellular functions, critical for the outcome of a wide variety of neurodegenerative diseases. These results open therapeutic opportunities by providing a route of entry and a repair mechanism for lysosomes in pathological situations.

  13. Lysosomal cell death at a glance

    DEFF Research Database (Denmark)

    Aits, Sonja; Jaattela, Marja

    2013-01-01

    Lysosomes serve as the cellular recycling centre and are filled with numerous hydrolases that can degrade most cellular macromolecules. Lysosomal membrane permeabilization and the consequent leakage of the lysosomal content into the cytosol leads to so-called "lysosomal cell death". This form...... of cell death is mainly carried out by the lysosomal cathepsin proteases and can have necrotic, apoptotic or apoptosis-like features depending on the extent of the leakage and the cellular context. This article summarizes our current knowledge on lysosomal cell death with an emphasis on the upstream...... mechanisms that lead to lysosomal membrane permeabilization....

  14. TMEM175 deficiency impairs lysosomal and mitochondrial function and increases α-synuclein aggregation.

    Science.gov (United States)

    Jinn, Sarah; Drolet, Robert E; Cramer, Paige E; Wong, Andus Hon-Kit; Toolan, Dawn M; Gretzula, Cheryl A; Voleti, Bhavya; Vassileva, Galya; Disa, Jyoti; Tadin-Strapps, Marija; Stone, David J

    2017-02-28

    Parkinson disease (PD) is a neurodegenerative disorder pathologically characterized by nigrostriatal dopamine neuron loss and the postmortem presence of Lewy bodies, depositions of insoluble α-synuclein, and other proteins that likely contribute to cellular toxicity and death during the disease. Genetic and biochemical studies have implicated impaired lysosomal and mitochondrial function in the pathogenesis of PD. Transmembrane protein 175 (TMEM175), the lysosomal K+ channel, is centered under a major genome-wide association studies peak for PD, making it a potential candidate risk factor for the disease. To address the possibility that variation in TMEM175 could play a role in PD pathogenesis, TMEM175 function was investigated in a neuronal model system. Studies confirmed that TMEM175 deficiency results in unstable lysosomal pH, which led to decreased lysosomal catalytic activity, decreased glucocerebrosidase activity, impaired autophagosome clearance by the lysosome, and decreased mitochondrial respiration. Moreover, TMEM175 deficiency in rat primary neurons resulted in increased susceptibility to exogenous α-synuclein fibrils. Following α-synuclein fibril treatment, neurons deficient in TMEM175 were found to have increased phosphorylated and detergent-insoluble α-synuclein deposits. Taken together, data from these studies suggest that TMEM175 plays a direct and critical role in lysosomal and mitochondrial function and PD pathogenesis and highlight this ion channel as a potential therapeutic target for treating PD.

  15. Cancer-associated lysosomal changes

    DEFF Research Database (Denmark)

    Kallunki, T; Olsen, O D; Jaattela, Marja

    2013-01-01

    -targeting anti-cancer drugs. In this review we compile our current knowledge on cancer-associated changes in lysosomal composition and discuss the consequences of these alterations to cancer progression and the possibilities they can bring to cancer therapy.Oncogene advance online publication, 9 July 2012; doi...

  16. Lysosomal glycosphingolipid catabolism by acid ceramidase: formation of glycosphingoid bases during deficiency of glycosidases.

    Science.gov (United States)

    Ferraz, Maria J; Marques, André R A; Appelman, Monique D; Verhoek, Marri; Strijland, Anneke; Mirzaian, Mina; Scheij, Saskia; Ouairy, Cécile M; Lahav, Daniel; Wisse, Patrick; Overkleeft, Herman S; Boot, Rolf G; Aerts, Johannes M

    2016-03-01

    Glycosphingoid bases are elevated in inherited lysosomal storage disorders with deficient activity of glycosphingolipid catabolizing glycosidases. We investigated the molecular basis of the formation of glucosylsphingosine and globotriaosylsphingosine during deficiency of glucocerebrosidase (Gaucher disease) and α-galactosidase A (Fabry disease). Independent genetic and pharmacological evidence is presented pointing to an active role of acid ceramidase in both processes through deacylation of lysosomal glycosphingolipids. The potential pathophysiological relevance of elevated glycosphingoid bases generated through this alternative metabolism in patients suffering from lysosomal glycosidase defects is discussed. © 2016 Federation of European Biochemical Societies.

  17. Selective autophagy: The new player in the fight against neurodegenerative diseases?

    Science.gov (United States)

    Wu, Ming-Yue; Song, Ju-Xian; Wang, Sheng-Fang; Cai, Cui-Zan; Li, Min; Lu, Jia-Hong

    2017-11-16

    Autophagy is the lysosome-mediated bulk degradation of cellular components for material recycling to maintain cellular homeostasis. Autophagy was initially regarded as a nonselective process, however, recent evidence indicates that this process can in fact be highly selective, especially for targeting and degrading organelles, invading pathogens and protein aggregates. Recent studies have revealed an intrinsic connection between selective autophagy and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Given the vital roles of selective autophagy in these neurodegenerative diseases, modulation of this process is emerging as a new therapeutic strategy for neuroprotection. This review introduces the concept of selective autophagy, provides an overview of the pathological connection between selective autophagy and neurodegenerative diseases, and discusses approaches to modulate selective autophagy for therapeutic effects against neurodegenerative diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Sleep disorders in neurodegenerative diseases.

    Science.gov (United States)

    Raggi, A; Ferri, R

    2010-11-01

    The aim of this review is to provide data on sleep disturbances in three categories of neurodegenerative disorders: synucleinopathies, tauopathies, and other diseases (this heterogeneous group includes also spinocerebellar degeneration and amyotrophic lateral sclerosis). Analysing and knowing sleep disorders in neurodegenerative diseases may offer important insights into the pathomechanism of some of these diseases and calls attention to the still insufficiently known 'sleep neurology'. The identification of sleep disorders in some neurodegenerative conditions may make their diagnosis easier and earlier; for example, rapid eye movements sleep behaviour disorder may precede any other clinical manifestation of synucleinopathies by more than 10 years. © 2010 The Author(s). Journal compilation © 2010 EFNS.

  19. Involvement of the endosomal-lysosomal system correlates with regional pathology in Creutzfeldt-Jakob disease

    DEFF Research Database (Denmark)

    Kovács, Gábor G; Gelpi, Ellen; Ströbel, Thomas

    2007-01-01

    these with the severity of neuropathologic changes. In regions with mild pathology and scant abnormal prion protein (PrP) deposition, neurons showed an increased volume of Rab5-immunopositive early endosomes. In contrast, neurons in regions with prominent pathology had an increased volume of cathepsin D- or B...... correlate with regional pathology. Overloading of this system might impair the function of lysosomal enzymes and thus may mimic some features of lysosomal storage disorders. Udgivelsesdato: 2007-Jul...

  20. DNA damage in neurodegenerative diseases

    Energy Technology Data Exchange (ETDEWEB)

    Coppedè, Fabio, E-mail: fabio.coppede@med.unipi.it; Migliore, Lucia, E-mail: lucia.migliore@med.unipi.it

    2015-06-15

    Highlights: • Oxidative DNA damage is one of the earliest detectable events in the neurodegenerative process. • The mitochondrial DNA is more vulnerable to oxidative attack than the nuclear DNA. • Cytogenetic damage has been largely documented in Alzheimer's disease patients. • The question of whether DNA damage is cause or consequence of neurodegeneration is still open. • Increasing evidence links DNA damage and repair with epigenetic phenomena. - Abstract: Following the observation of increased oxidative DNA damage in nuclear and mitochondrial DNA extracted from post-mortem brain regions of patients affected by neurodegenerative diseases, the last years of the previous century and the first decade of the present one have been largely dedicated to the search of markers of DNA damage in neuronal samples and peripheral tissues of patients in early, intermediate or late stages of neurodegeneration. Those studies allowed to demonstrate that oxidative DNA damage is one of the earliest detectable events in neurodegeneration, but also revealed cytogenetic damage in neurodegenerative conditions, such as for example a tendency towards chromosome 21 malsegregation in Alzheimer's disease. As it happens for many neurodegenerative risk factors the question of whether DNA damage is cause or consequence of the neurodegenerative process is still open, and probably both is true. The research interest in markers of oxidative stress was shifted, in recent years, towards the search of epigenetic biomarkers of neurodegenerative disorders, following the accumulating evidence of a substantial contribution of epigenetic mechanisms to learning, memory processes, behavioural disorders and neurodegeneration. Increasing evidence is however linking DNA damage and repair with epigenetic phenomena, thereby opening the way to a very attractive and timely research topic in neurodegenerative diseases. We will address those issues in the context of Alzheimer's disease

  1. Brief exposure to copper activates lysosomal exocytosis.

    Science.gov (United States)

    Peña, Karina; Coblenz, Jessica; Kiselyov, Kirill

    2015-04-01

    Copper (Cu) is essential mineral, but its toxicity necessitates existence of powerful machinery responsible for the extraction of excess Cu from the cell. Cu exposure was recently shown to induce the translocation of Cu pump ATP7B to the lysosomes followed by lysosomal exocytosis. Here we sought to investigate the mechanisms underlying the effect of Cu on lysosomal exocytosis. We found that brief exposure to Cu activates lysosomal exocytosis, which was measured as a release of the lysosomal digestive enzyme β-hexosaminidase (β-hex) into the extracellular medium and by the presence lysosomal protein LAMP1 at the plasma membrane. Such release depends on calcium (Ca) and on the lysosomal SNARE VAMP7. ATP7B knockdown using RNAi suppressed the basal lysosomal exocytosis, but did not affect the ability of Cu to activate it. ATP7B knockdown was associated with sustained oxidative stress. The removal of Ca from the extracellular medium suppressed the Cu-dependent component of the lysosomal exocytosis. We propose that Cu promotes lysosomal exocytosis by facilitating a Ca-dependent step of the lysosomal exocytosis. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Slow, continuous enzyme replacement via spinal CSF in dogs with the paediatric-onset neurodegenerative disease, MPS IIIA.

    Science.gov (United States)

    King, Barbara; Marshall, Neil R; Hassiotis, Sofia; Trim, Paul J; Tucker, Justin; Hattersley, Kathryn; Snel, Marten F; Jolly, Robert D; Hopwood, John J; Hemsley, Kim M

    2017-05-01

    Intra-cerebrospinal fluid (CSF) injection of recombinant human lysosomal enzyme is a potential treatment strategy for several neurodegenerative lysosomal storage disorders including Sanfilippo syndrome (Mucopolysaccharidosis type IIIA; MPS IIIA). Here we have utilised the MPS IIIA Huntaway dog model to compare the effectiveness of the repeated intermittent bolus injection strategy being used in the trials with an alternate approach; slow, continual infusion of replacement enzyme (recombinant human sulphamidase; rhSGSH) into the spinal CSF using a SynchroMed II® pump attached to a spinal infusion cannula. The ability of each enzyme delivery strategy to ameliorate lesions in MPS IIIA brain was determined in animals treated from ∼three- to six-months of age. Controls received buffer or no treatment. Significant reductions in heparan sulphate (primary substrate) were observed in brain samples from dogs treated via either cisternal or lumbar spinal CSF bolus injection methods and also in slow intra-spinal CSF infusion-treated dogs. The extent of the reduction differed regionally. Pump-delivered rhSGSH was less effective in reducing secondary substrate (GM3 ganglioside) in deeper aspects of cerebral cortex, and although near-amelioration of microglial activation was seen in superficial (but not deep) layers of cerebral cortex in both bolus enzyme-treated groups, pump-infusion of rhSGSH had little impact on microgliosis. While continual low-dose infusion of rhSGSH into MPS IIIA dog CSF reduces disease-based lesions in brain, it was not as efficacious as repeated cisternal or spinal CSF bolus infusion of rhSGSH over the time-frame of these experiments.

  3. Depressive symptoms in neurodegenerative diseases

    Science.gov (United States)

    Baquero, Miquel; Martín, Nuria

    2015-01-01

    Depressive symptoms are very common in chronic conditions. This is true so for neurodegenerative diseases. A number of patients with cognitive decline and dementia due to Alzheimer’s disease and related conditions like Parkinson’s disease, Lewy body disease, vascular dementia, frontotemporal degeneration amongst other entities, experience depressive symptoms in greater or lesser grade at some point during the course of the illness. Depressive symptoms have a particular significance in neurological disorders, specially in neurodegenerative diseases, because brain, mind, behavior and mood relationship. A number of patients may develop depressive symptoms in early stages of the neurologic disease, occurring without clear presence of cognitive decline with only mild cognitive deterioration. Classically, depression constitutes a reliable diagnostic challenge in this setting. However, actually we can recognize and evaluate depressive, cognitive or motor symptoms of neurodegenerative disease in order to establish their clinical significance and to plan some therapeutic strategies. Depressive symptoms can appear also lately, when the neurodegenerative disease is fully developed. The presence of depression and other neuropsychiatric symptoms have a negative impact on the quality-of-life of patients and caregivers. Besides, patients with depressive symptoms also tend to further decrease function and reduce cognitive abilities and also uses to present more affected clinical status, compared with patients without depression. Depressive symptoms are treatable. Early detection of depressive symptoms is very important in patients with neurodegenerative disorders, in order to initiate the most adequate treatment. We review in this paper the main neurodegenerative diseases, focusing in depressive symptoms of each other entities and current recommendations of management and treatment. PMID:26301229

  4. HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity.

    Science.gov (United States)

    Fan, Yan; He, Johnny J

    2016-10-21

    Tat interaction with astrocytes has been shown to be important for Tat neurotoxicity and HIV/neuroAIDS. We have recently shown that Tat expression leads to increased glial fibrillary acidic protein (GFAP) expression and aggregation and activation of unfolded protein response/endoplasmic reticulum (ER) stress in astrocytes and causes neurotoxicity. However, the exact molecular mechanism of astrocyte-mediated Tat neurotoxicity is not defined. In this study, we showed that neurotoxic factors other than Tat protein itself were present in the supernatant of Tat-expressing astrocytes. Two-dimensional gel electrophoresis and mass spectrometry revealed significantly elevated lysosomal hydrolytic enzymes and plasma membrane-associated proteins in the supernatant of Tat-expressing astrocytes. We confirmed that Tat expression and infection of pseudotyped HIV.GFP led to increased lysosomal exocytosis from mouse astrocytes and human astrocytes. We found that Tat-induced lysosomal exocytosis was tightly coupled to astrocyte-mediated Tat neurotoxicity. In addition, we demonstrated that Tat-induced lysosomal exocytosis was astrocyte-specific and required GFAP expression and was mediated by ER stress. Taken together, these results show for the first time that Tat promotes lysosomal exocytosis in astrocytes and causes neurotoxicity through GFAP activation and ER stress induction in astrocytes and suggest a common cascade through which aberrant astrocytosis/GFAP up-regulation potentiates neurotoxicity and contributes to neurodegenerative diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  5. HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity*

    Science.gov (United States)

    Fan, Yan

    2016-01-01

    Tat interaction with astrocytes has been shown to be important for Tat neurotoxicity and HIV/neuroAIDS. We have recently shown that Tat expression leads to increased glial fibrillary acidic protein (GFAP) expression and aggregation and activation of unfolded protein response/endoplasmic reticulum (ER) stress in astrocytes and causes neurotoxicity. However, the exact molecular mechanism of astrocyte-mediated Tat neurotoxicity is not defined. In this study, we showed that neurotoxic factors other than Tat protein itself were present in the supernatant of Tat-expressing astrocytes. Two-dimensional gel electrophoresis and mass spectrometry revealed significantly elevated lysosomal hydrolytic enzymes and plasma membrane-associated proteins in the supernatant of Tat-expressing astrocytes. We confirmed that Tat expression and infection of pseudotyped HIV.GFP led to increased lysosomal exocytosis from mouse astrocytes and human astrocytes. We found that Tat-induced lysosomal exocytosis was tightly coupled to astrocyte-mediated Tat neurotoxicity. In addition, we demonstrated that Tat-induced lysosomal exocytosis was astrocyte-specific and required GFAP expression and was mediated by ER stress. Taken together, these results show for the first time that Tat promotes lysosomal exocytosis in astrocytes and causes neurotoxicity through GFAP activation and ER stress induction in astrocytes and suggest a common cascade through which aberrant astrocytosis/GFAP up-regulation potentiates neurotoxicity and contributes to neurodegenerative diseases. PMID:27609518

  6. Novel mutations in lysosomal neuraminidase identify functional domains and determine clinical severity in sialidosis.

    Science.gov (United States)

    Bonten, E J; Arts, W F; Beck, M; Covanis, A; Donati, M A; Parini, R; Zammarchi, E; d'Azzo, A

    2000-11-01

    Lysosomal neuraminidase is the key enzyme for the intralysosomal catabolism of sialylated glycoconjugates and is deficient in two neurodegenerative lysosomal disorders, sialidosis and galactosialidosis. Here we report the identification of eight novel mutations in the neuraminidase gene of 11 sialidosis patients with various degrees of disease penetrance. Comparison of the primary structure of human neuraminidase with the primary and tertiary structures of bacterial sialidases indicated that most of the single amino acid substitutions occurred in functional motifs or conserved residues. On the basis of the subcellular distribution and residual catalytic activity of the mutant neuraminidases we assigned the mutant proteins to three groups: (i) catalytically inactive and not lysosomal; (ii) catalytically inactive, but localized in lysosome; and (iii) catalytically active and lysosomal. In general, there was a close correlation between the residual activity of the mutant enzymes and the clinical severity of disease. Patients with the severe infantile type II disease had mutations from group I, whereas patients with a mild form of type I disease had at least one mutation from group III. Mutations from the second group were mainly found in juvenile type II patients with intermediate clinical severity. Overall, our findings explain the clinical heterogeneity observed in sialidosis and may help in the assignment of existing or new allelic combinations to specific phenotypes.

  7. Personality and social cognition in neurodegenerative disease.

    Science.gov (United States)

    Shany-Ur, Tal; Rankin, Katherine P

    2011-12-01

    Neurodegenerative diseases often cause focal damage to brain structures mediating social cognition and personality, resulting in altered interpersonal communication and behavior. We review recent research describing this phenomenon in various aspects of social cognition. Corresponding to their pervasive socioemotional deficits, patients with frontotemporal dementia perform poorly on laboratory-based tasks including recognizing emotions, attending to salient information that guides social behavior, representing social knowledge, comprehending others' mental states, and maintaining insight to their own difficulties. Together with poor executive and regulation mechanisms, these social cognition deficits ultimately impact behavior. Patients with logopenic and nonfluent primary progressive aphasia have some deficits recognizing emotional prosody, whereas those with the semantic variant show more widespread deficits in social comprehension. Although Alzheimer's disease patients perform poorly on some social cognition tasks, this typically reflects general cognitive impairment, and their real-life social functioning is less affected than in diseases targeting frontotemporal structures. Studies in motor diseases such as Parkinson's suggest some degradation of emotion recognition and social comprehension, which should be investigated further. We summarize recent findings concerning perception and evaluation of socioemotional information, social knowledge storage and access, advanced information processing mechanisms, and behavioral response selection and regulation across various neurodegenerative diseases.

  8. Engineering of GlcNAc-1-Phosphotransferase for Production of Highly Phosphorylated Lysosomal Enzymes for Enzyme Replacement Therapy.

    Science.gov (United States)

    Liu, Lin; Lee, Wang-Sik; Doray, Balraj; Kornfeld, Stuart

    2017-06-16

    Several lysosomal enzymes currently used for enzyme replacement therapy in patients with lysosomal storage diseases contain very low levels of mannose 6-phosphate, limiting their uptake via mannose 6-phosphate receptors on the surface of the deficient cells. These enzymes are produced at high levels by mammalian cells and depend on endogenous GlcNAc-1-phosphotransferase α/β precursor to phosphorylate the mannose residues on their glycan chains. We show that co-expression of an engineered truncated GlcNAc-1-phosphotransferase α/β precursor and the lysosomal enzyme of interest in the producing cells resulted in markedly increased phosphorylation and cellular uptake of the secreted lysosomal enzyme. This method also results in the production of highly phosphorylated acid β-glucocerebrosidase, a lysosomal enzyme that normally has just trace amounts of this modification.

  9. BACE is degraded via the lysosomal pathway.

    Science.gov (United States)

    Koh, Young Ho; von Arnim, Christine A F; Hyman, Bradley T; Tanzi, Rudolph E; Tesco, Giuseppina

    2005-09-16

    Amyloid plaques are formed by aggregates of amyloid-beta-peptide, a 37-43-amino acid fragment (primarily Abeta(40) and Abeta(42)) generated by proteolytic processing of the amyloid precursor protein (APP) by beta- and gamma-secretases. A type I transmembrane aspartyl protease, BACE (beta-site APP cleaving enzyme), has been identified to be the beta-secretase. BACE is targeted through the secretory pathway to the plasma membrane where it can be internalized to endosomes. The carboxyl terminus of BACE contains a di-leucine-based signal for sorting of transmembrane proteins to endosomes and lysosomes. In this study, we set out to determine whether BACE is degraded by the lysosomal pathway and whether the di-leucine motif is necessary for targeting BACE to the lysosomes. Here we show that lysosomal inhibitors, chloroquine and NH(4)Cl, lead to accumulation of endogenous and ectopically expressed BACE in a variety of cell types, including primary neurons. Furthermore, the inhibition of lysosomal hydrolases results in the redistribution and accumulation of BACE in the late endosomal/lysosomal compartments (lysosome-associated membrane protein 2 (LAMP2)-positive). In contrast, the BACE-LL/AA mutant, in which Leu(499) and Leu(500) in the COOH-terminal sequence (DDISLLK) were replaced by alanines, only partially co-localized with LAMP2-positive compartments following inhibition of lysosomal hydrolases. Collectively, our data indicate that BACE is transported to the late endosomal/lysosomal compartments where it is degraded via the lysosomal pathway and that the di-leucine motif plays a role in sorting BACE to lysosomes.

  10. Delivery of lysosomal enzymes for therapeutic use: glucocerebrosidase as an example.

    Science.gov (United States)

    Grabowski, Gregory A

    2006-11-01

    Enzyme therapies for lysosomal storage diseases have developed over the past decade into the standard-of-care for affected patients. Such therapy for Gaucher disease has been the prototype, using natural source or recombinant forms of human acid beta-glucosidase (GCase). In Gaucher disease, macrophages are the repository for the pathological lipid and the target for delivery of GCase. The macrophage mannose receptor provides a Trojan horse for intracellular delivery of intravenously administered GCase (man-GCase) with mannosyl-terminated oligosaccharide chains. Passage through several hostile compartments (e.g., plasma) leads to inefficient delivery of man-GCase to macrophage lysosomes. However, regular infusions of man-GCase re-establishes health in affected patients. Similar results are being obtained in several other lysosomal storage diseases. Evolving gene and chaperone approaches provide alternative treatment strategies.

  11. Role of lysosomes in cancer therapy

    Directory of Open Access Journals (Sweden)

    Halaby R

    2015-09-01

    Full Text Available Reginald Halaby Department of Biology, Montclair State University, Montclair, NJ, USA Abstract: Lysosomes are acidic organelles that are involved in cellular digestion by endocytosis, phagocytosis, and autophagy. They contain more than 50 hydrolases that are capable of degrading all macromolecules. There is accumulating evidence that lysosomal enzymes can provoke apoptotic cell death. This has important implications for cancer, where proapoptotic genes are mutated and antiapoptotic genes are often overexpressed leading to chemoresistance. Lysosomes play a dual role in cancer development depending on their subcellular localization. When they are located extracellularly they can promote invasion, angiogenesis, and metastasis. However, when they are located intracellularly they can trigger apoptosis by leaking into the cytosol. In this review, we examine the pathways by which lysosomes can evoke both apoptosis and tumorigenesis. Although cancer cells have defects in their apoptotic machinery, they can still undergo lysosomal cell death. We offer several strategies to explain how targeting lysosomes can serve as a putative model for the development of novel anticancer agents. Furthermore, we propose that lysosomal cell death is an effective treatment against apoptosis-resistant cancer cells and thus holds great potential as a therapeutic strategy for circumventing apoptosis deficiency in tumors. Keywords: cathepsins, lysosomal membrane permeability, apoptosis, chemoresistance 

  12. The inactivation of the sortilin gene leads to a partial disruption of prosaposin trafficking to the lysosomes

    Energy Technology Data Exchange (ETDEWEB)

    Zeng, Jibin; Racicott, Jesse [Department of Anatomy and Cell Biology, McGill University, Montreal (Canada); Morales, Carlos R., E-mail: carlos.morales@mcgill.ca [Department of Anatomy and Cell Biology, McGill University, Montreal (Canada)

    2009-11-01

    Lysosomes are intracellular organelles which contain enzymes and activator proteins involved in the digestion and recycling of a variety of cellular and extracellular substances. We have identified a novel sorting receptor, sortilin, which is involved in the lysosomal trafficking of the sphingolipid activator proteins, prosaposin and GM{sub 2}AP, and the soluble hydrolases cathepsin D, cathepsin H, and acid sphingomyelinase. Sortilin belongs to a growing family of receptors with homology to the yeast Vps10 protein, which acts as a lysosomal sorting receptor for carboxypeptidase Y. In this study we examined the effects of the sortilin gene inactivation in mice. The inactivation of this gene did not yield any noticeable lysosomal pathology. To determine the existence of an alternative receptor complementing the sorting function of sortilin, we quantified the concentration of prosaposin in the lysosomes of the nonciliated epithelial cells lining the efferent ducts. These cells were chosen because they express sortilin and have a large number of lysosomes containing prosaposin. In addition, the nonciliated cells are known to endocytose luminal prosaposin that is synthesized and secreted by Sertoli cells into the seminiferous luminal fluids. Consequently, the nonciliated cells are capable of targeting both exogenous and endogenous prosaposin to the lysosomes. Using electron microscope immunogold labeling and quantitative analysis, our results demonstrate that inactivation of the sortilin gene produces a significant decrease of prosaposin in the lysosomes. When luminal prosaposin was excluded from the efferent ducts, the level of prosaposin in lysosomes was even lower in the mutant mice. Nonetheless, a significant amount of prosaposin continues to reach the lysosomal compartment. These results strongly suggest the existence of an alternative receptor that complements the function of sortilin and explains the lack of lysosomal storage disorders in the sortilin

  13. Animal models of neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Fabiola Mara Ribeiro

    2013-01-01

    Full Text Available The prevalence of neurodegenerative diseases, such as Alzheimer's disease (AD and Parkinson's disease (PD, increases with age, and the number of affected patients is expected to increase worldwide in the next decades. Accurately understanding the etiopathogenic mechanisms of these diseases is a crucial step for developing disease-modifying drugs able to preclude their emergence or at least slow their progression. Animal models contribute to increase the knowledge on the pathophysiology of neurodegenerative diseases. These models reproduce different aspects of a given disease, as well as the histopathological lesions and its main symptoms. The purpose of this review is to present the main animal models for AD, PD, and Huntington's disease.

  14. Reward processing in neurodegenerative disease

    Science.gov (United States)

    Perry, David C.; Kramer, Joel H.

    2015-01-01

    Representation of reward value involves a distributed network including cortical and subcortical structures. Because neurodegenerative illnesses target specific anatomic networks that partially overlap with the reward circuit they would be predicted to have distinct impairments in reward processing. This review presents the existing evidence of reward processing changes in neurodegenerative diseases including mild cognitive impairment, Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Parkinson's disease, and Huntington's disease, as well as in healthy aging. Carefully distinguishing the different aspects of reward processing (primary rewards, secondary rewards, reward-based learning, and reward-based decision-making) and using tasks that differentiate the stages of processing reward will lead to improved understanding of this fundamental process and clarify a contributing cause of behavioral change in these illnesses. PMID:24417286

  15. Molecular diagnostics of neurodegenerative disorders

    Directory of Open Access Journals (Sweden)

    Megha eAgrawal

    2015-09-01

    Full Text Available Molecular diagnostics provide a powerful method to detect and diagnose various neurological diseases such as Alzheimer’s and Parkinson’s disease. The confirmation of such diagnosis allows early detection and subsequent medical counseling that help specific patients to undergo clinically important drug trials. This provides a medical pathway to have better insight of neurogenesis and eventual cure of the neurodegenerative diseases. In this short review, we present recent advances in molecular diagnostics especially biomarkers and imaging spectroscopy for neurological diseases. We describe advances made in Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis and Huntington’s disease, and finally present a perspective on the future directions to provide a framework for further developments and refinements of molecular diagnostics to combat neurodegenerative disorders.

  16. Essential Tremor: A Neurodegenerative Disease?

    Directory of Open Access Journals (Sweden)

    Julian Benito-Leon

    2011-08-01

    Full Text Available Background: Essential tremor (ET is one of the most common neurological disorders among adults, and is the most common of the many tremor disorders. It has classically been viewed as a benign monosymptomatic condition, yet over the past decade, a growing body of evidence indicates that ET is a progressive condition that is clinically heterogeneous, as it may be associated with a spectrum of clinical features, with both motor and non‐motor elements. In this review, I will describe the most significant emerging milestones in research which, when taken together, suggest that ET is a neurodegenerative condition.Methods: A PubMed search conducted in June 2014 crossing the terms “essential tremor” (ET and “neurodegenerative” yielded 122 entries, 20 of which included the term “neurodegenerative” in the article title. This was supplemented by articles in the author's files that pertained to this topic.Results/Discussion: There is an open and active dialogue in the medical community as to whether ET is a neurodegenerative disease, with considerable evidence in favor of this. Specifically, ET is a progressive disorder of aging associated with neuronal loss (reduction in Purkinje cells as well as other post‐mortem changes that occur in traditional neurodegenerative disorders. Along with this, advanced neuroimaging techniques are now demonstrating distinct structural changes, several of which are consistent with neuronal loss, in patients with ET. However, further longitudinal clinical and neuroimaging longitudinal studies to assess progression are required.

  17. Metal imaging in neurodegenerative diseases

    Science.gov (United States)

    Bourassa, Megan W.

    2014-01-01

    Metal ions are known to play an important role in many neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and prion diseases. In these diseases, aberrant metal binding or improper regulation of redox active metal ions can induce oxidative stress by producing cytotoxic reactive oxygen species (ROS). Altered metal homeostasis is also frequently seen in the diseased state. As a result, the imaging of metals in intact biological cells and tissues has been very important for understanding the role of metals in neurodegenerative diseases. A wide range of imaging techniques have been utilized, including X-ray fluorescence microscopy (XFM), particle induced X-ray emission (PIXE), energy dispersive X-ray spectroscopy (EDS), laser ablation inductively coupled mass spectrometry (LA-ICP-MS), and secondary ion mass spectrometry (SIMS), all of which allow for the imaging of metals in biological specimens with high spatial resolution and detection sensitivity. These techniques represent unique tools for advancing the understanding of the disease mechanisms and for identifying possible targets for developing treatments. In this review, we will highlight the advances in neurodegenerative disease research facilitated by metal imaging techniques. PMID:22797194

  18. Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    Samantha Giordano

    2014-01-01

    Full Text Available Oxidative stress including DNA damage, increased lipid and protein oxidation, are important features of aging and neurodegeneration suggesting that endogenous antioxidant protective pathways are inadequate or overwhelmed. Importantly, oxidative protein damage contributes to age-dependent accumulation of dysfunctional mitochondria or protein aggregates. In addition, environmental toxins such as rotenone and paraquat, which are risk factors for the pathogenesis of neurodegenerative diseases, also promote protein oxidation. The obvious approach of supplementing the primary antioxidant systems designed to suppress the initiation of oxidative stress has been tested in animal models and positive results were obtained. However, these findings have not been effectively translated to treating human patients, and clinical trials for antioxidant therapies using radical scavenging molecules such as α-tocopherol, ascorbate and coenzyme Q have met with limited success, highlighting several limitations to this approach. These could include: (1 radical scavenging antioxidants cannot reverse established damage to proteins and organelles; (2 radical scavenging antioxidants are oxidant specific, and can only be effective if the specific mechanism for neurodegeneration involves the reactive species to which they are targeted and (3 since reactive species play an important role in physiological signaling, suppression of endogenous oxidants maybe deleterious. Therefore, alternative approaches that can circumvent these limitations are needed. While not previously considered an antioxidant system we propose that the autophagy-lysosomal activities, may serve this essential function in neurodegenerative diseases by removing damaged or dysfunctional proteins and organelles.

  19. Chameleon sequences in neurodegenerative diseases.

    Science.gov (United States)

    Bahramali, Golnaz; Goliaei, Bahram; Minuchehr, Zarrin; Salari, Ali

    2016-03-25

    Chameleon sequences can adopt either alpha helix sheet or a coil conformation. Defining chameleon sequences in PDB (Protein Data Bank) may yield to an insight on defining peptides and proteins responsible in neurodegeneration. In this research, we benefitted from the large PDB and performed a sequence analysis on Chameleons, where we developed an algorithm to extract peptide segments with identical sequences, but different structures. In order to find new chameleon sequences, we extracted a set of 8315 non-redundant protein sequences from the PDB with an identity less than 25%. Our data was classified to "helix to strand (HE)", "helix to coil (HC)" and "strand to coil (CE)" alterations. We also analyzed the occurrence of singlet and doublet amino acids and the solvent accessibility in the chameleon sequences; we then sorted out the proteins with the most number of chameleon sequences and named them Chameleon Flexible Proteins (CFPs) in our dataset. Our data revealed that Gly, Val, Ile, Tyr and Phe, are the major amino acids in Chameleons. We also found that there are proteins such as Insulin Degrading Enzyme IDE and GTP-binding nuclear protein Ran (RAN) with the most number of chameleons (640 and 405 respectively). These proteins have known roles in neurodegenerative diseases. Therefore it can be inferred that other CFP's can serve as key proteins in neurodegeneration, and a study on them can shed light on curing and preventing neurodegenerative diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Chameleon sequences in neurodegenerative diseases

    Energy Technology Data Exchange (ETDEWEB)

    Bahramali, Golnaz [Institute of Biochemistry and Biophysics, University of Tehran, Tehran (Iran, Islamic Republic of); Goliaei, Bahram, E-mail: goliaei@ut.ac.ir [Institute of Biochemistry and Biophysics, University of Tehran, Tehran (Iran, Islamic Republic of); Minuchehr, Zarrin, E-mail: minuchehr@nigeb.ac.ir [Department of Systems Biotechnology, National Institute of Genetic Engineering and Biotechnology, (NIGEB), Tehran (Iran, Islamic Republic of); Salari, Ali [Department of Systems Biotechnology, National Institute of Genetic Engineering and Biotechnology, (NIGEB), Tehran (Iran, Islamic Republic of)

    2016-03-25

    Chameleon sequences can adopt either alpha helix sheet or a coil conformation. Defining chameleon sequences in PDB (Protein Data Bank) may yield to an insight on defining peptides and proteins responsible in neurodegeneration. In this research, we benefitted from the large PDB and performed a sequence analysis on Chameleons, where we developed an algorithm to extract peptide segments with identical sequences, but different structures. In order to find new chameleon sequences, we extracted a set of 8315 non-redundant protein sequences from the PDB with an identity less than 25%. Our data was classified to “helix to strand (HE)”, “helix to coil (HC)” and “strand to coil (CE)” alterations. We also analyzed the occurrence of singlet and doublet amino acids and the solvent accessibility in the chameleon sequences; we then sorted out the proteins with the most number of chameleon sequences and named them Chameleon Flexible Proteins (CFPs) in our dataset. Our data revealed that Gly, Val, Ile, Tyr and Phe, are the major amino acids in Chameleons. We also found that there are proteins such as Insulin Degrading Enzyme IDE and GTP-binding nuclear protein Ran (RAN) with the most number of chameleons (640 and 405 respectively). These proteins have known roles in neurodegenerative diseases. Therefore it can be inferred that other CFP's can serve as key proteins in neurodegeneration, and a study on them can shed light on curing and preventing neurodegenerative diseases.

  1. Tau imaging in neurodegenerative diseases

    Energy Technology Data Exchange (ETDEWEB)

    Dani, M.; Edison, P. [Imperial College London, Neurology Imaging Unit, Division of Neuroscience, London (United Kingdom); Brooks, D.J. [Imperial College London, Neurology Imaging Unit, Division of Neuroscience, London (United Kingdom); Aarhus University, Institute of Clinical Medicine, Aarhus (Denmark)

    2016-06-15

    Aggregated tau protein is a major neuropathological substrate central to the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and chronic traumatic encephalopathy. In AD, it has been shown that the density of hyperphosphorylated tau tangles correlates closely with neuronal dysfunction and cell death, unlike β-amyloid. Until now, diagnostic and pathologic information about tau deposition has only been available from invasive techniques such as brain biopsy or autopsy. The recent development of selective in-vivo tau PET imaging ligands including [{sup 18}F]THK523, [{sup 18}F]THK5117, [{sup 18}F]THK5105 and [{sup 18}F]THK5351, [{sup 18}F]AV1451(T807) and [{sup 11}C]PBB3 has provided information about the role of tau in the early phases of neurodegenerative diseases, and provided support for diagnosis, prognosis, and imaging biomarkers to track disease progression. Moreover, the spatial and longitudinal relationship of tau distribution compared with β - amyloid and other pathologies in these diseases can be mapped. In this review, we discuss the role of aggregated tau in tauopathies, the challenges posed in developing selective tau ligands as biomarkers, the state of development in tau tracers, and the new clinical information that has been uncovered, as well as the opportunities for improving diagnosis and designing clinical trials in the future. (orig.)

  2. Lysosomes convene to keep the synapse clean.

    Science.gov (United States)

    Kononenko, Natalia L

    2017-07-19

    In neurons, lysosomes regulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor levels at the plasma membrane, although their presence at distal dendrites is controversial. In this issue, Goo et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201704068) show for the first time that neuronal activity positions lysosomes at the dendritic spines to facilitate synaptic remodeling through local protein degradation. © 2017 Kononenko.

  3. Endocannabinoid system in neurodegenerative disorders.

    Science.gov (United States)

    Basavarajappa, Balapal S; Shivakumar, Madhu; Joshi, Vikram; Subbanna, Shivakumar

    2017-09-01

    Most neurodegenerative disorders (NDDs) are characterized by cognitive impairment and other neurological defects. The definite cause of and pathways underlying the progression of these NDDs are not well-defined. Several mechanisms have been proposed to contribute to the development of NDDs. These mechanisms may proceed concurrently or successively, and they differ among cell types at different developmental stages in distinct brain regions. The endocannabinoid system, which involves cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), endogenous cannabinoids and the enzymes that catabolize these compounds, has been shown to contribute to the development of NDDs in several animal models and human studies. In this review, we discuss the functions of the endocannabinoid system in NDDs and converse the therapeutic efficacy of targeting the endocannabinoid system to rescue NDDs. © 2017 International Society for Neurochemistry.

  4. [Application of lysosomal detection in marine pollution monitoring: research progress].

    Science.gov (United States)

    Weng, You-Zhu; Fang, Yong-Qiang; Zhang, Yu-Sheng

    2013-11-01

    Lysosome is an important organelle existing in eukaryotic cells. With the development of the study on the structure and function of lysosome in recent years, lysosome is considered as a target of toxic substances on subcellular level, and has been widely applied abroad in marine pollution monitoring. This paper summarized the biological characteristics of lysosomal marker enzyme, lysosome-autophagy system, and lysosomal membrane, and introduced the principles and methods of applying lysosomal detection in marine pollution monitoring. Bivalve shellfish digestive gland and fish liver are the most sensitive organs for lysosomal detection. By adopting the lysosomal detection techniques such as lysosomal membrane stability (LMS) test, neutral red retention time (NRRT) assay, morphological measurement (MM) of lysosome, immunohistochemical (Ih) assay of lysosomal marker enzyme, and electron microscopy (EM), the status of marine pollution can be evaluated. It was suggested that the lysosome could be used as a biomarker for monitoring marine environmental pollution. The advantages and disadvantages of lysosomal detection and some problems worthy of attention were analyzed, and the application prospects of lysosomal detection were discussed.

  5. Beta-glucuronidase and hexosaminidase are marker enzymes for different compartments of the endo-lysosomal system in mussel digestive cells.

    Science.gov (United States)

    Izagirre, U; Angulo, E; Wade, S C; ap Gwynn, I; Marigómez, I

    2009-02-01

    In environmental toxicology, the most commonly used techniques used to visualise lysosomes in order to determine their responses to pollutants (LSC test: lysosomal structural changes test; LMS test: lysosomal membrane stability test) are based on the histochemical application of lysosomal marker enzymes. In mussel digestive cells, the marker enzymes used are beta-glucuronidase (beta-Gus) and hexosaminidase (Hex). The present work has been aimed at determining the distribution of these lysosomal marker enzymes in the various compartments of the endo-lysosomal system (ELS) of mussel digestive cells and at exploring whether intercellular transfer of lysosomal enzymes occurs between digestive and basophilic cells. Immunogold cytochemistry has allowed us to conclude that beta-Gus is present in every compartment of the digestive cell ELS, whereas Hex is not so widely distributed. Moreover, Hex is intimately linked to the lysosomal membrane, whereas beta-Gus appears to be not necessarily membrane-bound. Therefore, two populations of heterolysosomes with different enzyme load and membrane stability have been distinguished in the digestive cell. In addition, heterolysosomes of different electron density have been commonly observed merging together by contact; we suggest that some might act as storage granules for lysosomal enzymes. On the other hand, beta-Gus seems to be released to the digestive alveolar lumen in secretory lysosomes produced by basophilic cells and endocytosed by digestive cells. Regarding the implications of the present study on the interpretation of lysosomal biomarkers, we conclude that beta-Gus, but not Hex, histochemistry provides an appropriate marker for the LSC test and that, although both lysosomal marker enzymes can be employed in the LMS test, different values would be obtained depending on the marker enzyme employed.

  6. Early involvement of lysosome dysfunction in the degeneration of cerebral cortical neurons caused by the lipid peroxidation product 4-hydroxynonenal.

    Science.gov (United States)

    Zhang, Shi; Eitan, Erez; Mattson, Mark P

    2017-03-01

    Free radical-mediated oxidative damage to proteins, lipids, and DNA occurs in neurons during acute brain injuries and in neurodegenerative disorders. Membrane lipid peroxidation contributes to neuronal dysfunction and death, in part by disrupting neuronal ion homeostasis and cellular bioenergetics. Emerging findings suggest that 4-hydroxynonenal (HNE), an aldehyde produced during lipid peroxidation, impairs the function of various proteins involved in neuronal homeostasis. Here we tested the hypothesis that HNE impairs the cellular system that removes damaged proteins and organelles, the autophagy-lysosome pathway in rat primary cortical neurons. We found that HNE, at a concentration that causes apoptosis over a 48-72 h period, increases protein levels of LC3 II and p62 and within 1 and 4 h of exposure, respectively; LC3 II and p62 immunoreactive puncta were observed in the cytoplasm of HNE-treated neurons at 6 h. The extent of up-regulation of p62 and LC3 II in response to HNE was not affected by co-treatment with the lysosome inhibitor bafilomycin A1, suggesting that the effects of HNE on autophagy were secondary to lysosome inhibition. Indeed, we found that neurons exposed to HNE exhibit elevated pH levels, and decreased protein substrate hydrolysis and cathepsin B activity. Neurons exposed to HNE also exhibited the accumulation of K63-linked polyubiquitinated proteins, which are substrates targeted for lysosomal degradation. Moreover, we found that the levels of LAMP2a and constitutively active heat-shock protein 70, and numbers of LAMP2a-positive lysosomes, are decreased in neurons exposed to HNE. Our findings demonstrate that the lipid peroxidation product HNE causes early impairment of lysosomes which may contribute to the accumulation of damaged and dysfunctional proteins and organelles and consequent neuronal death. Because impaired lysosome function is increasingly recognized as an early event in the neuronal death that occurs in neurodegenerative

  7. Apoptotic photoreceptor loss and altered expression of lysosomal proteins in the nclf mouse model of neuronal ceroid lipofuscinosis.

    Science.gov (United States)

    Bartsch, Udo; Galliciotti, Giovanna; Jofre, Guillermo F; Jankowiak, Wanda; Hagel, Christian; Braulke, Thomas

    2013-10-23

    Mutations in the CLN6 gene cause variant late-infantile neuronal ceroid lipofuscinosis, a lysosomal storage disorder clinically characterized by progressive loss of vision, dementia, seizures, and early death. Here, we analyzed the time course of photoreceptor loss and the role of lysosomes in nclf mice, an animal model of the human CLN6 disease. Labeling of apoptotic cells, activated astrocytes, and Müller cells, and expression analyses of glial fibrillary acidic protein, rhodopsin, and lysosomal proteins were performed on nclf mice during the course of retinal degeneration. In addition, the distribution and variability of storage material was examined at the ultrastructural level. Progressive apoptotic loss of photoreceptor cells was observed in nclf mice, resulting in reduction of the outer nuclear layer to approximately 3 rows of photoreceptor cells at 9 months of age. Onset of reactive gliosis was observed in 1-month-old nclf mice. Ultrastructural analysis revealed lysosomal storage material containing curvilinear and fingerprint-like inclusions in various retinal cell types. Expression levels of soluble mannose 6-phosphate-containing lysosomal enzymes, such as cathepsin D and the lysosomal membrane protein Lamp1, were increased in retinal cells of nclf mice. Accumulation of heterogeneous nondegraded macromolecules in dysfunctional lysosomes and autolysosomes impairs photoreceptor cells, ultimately leading to early-onset apoptotic death with subsequent activation of astrocytes and Müller cells in the retina of nclf mice. The defined steps of photoreceptor degeneration suggest that nclf mice might serve as an ideal animal model for experimental therapeutic approaches aimed at attenuating vision loss in neuronal ceroid lipofuscinosis.

  8. A mouse model for fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease

    DEFF Research Database (Denmark)

    Wolf, Heike; Damme, Markus; Stroobants, Stijn

    2016-01-01

    Fucosidosis is a rare lysosomal storage disorder caused by the inherited deficiency of the lysosomal hydrolase α-L-fucosidase, which leads to an impaired degradation of fucosylated glycoconjugates. Here we report the generation of a fucosidosis mouse model, in which the gene for lysosomal α-L-fuc...

  9. Selenium, selenoproteins and neurodegenerative diseases.

    Science.gov (United States)

    Cardoso, Bárbara Rita; Roberts, Blaine R; Bush, Ashley I; Hare, Dominic J

    2015-08-01

    It is unsurprising that our understanding of the role of selenium in neurological function is somewhat immature, considering its relatively recent discovery as an essential element to human health. Selenocysteine, the 21st amino acid, is the defining feature of the 25 selenoprotein-encoding genes so far discovered within the human genome. The low abundance of these proteins in the brain belies the integral role they play in normal neurological function, from well-characterised antioxidant activity in the periphery to poorly understood mechanisms that modulate mitochondrial function and response to brain pathology. Selenium has been identified as playing a role in several neurodegenerative disorders, including Alzheimer's and Parkinson's disease, though its function as a 'cause or effect' of disease process remains unclear. This review discusses selenium metabolism in detail, specifically with regard to the role it plays within the central nervous system, and examines the most current literature investigating how selenium may be involved in chronic diseases of the central nervous system.

  10. Newborn Screening for Lysosomal Storage Disorders and Other Neuronopathic Conditions

    Science.gov (United States)

    Matern, Dietrich; Oglesbee, Devin; Tortorelli, Silvia

    2013-01-01

    Newborn screening (NBS) is a public health program aimed at identifying treatable conditions in presymptomatic newborns to avoid premature mortality, morbidity, and disabilities. Currently, every newborn in the Unites States is screened for at least 29 conditions where evidence suggests that early detection is possible and beneficial. With new or…

  11. Lysosomal destabilization in p53-induced apoptosis

    OpenAIRE

    Yuan, Xi-Ming; Li, Wei; Dalen, Helge; Lotem, Joseph; Kama, Rachel; Sachs, Leo; Brunk, Ulf T.

    2002-01-01

    The tumor suppressor wild-type p53 can induce apoptosis. M1-t-p53 myeloid leukemic cells have a temperature-sensitive p53 protein that changes its conformation to wild-type p53 after transfer from 37°C to 32°C. We have now found that these cells showed an early lysosomal rupture after transfer to 32°C. Mitochondrial damage, including decreased membrane potential and release of cytochrome c, and the appearance of apoptotic cells occurred later. Lysosomal rupture, mitochondrial damage, and apop...

  12. Lysosomes as mediators of drug resistance in cancer.

    Science.gov (United States)

    Zhitomirsky, Benny; Assaraf, Yehuda G

    2016-01-01

    Drug resistance remains a leading cause of chemotherapeutic treatment failure and cancer-related mortality. While some mechanisms of anticancer drug resistance have been well characterized, multiple mechanisms remain elusive. In this respect, passive ion trapping-based lysosomal sequestration of multiple hydrophobic weak-base chemotherapeutic agents was found to reduce the accessibility of these drugs to their target sites, resulting in a markedly reduced cytotoxic effect and drug resistance. Recently we have demonstrated that lysosomal sequestration of hydrophobic weak base drugs triggers TFEB-mediated lysosomal biogenesis resulting in an enlarged lysosomal compartment, capable of enhanced drug sequestration. This study further showed that cancer cells with an increased number of drug-accumulating lysosomes are more resistant to lysosome-sequestered drugs, suggesting a model of drug-induced lysosome-mediated chemoresistance. In addition to passive drug sequestration of hydrophobic weak base chemotherapeutics, other mechanisms of lysosome-mediated drug resistance have also been reported; these include active lysosomal drug sequestration mediated by ATP-driven transporters from the ABC superfamily, and a role for lysosomal copper transporters in cancer resistance to platinum-based chemotherapeutics. Furthermore, lysosomal exocytosis was suggested as a mechanism to facilitate the clearance of chemotherapeutics which highly accumulated in lysosomes, thus providing an additional line of resistance, supplementing the organelle entrapment of chemotherapeutics away from their target sites. Along with these mechanisms of lysosome-mediated drug resistance, several approaches were recently developed for the overcoming of drug resistance or exploiting lysosomal drug sequestration, including lysosomal photodestruction and drug-induced lysosomal membrane permeabilization. In this review we explore the current literature addressing the role of lysosomes in mediating cancer drug

  13. Induced pluripotent stem cell-based modeling of neurodegenerative diseases: a focus on autophagy.

    Science.gov (United States)

    Jungverdorben, Johannes; Till, Andreas; Brüstle, Oliver

    2017-07-01

    The advent of cell reprogramming has enabled the generation of induced pluripotent stem cells (iPSCs) from patient skin fibroblasts or blood cells and their subsequent differentiation into tissue-specific cells, including neurons and glia. This approach can be used to recapitulate disease-specific phenotypes in classical cell culture paradigms and thus represents an invaluable asset for disease modeling and drug validation in the framework of personalized medicine. The autophagy pathway is a ubiquitous eukaryotic degradation and recycling system, which relies on lysosomal degradation of unwanted and potentially cytotoxic components. The relevance of autophagy in the pathogenesis of neurodegenerative diseases is underlined by the observation that disease-linked genetic variants of susceptibility factors frequently result in dysregulation of autophagic-lysosomal pathways. In particular, disrupted autophagy is implied in the accumulation of potentially neurotoxic products such as protein aggregates and their precursors and defective turnover of dysfunctional mitochondria. Here, we review the current state of iPSC-based assessment of autophagic dysfunction in the context of neurodegenerative disease modeling. The collected data show that iPSC technology is capable to reveal even subtle alterations in subcellular homeostatic processes, which form the molecular basis for disease manifestation.

  14. Neuraminidase 1 is a Negative Regulator of Lysosomal Exocytosis

    Science.gov (United States)

    Yogalingam, Gouri; Bonten, Erik J.; van de Vlekkert, Diantha; Hu, Huimin; Moshiach, Simon; Connell, Samuel A.; d’Azzo, Alessandra

    2009-01-01

    SUMMARY Lysosomal exocytosis is a Ca2+-regulated mechanism that involves proteins responsible for cytoskeletal attachment and fusion of lysosomes with the plasma membrane. However, whether luminal lysosomal enzymes contribute to this process remains unknown. Here we show that neuraminidase Neu1 negatively regulates lysosomal exocytosis in hematopoietic cells by processing the sialic acids on the lysosomal membrane protein Lamp-1. In macrophages from Neu1-deficient mice, a model of the disease sialidosis, and in patients’ fibroblasts, oversialylated Lamp-1 enhances lysosomal exocytosis. Silencing of Lamp-1 reverts this phenotype by interfering with the docking of lysosomes at the plasma membrane. In Neu1-/- mice the excessive exocytosis of serine proteases in the bone niche leads to inactivation of extracellular serpins, premature degradation of VCAM-1, and loss of bone marrow retention. Our findings uncover an unexpected mechanism influencing lysosomal exocytosis and argue that exacerbations of this process form the basis for certain genetic diseases. PMID:18606142

  15. Lysosomal stress: a new player in perturbed lipid metabolism

    NARCIS (Netherlands)

    Gabriel, T.L.

    2017-01-01

    Lysosomes are involved in many different essential cellular processes, among others organelle and molecule degradation, exocytosis, cell energy metabolism, cholesterol and sphingolipid level regulation. Lysosomal stress has a strong impact on the immune system, affecting specially macrophages as

  16. Autophagy and ageing: implications for age-related neurodegenerative diseases.

    Science.gov (United States)

    Carroll, Bernadette; Hewitt, Graeme; Korolchuk, Viktor I

    2013-01-01

    Autophagy is a process of lysosome-dependent intracellular degradation that participates in the liberation of resources including amino acids and energy to maintain homoeostasis. Autophagy is particularly important in stress conditions such as nutrient starvation and any perturbation in the ability of the cell to activate or regulate autophagy can lead to cellular dysfunction and disease. An area of intense research interest is the role and indeed the fate of autophagy during cellular and organismal ageing. Age-related disorders are associated with increased cellular stress and assault including DNA damage, reduced energy availability, protein aggregation and accumulation of damaged organelles. A reduction in autophagy activity has been observed in a number of ageing models and its up-regulation via pharmacological and genetic methods can alleviate age-related pathologies. In particular, autophagy induction can enhance clearance of toxic intracellular waste associated with neurodegenerative diseases and has been comprehensively demonstrated to improve lifespan in yeast, worms, flies, rodents and primates. The situation, however, has been complicated by the identification that autophagy up-regulation can also occur during ageing. Indeed, in certain situations, reduced autophagosome induction may actually provide benefits to ageing cells. Future studies will undoubtedly improve our understanding of exactly how the multiple signals that are integrated to control appropriate autophagy activity change during ageing, what affect this has on autophagy and to what extent autophagy contributes to age-associated pathologies. Identification of mechanisms that influence a healthy lifespan is of economic, medical and social importance in our 'ageing' world.

  17. A Proteolytic Cascade Controls Lysosome Rupture and Necrotic Cell Death Mediated by Lysosome-Destabilizing Adjuvants

    OpenAIRE

    Jürgen Brojatsch; Heriberto Lima; Alak K Kar; Jacobson, Lee S.; Muehlbauer, Stefan M.; Kartik Chandran; Felipe Diaz-Griffero

    2014-01-01

    Recent studies have linked necrotic cell death and proteolysis of inflammatory proteins to the adaptive immune response mediated by the lysosome-destabilizing adjuvants, alum and Leu-Leu-OMe (LLOMe). However, the mechanism by which lysosome-destabilizing agents trigger necrosis and proteolysis of inflammatory proteins is poorly understood. The proteasome is a cellular complex that has been shown to regulate both necrotic cell death and proteolysis of inflammatory proteins. We found that the p...

  18. The physiological determinants of drug-induced lysosomal stress resistance.

    Directory of Open Access Journals (Sweden)

    Tehetina Woldemichael

    Full Text Available Many weakly basic, lipophilic drugs accumulate in lysosomes and exert complex, pleiotropic effects on organelle structure and function. Thus, modeling how perturbations of lysosomal physiology affect the maintenance of lysosomal ion homeostasis is necessary to elucidate the key factors which determine the toxicological effects of lysosomotropic agents, in a cell-type dependent manner. Accordingly, a physiologically-based mathematical modeling and simulation approach was used to explore the dynamic, multi-parameter phenomenon of lysosomal stress. With this approach, parameters that are either directly involved in lysosomal ion transportation or lysosomal morphology were transiently altered to investigate their downstream effects on lysosomal physiology reflected by the changes they induce in lysosomal pH, chloride, and membrane potential. In addition, combinations of parameters were simultaneously altered to assess which parameter was most critical for recovery of normal lysosomal physiology. Lastly, to explore the relationship between organelle morphology and induced stress, we investigated the effects of parameters controlling organelle geometry on the restoration of normal lysosomal physiology following a transient perturbation. Collectively, our results indicate a key, interdependent role of V-ATPase number and membrane proton permeability in lysosomal stress tolerance. This suggests that the cell-type dependent regulation of V-ATPase subunit expression and turnover, together with the proton permeability properties of the lysosomal membrane, is critical to understand the differential sensitivity or resistance of different cell types to the toxic effects of lysosomotropic drugs.

  19. Sleep in Neurodevelopmental and Neurodegenerative Disorders.

    Science.gov (United States)

    Kotagal, Suresh

    2015-06-01

    There is a close relationship between sleep and childhood neurodevelopmental/neurodegenerative disorders. Understanding the sleep issues may provide greater insight into pathophysiology and treatment of these disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. [Neuropathological diagnosis of neurodegenerative and dementia diseases].

    Science.gov (United States)

    Kretzschmar, H A; Neumann, M

    2000-09-01

    Neurodegenerative and dementing disorders such as Parkinson disease and Alzheimer disease are among the most common diseases of advanced age. Despite progress in the clinical diagnosis of neurodegenerative disorders, definite diagnosis for most of these disorders is still possible only by neuropathological examination of the brain. The neuropathological diagnosis and classification of neurodegenerative disorders has made clear advances in recent years, particularly due to the results of genetic and biochemical studies, resulting in the development of new disease-specific antibodies. Internationally recognized consensus criteria for most neurodegenerative disorders allow a definite and standardized diagnosis to be made. To obtain further knowledge about the etiopathogenesis, particularly with regard to new therapeutic strategies, studies with clinically and neuropathologically well-documented cases are needed. The project "Brain-Net" has therefore been established with the aim of setting up a German Brain and Tissue Bank for Diseases of the Central Nervous System. The project is funded by the Federal Ministry of Education and Research.

  1. Visual Spatial Cognition in Neurodegenerative Disease

    OpenAIRE

    Possin, Katherine L.

    2010-01-01

    Visual spatial impairment is often an early symptom of neurodegenerative disease; however, this multi-faceted domain of cognition is not well-assessed by most typical dementia evaluations. Neurodegenerative diseases cause circumscribed atrophy in distinct neural networks, and accordingly, they impact visual spatial cognition in different and characteristic ways. Anatomically-focused visual spatial assessment can assist the clinician in making an early and accurate diagnosis. This article will...

  2. Inhibition of storage pathology in prenatal CLN5-deficient sheep neural cultures by lentiviral gene therapy.

    Science.gov (United States)

    Hughes, Stephanie M; Hope, Katie M; Xu, Janet Boyu; Mitchell, Nadia L; Palmer, David N

    2014-02-01

    The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are inherited neurodegenerative lysosomal storage diseases caused by mutations in several different genes. Mutations in CLN5 cause a variant late-infantile human disease and some cases of juvenile and adult clinical disease. NCLs also occur in animals, and a flock of New Zealand Borderdale sheep with a CLN5 splice-site mutation has been developed for model studies. Dissociated mixed neural cells from CLN5-deficient foetal sheep brains contained no obvious storage bodies at plating but these accumulated rapidly in culture, mainly in microglial cells and also in neurons and astrocytes. Accumulation was very obvious after a week, as monitored by fluorescent microscopy and immunostaining for subunit c of mitochondrial ATP synthase. Photography at intervals revealed the dynamic nature of the cultures and a flow of storage bodies between cells, specifically the phagocytosis of storage-body containing cells by microglia and incorporation of the storage bodies into the host cells. No storage was observed in cultured control cells. Transduction of cell cultures with a lentiviral vector expressing a C-terminal Myc tagged CLN5 resulted in secretion of post-translationally glycosylated and processed CLN5. Transduction of CLN5-deficient cultures with this construct rapidly reversed storage body accumulation, to less than half in only six days. These results show that storage body accumulation is reversible with enzyme correction and support the use of these cultures for testing of therapeutics prior to whole animal studies. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Neurobiology of sleep disturbances in neurodegenerative disorders.

    Science.gov (United States)

    Gagnon, J-F; Petit, D; Latreille, V; Montplaisir, J

    2008-01-01

    This review presents sleep disturbances and their underlying pathophysiology in three categories of neurodegenerative disorders namely tauopathies, synucleinopathies, and Huntington's disease (HD) and prion-related diseases. Sleep abnormalities are a major and early feature of neurodegenerative disorders, especially for synucleinopathies, HD and prion-related diseases, in which the sleep-related brainstem regions are severely altered and impaired sooner than in most of the tauopathies. In synucleinopathies, HD and prion-related diseases, specific sleep disturbances, different from those observed in tauopathies, are considered as core manifestations of the disease and in some cases, as preclinical signs. For this reason, the evaluation of sleep components in these neurodegenerative disorders may be useful to make a diagnosis and to assess the efficacy of pharmacotherapy. Since sleep disruption may occur early in the course of neurodegeneration, sleep disturbance may serve as groundwork to study the efficacy of neuroprotective agents to prevent or delay the development of a full-blown neurodegenerative disorder. The cause of sleep disturbances in neurodegenerative disorders may be attributed to several factors, including age-related modifications, symptoms of the disease, comorbid conditions and the neurodegenerative process itself.

  4. Coenzyme Q10 effects in neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    Meredith Spindler

    2009-11-01

    Full Text Available Meredith Spindler1, M Flint Beal1,2, Claire Henchcliffe1,21Department of Neurology, 2Department of Neuroscience, Weill Medical College of Cornell University, New York, NY, USAAbstract: Coenzyme Q10 (CoQ10 is an essential cofactor in the mitochondrial respiratory chain, and as a dietary supplement it has recently gained attention for its potential role in the treatment of neurodegenerative disease. Evidence for mitochondrial dysfunction in neurodegenerative disorders derives from animal models, studies of mitochondria from patients, identification of genetic defects in patients with neurodegenerative disease, and measurements of markers of oxidative stress. Studies of in vitro models of neuronal toxicity and animal models of neurodegenerative disorders have demonstrated potential neuroprotective effects of CoQ10. With this data in mind, several clinical trials of CoQ10 have been performed in Parkinson’s disease and atypical Parkinson’s syndromes, Huntington’s disease, Alzheimer disease, Friedreich’s ataxia, and amyotrophic lateral sclerosis, with equivocal findings. CoQ10 is widely available in multiple formulations and is very well tolerated with minimal adverse effects, making it an attractive potential therapy. Phase III trials of high-dose CoQ10 in large sample sizes are needed to further ascertain the effects of CoQ10 in neurodegenerative diseases.Keywords: coenzyme Q10, neurodegenerative disease, Parkinson’s disease, Huntington’s disease, mitochondrial dysfunction

  5. From bedside to cell biology: a century of history on lysosomal dysfunction.

    Science.gov (United States)

    Coutinho, Maria Francisca; Matos, Liliana; Alves, Sandra

    2015-01-15

    Lysosomal storage disorders (LSDs) are a group of rare genetic diseases, generally caused by a deficiency of specific lysosomal enzymes, which results in abnormal accumulation of undegraded substrates. The first clinical reports describing what were later shown to be LSDs were published more than a hundred years ago. In general, the history and pathophysiology of LSDs has impacted on our current knowledge of lysosomal biology. Classically, depending on the nature of the substrates, LSDs can be divided into different subgroups. The mucopolysaccharidoses (MPSs) are those caused by impaired degradation of glycosaminoglycans (GAGs). Amongst LSDs, the MPSs are a major group of pathologies with crucial historical relevance, since their study has revealed important biological pathways and highlighted interconnecting pathological cascades which are still being unveiled nowadays. Here we review the major historical discoveries in the field of LSDs and their impact on basic cellular knowledge and practical applications. Attention will be focused on the MPSs, with occasional references to other LSDs. We will show as studies on the metabolic basis of this group of diseases have increased our knowledge of the complex degradative pathways associated with the lysosome and established the basis to the development of specific therapeutic approaches aiming at correcting or, at least ameliorating their associated phenotypes. Copyright © 2014 Elsevier B.V. All rights reserved.

  6. ErbB2-associated changes in the lysosomal proteome

    DEFF Research Database (Denmark)

    Nylandsted, Jesper; Becker, Andrea C; Bunkenborg, Jakob

    2011-01-01

    Late endosomes and lysosomes (hereafter referred to as lysosomes) play an essential role in the turnover of cellular macromolecules and organelles. Their biochemical characterization has so far depended on purification methods based on either density gradient centrifugations or magnetic purificat......Late endosomes and lysosomes (hereafter referred to as lysosomes) play an essential role in the turnover of cellular macromolecules and organelles. Their biochemical characterization has so far depended on purification methods based on either density gradient centrifugations or magnetic...... purification of iron-loaded organelles. Owing to dramatic changes in lysosomal density and stability associated with lysosomal diseases and cancer, these methods are not optimal for the comparison of normal and pathological lysosomes. Here, we introduce an efficient method for the purification of intact...

  7. Lysosomal adaptation: How cells respond to lysosomotropic compounds

    Science.gov (United States)

    Lu, Shuyan; Sung, Tae; Lin, Nianwei; Abraham, Robert T.; Jessen, Bart A.

    2017-01-01

    Lysosomes are acidic organelles essential for degradation and cellular homoeostasis and recently lysosomes have been shown as signaling hub to respond to the intra and extracellular changes (e.g. amino acid availability). Compounds including pharmaceutical drugs that are basic and lipophilic will become sequestered inside lysosomes (lysosomotropic). How cells respond to the lysosomal stress associated with lysosomotropism is not well characterized. Our goal is to assess the lysosomal changes and identify the signaling pathways that involve in the lysosomal changes. Eight chemically diverse lysosomotropic drugs from different therapeutic areas were subjected to the evaluation using the human adult retinal pigmented epithelium cell line, ARPE-19. All lysosomotropic drugs tested triggered lysosomal activation demonstrated by increased lysosotracker red (LTR) and lysosensor green staining, increased cathepsin activity, and increased LAMP2 staining. However, tested lysosomotropic drugs also prompted lysosomal dysfunction exemplified by intracellular and extracellular substrate accumulation including phospholipid, SQSTM1/p62, GAPDH (Glyceraldehyde 3-phosphate dehydrogenase) and opsin. Lysosomal activation observed was likely attributed to lysosomal dysfunction, leading to compensatory responses including nuclear translocation of transcriptional factors TFEB, TFE3 and MITF. The adaptive changes are protective to the cells under lysosomal stress. Mechanistic studies implicate calcium and mTORC1 modulation involvement in the adaptive changes. These results indicate that lysosomotropic compounds could evoke a compensatory lysosomal biogenic response but with the ultimate consequence of lysosomal functional impairment. This work also highlights a pathway of response to lysosomal stress and evidences the role of TFEB, TFE3 and MITF in the stress response. PMID:28301521

  8. 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.

  9. Lysosomal targeting with stable and sensitive fluorescent probes (Superior LysoProbes): applications for lysosome labeling and tracking during apoptosis.

    Science.gov (United States)

    Chen, Xin; Bi, Yue; Wang, Tianyang; Li, Pengfei; Yan, Xin; Hou, Shanshan; Bammert, Catherine E; Ju, Jingfang; Gibson, K Michael; Pavan, William J; Bi, Lanrong

    2015-03-11

    Intracellular pH plays an important role in the response to cancer invasion. We have designed and synthesized a series of new fluorescent probes (Superior LysoProbes) with the capacity to label acidic organelles and monitor lysosomal pH. Unlike commercially available fluorescent dyes, Superior LysoProbes are lysosome-specific and are highly stable. The use of Superior LysoProbes facilitates the direct visualization of the lysosomal response to lobaplatin elicited in human chloangiocarcinoma (CCA) RBE cells, using confocal laser scanning microscopy. Additionally, we have characterized the role of lysosomes in autophagy, the correlation between lysosome function and microtubule strength, and the alteration of lysosomal morphology during apoptosis. Our findings indicate that Superior LysoProbes offer numerous advantages over previous reagents to examine the intracellular activities of lysosomes.

  10. Genetically modified pig models for neurodegenerative disorders.

    Science.gov (United States)

    Holm, Ida E; Alstrup, Aage Kristian Olsen; Luo, Yonglun

    2016-01-01

    Increasing incidence of neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease has become one of the most challenging health issues in ageing humans. One approach to combat this is to generate genetically modified animal models of neurodegenerative disorders for studying pathogenesis, prognosis, diagnosis, treatment, and prevention. Owing to the genetic, anatomic, physiologic, pathologic, and neurologic similarities between pigs and humans, genetically modified pig models of neurodegenerative disorders have been attractive large animal models to bridge the gap of preclinical investigations between rodents and humans. In this review, we provide a neuroanatomical overview in pigs and summarize and discuss the generation of genetically modified pig models of neurodegenerative disorders including Alzheimer's diseases, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, spinal muscular atrophy, and ataxia-telangiectasia. We also highlight how non-invasive bioimaging technologies such as positron emission tomography (PET), computer tomography (CT), and magnetic resonance imaging (MRI), and behavioural testing have been applied to characterize neurodegenerative pig models. We further propose a multiplex genome editing and preterm recloning (MAP) approach by using the rapid growth of the ground-breaking precision genome editing technology CRISPR/Cas9 and somatic cell nuclear transfer (SCNT). With this approach, we hope to shorten the temporal requirement in generating multiple transgenic pigs, increase the survival rate of founder pigs, and generate genetically modified pigs that will more closely resemble the disease-causing mutations and recapitulate pathological features of human conditions. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  11. Ubiquitous transgene expression of the glucosylceramide-synthesizing enzyme accelerates glucosylceramide accumulation and storage cells in a Gaucher disease mouse model.

    Science.gov (United States)

    Barnes, Sonya; Xu, You-Hai; Zhang, Wujuan; Liou, Benjamin; Setchell, Kenneth D R; Bao, Liming; Grabowski, Gregory A; Sun, Ying

    2014-01-01

    Gaucher disease is a lysosomal storage disease caused by defective activity of acid β-glucosidase (GCase), which leads to the accumulation of its major substrates, glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph) in many cells. To modulate cellular substrate concentration in viable mouse models of Gaucher disease (Gba1 mutants), a novel mouse model was created with enhanced glycosphingolipid biosynthesis. This was accomplished by cross-breeding Gba1 mutant mice with mice expressing a transgene (GCStg) containing the mouse glucosylceramide synthase (GCS, Ugcg) cDNA driven by the ROSA promoter, yielding GCStg/Gba1 mice. The GCStg rescued Ugcg null mice from embryonic lethality. GCStg/Gba1 mice showed 2-3 fold increases in tissue GCS activity as well as accelerated GlcCer accumulation and the appearance of lipid-laden CD68 positive macrophages in visceral organs. Although GlcCer/GlcSph concentrations were elevated in the brain, there was no neurodegenerative phenotype up to 1 yr of age conceivably due to the greater residual GCase hydrolytic activity in the brains than in the visceral tissues of 9V/null mice. These studies provide 'proof of principle' for threshold substrate flux that modifies phenotypic development in Gaucher disease and other lysosomal storage diseases.

  12. Ubiquitous transgene expression of the glucosylceramide-synthesizing enzyme accelerates glucosylceramide accumulation and storage cells in a Gaucher disease mouse model.

    Directory of Open Access Journals (Sweden)

    Sonya Barnes

    Full Text Available Gaucher disease is a lysosomal storage disease caused by defective activity of acid β-glucosidase (GCase, which leads to the accumulation of its major substrates, glucosylceramide (GlcCer and glucosylsphingosine (GlcSph in many cells. To modulate cellular substrate concentration in viable mouse models of Gaucher disease (Gba1 mutants, a novel mouse model was created with enhanced glycosphingolipid biosynthesis. This was accomplished by cross-breeding Gba1 mutant mice with mice expressing a transgene (GCStg containing the mouse glucosylceramide synthase (GCS, Ugcg cDNA driven by the ROSA promoter, yielding GCStg/Gba1 mice. The GCStg rescued Ugcg null mice from embryonic lethality. GCStg/Gba1 mice showed 2-3 fold increases in tissue GCS activity as well as accelerated GlcCer accumulation and the appearance of lipid-laden CD68 positive macrophages in visceral organs. Although GlcCer/GlcSph concentrations were elevated in the brain, there was no neurodegenerative phenotype up to 1 yr of age conceivably due to the greater residual GCase hydrolytic activity in the brains than in the visceral tissues of 9V/null mice. These studies provide 'proof of principle' for threshold substrate flux that modifies phenotypic development in Gaucher disease and other lysosomal storage diseases.

  13. The lysosomal sialic acid transporter sialin is required for normal CNS myelination.

    Science.gov (United States)

    Prolo, Laura M; Vogel, Hannes; Reimer, Richard J

    2009-12-09

    Salla disease and infantile sialic acid storage disease are autosomal recessive lysosomal storage disorders caused by mutations in the gene encoding sialin, a membrane protein that transports free sialic acid out of the lysosome after it is cleaved from sialoglycoconjugates undergoing degradation. Accumulation of sialic acid in lysosomes defines these disorders, and the clinical phenotype is characterized by neurodevelopmental defects, including severe CNS hypomyelination. In this study, we used a sialin-deficient mouse to address how loss of sialin leads to the defect in myelination. Behavioral analysis of the sialin(-/-) mouse demonstrates poor coordination, seizures, and premature death. Analysis by histology, electron microscopy, and Western blotting reveals a decrease in myelination of the CNS but normal neuronal cytoarchitecture and normal myelination of the PNS. To investigate potential mechanisms underlying CNS hypomyelination, we studied myelination and oligodendrocyte development in optic nerves. We found reduced numbers of myelinated axons in optic nerves from sialin(-/-) mice, but the myelin that was present appeared grossly normal. Migration and density of oligodendrocyte precursor cells were normal; however, a marked decrease in the number of postmitotic oligodendrocytes and an associated increase in the number of apoptotic cells during the later stages of myelinogenesis were observed. These findings suggest that a defect in maturation of cells in the oligodendrocyte lineage leads to increased apoptosis and underlies the myelination defect associated with sialin loss.

  14. Visual spatial cognition in neurodegenerative disease.

    Science.gov (United States)

    Possin, Katherine L

    2010-12-01

    Visual spatial impairment is often an early symptom of neurodegenerative disease; however, this multi-faceted domain of cognition is not well-assessed by most typical dementia evaluations. Neurodegenerative diseases cause circumscribed atrophy in distinct neural networks, and accordingly, they impact visual spatial cognition in different and characteristic ways. Anatomically-focused visual spatial assessment can assist the clinician in making an early and accurate diagnosis. This article will review the literature on visual spatial cognition in neurodegenerative disease clinical syndromes, and where research is available, by neuropathologic diagnoses. Visual spatial cognition will be organized primarily according to the following schemes: bottom-up/top-down processing, dorsal/ventral stream processing, and egocentric/allocentric frames of reference.

  15. The impact of obesity on neurodegenerative diseases.

    Science.gov (United States)

    Mazon, Janaína Niero; de Mello, Aline Haas; Ferreira, Gabriela Kozuchovski; Rezin, Gislaine Tezza

    2017-08-01

    Neurodegenerative diseases are a growing health concern. The increasing incidences of these disorders have a great impact on the patients' quality of life. Although the mechanisms of neurodegenerative diseases are still far from being clarified, several studies look for new discoveries about their pathophysiology and prevention. Furthermore, evidence has shown a strong correlation between obesity and the development of Alzheimer's disease (AD) and Parkinson's disease (PD). Metabolic changes caused by overweight are related to damage to the central nervous system (CNS), which can lead to neural death, either by apoptosis or cell necrosis, as well as alter the synaptic plasticity of the neuron. This review aims to show the association between neurodegenerative diseases, focusing on AD and PD, and metabolic alterations. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Antibody-mediated enzyme replacement therapy targeting both lysosomal and cytoplasmic glycogen in Pompe disease.

    Science.gov (United States)

    Yi, Haiqing; Sun, Tao; Armstrong, Dustin; Borneman, Scott; Yang, Chunyu; Austin, Stephanie; Kishnani, Priya S; Sun, Baodong

    2017-05-01

    Pompe disease is characterized by accumulation of both lysosomal and cytoplasmic glycogen primarily in skeletal and cardiac muscles. Mannose-6-phosphate receptor-mediated enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) targets the enzyme to lysosomes and thus is unable to digest cytoplasmic glycogen. Studies have shown that anti-DNA antibody 3E10 penetrates living cells and delivers "cargo" proteins to the cytosol or nucleus via equilibrative nucleoside transporter ENT2. We speculate that 3E10-mediated ERT with GAA will target both lysosomal and cytoplasmic glycogen in Pompe disease. A fusion protein (FabGAA) containing a humanized Fab fragment derived from the murine 3E10 antibody and the 110 kDa human GAA precursor was constructed and produced in CHO cells. Immunostaining with an anti-Fab antibody revealed that the Fab signals did not co-localize with the lysosomal marker LAMP2 in cultured L6 myoblasts or Pompe patient fibroblasts after incubation with FabGAA. Western blot with an anti-GAA antibody showed presence of the 150 kDa full-length FabGAA in the cell lysates, in addition to the 95- and 76 kDa processed forms of GAA that were also seen in the rhGAA-treated cells. Blocking of mannose-6-phosphate receptor with mannose-6-phosphate markedly reduced the 95- and the 76 kDa forms but not the 150 kDa form. In GAA-KO mice, FabGAA achieved similar treatment efficacy as rhGAA at an equal molar dose in reducing tissue glycogen contents. Our data suggest that FabGAA retains the ability of rhGAA to treat lysosomal glycogen accumulation and has the beneficial potential over rhGAA to reduce cytoplasmic glycogen storage in Pompe disease. FabGAA can be delivered to both the cytoplasm and lysosomes in cultured cells. FabGAA equally reduced lysosomal glycogen accumulation as rhGAA in GAA-KO mice. FabGAA has the beneficial potential over rhGAA to clear cytoplasmic glycogen. This study suggests a novel antibody-enzyme fusion protein therapy

  17. REM behaviour disorder and neurodegenerative diseases.

    Science.gov (United States)

    Zanigni, Stefano; Calandra-Buonaura, Giovanna; Grimaldi, Daniela; Cortelli, Pietro

    2011-12-01

    Rapid-eye movement (REM) sleep behaviour disorder (RBD) is an REM sleep parasomnia characterized by enactment of dream content during REM sleep associated with loss of muscle atonia. RBD can be either idiopathic or secondary to drugs or other diseases. The best recognized association is with neurodegenerative diseases, namely alpha-synucleinopathies. RBD may represent the first feature of neurodegeneration and can be considered an early marker of these disorders. This review describes the main clinical, pathogenetic, and therapeutic features of RBD, pointing to its association with neurodegenerative diseases and emphasizing the clinical and prognostic implications. Copyright © 2011 Elsevier B.V. All rights reserved.

  18. Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes.

    Science.gov (United States)

    Abu-Remaileh, Monther; Wyant, Gregory A; Kim, Choah; Laqtom, Nouf N; Abbasi, Maria; Chan, Sze Ham; Freinkman, Elizaveta; Sabatini, David M

    2017-11-10

    The lysosome degrades and recycles macromolecules, signals to the cytosol and nucleus, and is implicated in many diseases. Here, we describe a method for the rapid isolation of mammalian lysosomes and use it to quantitatively profile lysosomal metabolites under various cell states. Under nutrient-replete conditions, many lysosomal amino acids are in rapid exchange with those in the cytosol. Loss of lysosomal acidification through inhibition of the vacuolar H+-adenosine triphosphatase (V-ATPase) increased the luminal concentrations of most metabolites but had no effect on those of the majority of essential amino acids. Instead, nutrient starvation regulates the lysosomal concentrations of these amino acids, an effect we traced to regulation of the mechanistic target of rapamycin (mTOR) pathway. Inhibition of mTOR strongly reduced the lysosomal efflux of most essential amino acids, converting the lysosome into a cellular depot for them. These results reveal the dynamic nature of lysosomal metabolites and that V-ATPase- and mTOR-dependent mechanisms exist for controlling lysosomal amino acid efflux. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

  19. A novel approach to analyze lysosomal dysfunctions through subcellular proteomics and lipidomics: the case of NPC1 deficiency

    Science.gov (United States)

    Tharkeshwar, Arun Kumar; Trekker, Jesse; Vermeire, Wendy; Pauwels, Jarne; Sannerud, Ragna; Priestman, David A.; Te Vruchte, Danielle; Vints, Katlijn; Baatsen, Pieter; Decuypere, Jean-Paul; Lu, Huiqi; Martin, Shaun; Vangheluwe, Peter; Swinnen, Johannes V.; Lagae, Liesbet; Impens, Francis; Platt, Frances M.; Gevaert, Kris; Annaert, Wim

    2017-01-01

    Superparamagnetic iron oxide nanoparticles (SPIONs) have mainly been used as cellular carriers for genes and therapeutic products, while their use in subcellular organelle isolation remains underexploited. We engineered SPIONs targeting distinct subcellular compartments. Dimercaptosuccinic acid-coated SPIONs are internalized and accumulate in late endosomes/lysosomes, while aminolipid-SPIONs reside at the plasma membrane. These features allowed us to establish standardized magnetic isolation procedures for these membrane compartments with a yield and purity permitting proteomic and lipidomic profiling. We validated our approach by comparing the biomolecular compositions of lysosomes and plasma membranes isolated from wild-type and Niemann-Pick disease type C1 (NPC1) deficient cells. While the accumulation of cholesterol and glycosphingolipids is seen as a primary hallmark of NPC1 deficiency, our lipidomics analysis revealed the buildup of several species of glycerophospholipids and other storage lipids in selectively late endosomes/lysosomes of NPC1-KO cells. While the plasma membrane proteome remained largely invariable, we observed pronounced alterations in several proteins linked to autophagy and lysosomal catabolism reflecting vesicular transport obstruction and defective lysosomal turnover resulting from NPC1 deficiency. Thus the use of SPIONs provides a major advancement in fingerprinting subcellular compartments, with an increased potential to identify disease-related alterations in their biomolecular compositions.

  20. Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    William M. Johnson

    2012-10-01

    Full Text Available Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the induction and progression of neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, and Friedreich’s ataxia. In this review background is provided on the steady-state synthesis, regulation, and transport of glutathione, with primary focus on the brain. A brief overview is presented on the distinct but vital roles of glutathione in cellular maintenance and survival, and on the functions of key glutathione-dependent enzymes. Major contributors to initiation and progression of neurodegenerative diseases are considered, including oxidative stress, protein misfolding, and protein aggregation. In each case examples of key regulatory mechanisms are identified that are sensitive to changes in glutathione redox status and/or in the activities of glutathione-dependent enzymes. Mechanisms of dysregulation of glutathione and/or glutathione-dependent enzymes are discussed that are implicated in pathogenesis of each neurodegenerative disease. Limitations in information or interpretation are identified, and possible avenues for further research are described with an aim to elucidating novel targets for therapeutic interventions. The pros and cons of administration of N-acetylcysteine or glutathione as therapeutic agents for neurodegenerative diseases, as well as the potential utility of serum glutathione as a biomarker, are critically evaluated.

  1. Mesenchymal Stem Cells in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Olcay Ergurhan Kiroglu

    2015-03-01

    Full Text Available Neurodegenerative diseases are almost incurable, debilitating, and they might be fatal, because of limited neurogenesis in nervous system, presence of inhibitory substances and inhibition of recovery due to development of glial scar. Despite many treatment strategies of neurodegenerative diseases no full cure has been achieved. The successful results for mesenchymal stem cells applications on muscles, heart and liver diseases and the application of these cells to the damaged area in particular, hypoxia, inflammation and apoptosis promise hope of using them for neurodegenerative diseases. Mesenchymal stem cells applications constitute a vascular and neuronal phenotype in Parkinsons disease, Huntingtons disease, Amyotrophic lateral sclerosis and Alzheimers disease. Stem cells release bioactive agents that lead to suppression of local immune system, reduction of free radicals, increase in angiogenesis, inhibition of fibrosis, and apoptosis. In addition, tissue stem cells, increase neuronal healing, stimulate proliferation and differentiation. These findings show that stem cells might be a hope of a cure in the treatment of neurodegenerative diseases and intensive work on this issue should continue.

  2. Dysregulation of Glutathione Homeostasis in Neurodegenerative Diseases

    Science.gov (United States)

    Johnson, William M.; Wilson-Delfosse, Amy L.; Mieyal, John. J.

    2012-01-01

    Dysregulation of glutathione homeostasis and alterations in glutathione-dependent enzyme activities are increasingly implicated in the induction and progression of neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s diseases, amyotrophic lateral sclerosis, and Friedreich’s ataxia. In this review background is provided on the steady-state synthesis, regulation, and transport of glutathione, with primary focus on the brain. A brief overview is presented on the distinct but vital roles of glutathione in cellular maintenance and survival, and on the functions of key glutathione-dependent enzymes. Major contributors to initiation and progression of neurodegenerative diseases are considered, including oxidative stress, protein misfolding, and protein aggregation. In each case examples of key regulatory mechanisms are identified that are sensitive to changes in glutathione redox status and/or in the activities of glutathione-dependent enzymes. Mechanisms of dysregulation of glutathione and/or glutathione-dependent enzymes are discussed that are implicated in pathogenesis of each neurodegenerative disease. Limitations in information or interpretation are identified, and possible avenues for further research are described with an aim to elucidating novel targets for therapeutic interventions. The pros and cons of administration of N-acetylcysteine or glutathione as therapeutic agents for neurodegenerative diseases, as well as the potential utility of serum glutathione as a biomarker, are critically evaluated. PMID:23201762

  3. Lysosome acidification by photoactivated nanoparticles restores autophagy under lipotoxicity.

    Science.gov (United States)

    Trudeau, Kyle M; Colby, Aaron H; Zeng, Jialiu; Las, Guy; Feng, Jiazuo H; Grinstaff, Mark W; Shirihai, Orian S

    2016-07-04

    In pancreatic β-cells, liver hepatocytes, and cardiomyocytes, chronic exposure to high levels of fatty acids (lipotoxicity) inhibits autophagic flux and concomitantly decreases lysosomal acidity. Whether impaired lysosomal acidification is causally inhibiting autophagic flux and cellular functions could not, up to the present, be determined because of the lack of an approach to modify lysosomal acidity. To address this question, lysosome-localizing nanoparticles are described that, upon UV photoactivation, enable controlled acidification of impaired lysosomes. The photoactivatable, acidifying nanoparticles (paNPs) demonstrate lysosomal uptake in INS1 and mouse β-cells. Photoactivation of paNPs in fatty acid-treated INS1 cells enhances lysosomal acidity and function while decreasing p62 and LC3-II levels, indicating rescue of autophagic flux upon acute lysosomal acidification. Furthermore, paNPs improve glucose-stimulated insulin secretion that is reduced under lipotoxicity in INS1 cells and mouse islets. These results establish a causative role for impaired lysosomal acidification in the deregulation of autophagy and β-cell function under lipotoxicity. © 2016 Trudeau et al.

  4. Biochemical characterization of lysosomes in unfertilized eggs of Xenopus laevis.

    Science.gov (United States)

    Decroly, M; Goldfinger, M; Six-Tondeur, N

    1979-11-01

    Relations between lysosomes and yolk platelets of amphibian eggs have been suggested. This work demonstrates the presence of acid hydrolases in oocytes induced to ovulate in vitro. About 40% of the acid hydrolases are found in a sedimentable fraction, and, in accordance with the lysosomal concept, they display structural latency. Biochemical data did not indicate any association between lysosomal enzymes and yolk platelets. The mechanism of yolk resorption is discussed and it is suggested that the fusion of lysosomes and yolk platelets might be one of the mechanisms involved in yolk digestion.

  5. Lysosomal Targeting with Stable and Sensitive Fluorescent Probes (Superior LysoProbes): Applications for Lysosome Labeling and Tracking during Apoptosis

    OpenAIRE

    Xin Chen; Yue Bi; Tianyang Wang; Pengfei Li; Xin Yan; Shanshan Hou; Bammert, Catherine E.; Jingfang Ju; K. Michael Gibson; Pavan, William J.; Lanrong Bi

    2015-01-01

    Intracellular pH plays an important role in the response to cancer invasion. We have designed and synthesized a series of new fluorescent probes (Superior LysoProbes) with the capacity to label acidic organelles and monitor lysosomal pH. Unlike commercially available fluorescent dyes, Superior LysoProbes are lysosome-specific and are highly stable. The use of Superior LysoProbes facilitates the direct visualization of the lysosomal response to lobaplatin elicited in human chloangiocarcinoma (...

  6. Abnormal Localization of Leucine-Rich Repeat Kinase 2 to the Endosomal-Lysosomal Compartment in Lewy Body Disease

    Science.gov (United States)

    Higashi, Shinji; Moore, Darren J; Yamamoto, Ryoko; Minegishi, Michiko; Sato, Kiyoshi; Togo, Takashi; Katsuse, Omi; Uchikado, Hirotake; Furukawa, Yoshiko; Hino, Hiroaki; Kosaka, Kenji; Emson, Piers C.; Wada, Keiji; Dawson, Valina L; Dawson, Ted M.; Arai, Heii; Iseki, Eizo

    2009-01-01

    Missense mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common causes of both familial and sporadic forms of Parkinson disease (PD) and are also associated with a diverse pathological alterations. The mechanisms whereby LRRK2 mutations cause these pathological phenotypes are unknown. We employed immunohistochemistry with 3 distinct anti-LRRK2 antibodies to characterize the expression of LRRK2 in the brains of 21 subjects with various neurodegenerative disorders and 7 controls. LRRK2 immunoreactivity was localized in a subset of brainstem-type Lewy bodies (LBs) but not in cortical-type LBs, tau-positive inclusions or TAR-DNA binding protein-43-positive inclusions. LRRK2 immunoreactivity frequently appeared as enlarged granules or vacuoles within neurons of affected brain regions, including the substantia nigra, amygdala and entorhinal cortex in patients with PD or dementia with Lewy bodies (DLB). The volumes of LRRK2-positive granular structures in neurons of the entorhinal cortex were significantly increased in DLB brains compared to aged-matched control brains (p<0.05). Double immunolabeling demonstrated that these LRRK2-positive granular structures frequently colocalized with the late-endosomal marker Rab7B and occasionally with the lysosomal marker, LAMP2. These results suggest that LRRK2 normally localizes to the endosomal-lysosomal compartment within morphologically altered neurons in neurodegenerative diseases, particularly in the brains of patients with LB diseases. PMID:19680143

  7. Spastic paraplegia proteins spastizin and spatacsin mediate autophagic lysosome reformation.

    Science.gov (United States)

    Chang, Jaerak; Lee, Seongju; Blackstone, Craig

    2014-12-01

    Autophagy allows cells to adapt to changes in their environment by coordinating the degradation and recycling of cellular components and organelles to maintain homeostasis. Lysosomes are organelles critical for terminating autophagy via their fusion with mature autophagosomes to generate autolysosomes that degrade autophagic materials; therefore, maintenance of the lysosomal population is essential for autophagy-dependent cellular clearance. Here, we have demonstrated that the two most common autosomal recessive hereditary spastic paraplegia gene products, the SPG15 protein spastizin and the SPG11 protein spatacsin, are pivotal for autophagic lysosome reformation (ALR), a pathway that generates new lysosomes. Lysosomal targeting of spastizin required an intact FYVE domain, which binds phosphatidylinositol 3-phosphate. Loss of spastizin or spatacsin resulted in depletion of free lysosomes, which are competent to fuse with autophagosomes, and an accumulation of autolysosomes, reflecting a failure in ALR. Moreover, spastizin and spatacsin were essential components for the initiation of lysosomal tubulation. Together, these results link dysfunction of the autophagy/lysosomal biogenesis machinery to neurodegeneration.

  8. Quantitative modeling of selective lysosomal targeting for drug design

    DEFF Research Database (Denmark)

    Trapp, Stefan; Rosania, G.; Horobin, R.W.

    2008-01-01

    Lysosomes are acidic organelles and are involved in various diseases, the most prominent is malaria. Accumulation of molecules in the cell by diffusion from the external solution into cytosol, lysosome and mitochondrium was calculated with the Fick–Nernst–Planck equation. The cell model considers...

  9. Fluorometric Assessment Of Lysosomal Enzymes In Garlic Oil ...

    African Journals Online (AJOL)

    The effect of Garlic oil on Lysosomal enzymes in streptozotocin-induced diabetic rats were investigated fluorometrically. The serum lysosomal enzymes assayed include β-glucuronidase, N-acetylglucosaminidase (NAG) β-D-galactosidase and α-D-galactosidase. The results of the study in nMole-4Mu/hr/ml show that ...

  10. Alpha Adrenergic Induction of Transport of Lysosomal Enzyme across the Blood-Brain Barrier.

    Directory of Open Access Journals (Sweden)

    Akihiko Urayama

    Full Text Available The impermeability of the adult blood-brain barrier (BBB to lysosomal enzymes impedes the ability to treat the central nervous system manifestations of lysosomal storage diseases. Here, we found that simultaneous stimulation of the alpha1 and alpha2 adrenoreceptor restores in adult mice the high rate of transport for the lysosomal enzyme P-GUS that is seen in neonates but lost with development. Beta adrenergics, other monoamines, and acetylcholine did not restore this transport. A high dose (500 microg/mouse of clonidine, a strong alpha2 and weak alpha1 agonist, was able to act as monotherapy in the stimulation of P-GUS transport. Neither use of alpha1 plus alpha2 agonists nor the high dose clonidine disrupted the BBB to albumin. In situ brain perfusion and immunohistochemistry studies indicated that adrengerics act on transporters already at the luminal surface of brain endothelial cells. These results show that adrenergic stimulation, including monotherapy with clonidine, could be key for CNS enzyme replacement therapy.

  11. The role of sebelipase alfa in the treatment of lysosomal acid lipase deficiency.

    Science.gov (United States)

    Erwin, Angelika L

    2017-07-01

    Lysosomal acid lipase deficiency (LALD) is a lysosomal storage disorder (LSD) characterized either by infantile onset with fulminant clinical course and very poor prognosis or childhood/adult-onset disease with an attenuated phenotype. The disorder is often misdiagnosed or remains undiagnosed in children and adults due to a rather unspecific clinical presentation with dyslipidemia and steatohepatitis. Until recently, no good treatment options were available for LALD. Despite supportive and symptomatic therapies, death occurred before 1 year of age in patients with infantile-onset disease and patients with childhood/adult-onset LALD suffered from significant complications, such as liver cirrhosis, requiring liver transplantation and early-onset cardiovascular disease. With the recent approval of sebelipase alfa for clinical use in infantile- as well as childhood/adult-onset LALD, a new treatment era for this disorder has begun. Sebelipase alfa is a recombinant human lysosomal acid lipase (LAL), which is administered via the intravenous route. Clinical trials have shown significant improvement of disease parameters such as liver transaminases, hepatomegaly, and dyslipidemia in childhood/adult-onset LALD patients. Treatment of infants with the severe infantile-onset form of the disease has led to improved survival beyond the age of 1 year, and also showed improvement of hepatic and gastrointestinal symptoms, as well as growth. Overall, sebelipase alfa has a favorable safety profile and promises to be a good long-term treatment option for patients with LALD, with significant reduction of disease burden and increased life expectancy.

  12. Protective effect of enterosgel on rat liver lysosomes during cytostatic treatment.

    Science.gov (United States)

    Grek, O R; Mishenina, S V; Pupyshev, A B

    2002-10-01

    Polychemotherapy with a complex of cytostatics (cyclophosphamide, doxorubicin, vincristine, prednisolone) induces progressive damage to hepatocyte membranes, which manifested in labilization of lysosomes and activation of lysosomal enzymes and serum transaminases. Enterosgel stabilized liver lysosomes and reduced manifestation of hepatocyte cytolysis.

  13. Antisense oligonucleotide therapeutics for inherited neurodegenerative diseases.

    Science.gov (United States)

    Southwell, Amber L; Skotte, Niels H; Bennett, C Frank; Hayden, Michael R

    2012-11-01

    The rising median age of our population and the age-dependent risk of neurodegeneration translate to exponentially increasing numbers of afflicted individuals in the coming years. Although symptomatic treatments are available for some neurodegenerative diseases, most are only moderately efficacious and are often associated with significant side effects. The development of small molecule, disease-modifying drugs has been hindered by complex pathogenesis and a failure to clearly define the rate-limiting steps in disease progression. An alternative approach is to directly target the mutant gene product or a defined causative protein. Antisense oligonucleotides (ASOs) - with their diverse functionality, high target specificity, and relative ease of central nervous system (CNS) delivery - are uniquely positioned as potential therapies for neurological diseases. Here we review the development of ASOs for the treatment of inherited neurodegenerative diseases. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Transmission of Neurodegenerative Disorders Through Blood Transfusion

    DEFF Research Database (Denmark)

    Edgren, Gustaf; Hjalgrim, Henrik; Rostgaard, Klaus

    2016-01-01

    : Multivariable Cox regression models were used to estimate hazard ratios for dementia of any type, Alzheimer disease, and Parkinson disease in patients receiving blood transfusions from donors who were later diagnosed with any of these diseases versus patients who received blood from healthy donors. Whether...... excess occurrence of neurodegenerative disease occurred among recipients of blood from a subset of donors was also investigated. As a positive control, transmission of chronic hepatitis before and after implementation of hepatitis C virus screening was assessed. RESULTS: Among included patients, 2.......9% received a transfusion from a donor diagnosed with one of the studied neurodegenerative diseases. No evidence of transmission of any of these diseases was found, regardless of approach. The hazard ratio for dementia in recipients of blood from donors with dementia versus recipients of blood from healthy...

  15. Engineering enhanced protein disaggregases for neurodegenerative disease

    OpenAIRE

    Jackrel, Meredith E.; Shorter, James

    2015-01-01

    Abstract Protein misfolding and aggregation underpin several fatal neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). There are no treatments that directly antagonize the protein-misfolding events that cause these disorders. Agents that reverse protein misfolding and restore proteins to native form and function could simultaneously eliminate any deleterious loss-of-function or toxic gain-of-function caused by...

  16. Synthetic prions and other human neurodegenerative proteinopathies.

    Science.gov (United States)

    Le, Nhat Tran Thanh; Narkiewicz, Joanna; Aulić, Suzana; Salzano, Giulia; Tran, Hoa Thanh; Scaini, Denis; Moda, Fabio; Giachin, Gabriele; Legname, Giuseppe

    2015-09-02

    Transmissible spongiform encephalopathies (TSE) are a heterogeneous group of neurodegenerative disorders. The common feature of these diseases is the pathological conversion of the normal cellular prion protein (PrP(C)) into a β-structure-rich conformer-termed PrP(Sc). The latter can induce a self-perpetuating process leading to amplification and spreading of pathological protein assemblies. Much evidence suggests that PrP(Sc) itself is able to recruit and misfold PrP(C) into the pathological conformation. Recent data have shown that recombinant PrP(C) can be misfolded in vitro and the resulting synthetic conformers are able to induce the conversion of PrP(C) into PrP(Sc)in vivo. In this review we describe the state-of-the-art of the body of literature in this field. In addition, we describe a cell-based assay to test synthetic prions in cells, providing further evidence that synthetic amyloids are able to template conversion of PrP into prion inclusions. Studying prions might help to understand the pathological mechanisms governing other neurodegenerative diseases. Aggregation and deposition of misfolded proteins is a common feature of several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and other disorders. Although the proteins implicated in each of these diseases differ, they share a common prion mechanism. Recombinant proteins are able to aggregate in vitro into β-rich amyloid fibrils, sharing some features of the aggregates found in the brain. Several studies have reported that intracerebral inoculation of synthetic aggregates lead to unique pathology, which spread progressively to distal brain regions and reduced survival time in animals. Here, we review the prion-like features of different proteins involved in neurodegenerative disorders, such as α-synuclein, superoxide dismutase-1, amyloid-β and tau. Copyright © 2014 Elsevier B.V. All rights reserved.

  17. A novel human model of the neurodegenerative disease GM1 gangliosidosis using induced pluripotent stem cells demonstrates inflammasome activation.

    Science.gov (United States)

    Son, Mi-Young; Kwak, Jae Eun; Seol, Binna; Lee, Da Yong; Jeon, Hyejin; Cho, Yee Sook

    2015-09-01

    GM1 gangliosidosis (GM1) is an inherited neurodegenerative disorder caused by mutations in the lysosomal β-galactosidase (β-gal) gene. Insufficient β-gal activity leads to abnormal accumulation of GM1 gangliosides in tissues, particularly in the central nervous system, resulting in progressive neurodegeneration. Here, we report an in vitro human GM1 model, based on induced pluripotent stem cell (iPSC) technology. Neural progenitor cells differentiated from GM1 patient-derived iPSCs (GM1-NPCs) recapitulated the biochemical and molecular phenotypes of GM1, including defective β-gal activity and increased lysosomes. Importantly, the characterization of GM1-NPCs established that GM1 is significantly associated with the activation of inflammasomes, which play a critical role in the pathogenesis of various neurodegenerative diseases. Specific inflammasome inhibitors potently alleviated the disease-related phenotypes of GM1-NPCs in vitro and in vivo. Our data demonstrate that GM1-NPCs are a valuable in vitro human GM1 model and suggest that inflammasome activation is a novel target pathway for GM1 drug development. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  18. Chronic neurodegenerative consequences of traumatic brain injury.

    Science.gov (United States)

    Chauhan, Neelima B

    2014-01-01

    Traumatic brain injury (TBI) is a serious public health concern and a major cause of death and disability worldwide. Each year, an estimated 1.7 million Americans sustain TBI of which ~52,000 people die, ~275,000 people are hospitalized and 1,365,000 people are treated as emergency outpatients. Currently there are ~5.3 million Americans living with TBI. TBI is more of a disease process than of an event that is associated with immediate and long-term sensomotor, psychological and cognitive impairments. TBI is the best known established epigenetic risk factor for later development of neurodegenerative diseases and dementia. People sustaining TBI are ~4 times more likely to develop dementia at a later stage than people without TBI. Single brain injury is linked to later development of symptoms resembling Alzheimer's disease while repetitive brain injuries are linked to later development of chronic traumatic encephalopathy (CTE) and/or Dementia Pugilistica (DP). Furthermore, genetic background of ß-amyloid precursor protein (APP), Apolipoprotein E (ApoE), presenilin (PS) and neprilysin (NEP) genes is associated with exacerbation of neurodegenerative process after TBI. This review encompasses acute effects and chronic neurodegenerative consequences after TBI.

  19. Exosomes in the Pathology of Neurodegenerative Diseases.

    Science.gov (United States)

    Howitt, Jason; Hill, Andrew F

    2016-12-23

    More than 30 years ago, two unexpected findings were discovered that challenged conventional thinking in biology. The first was the identification of a misfolded protein with transmissible properties associated with a group of neurodegenerative diseases known as transmissible spongiform encephalopathies. The second was the discovery of a new pathway used for the extracellular release of biomolecules, including extracellular vesicles called exosomes. Two decades later, the convergence of these pathways was shown when exosomes were found to play a significant role in both the transmission and propagation of protein aggregates in disease. Recent research has now revealed that the majority of proteins involved in neurodegenerative diseases are transported in exosomes, and that external stresses due to age-related impairment of protein quality control mechanisms can promote the transcellular flux of these proteins in exosomes. Significantly, exosomes provide an environment that can induce the conformational conversion of native proteins into aggregates that can be transmitted to otherwise aggregate-free cells in the brain. Here we review the current roles of exosomes in the pathology of neurodegenerative diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  20. Metals and neurodegenerative diseases. A systematic review.

    Science.gov (United States)

    Cicero, Calogero Edoardo; Mostile, Giovanni; Vasta, Rosario; Rapisarda, Venerando; Signorelli, Salvatore Santo; Ferrante, Margherita; Zappia, Mario; Nicoletti, Alessandra

    2017-11-01

    Neurodegenerative processes encompass a large variety of diseases with different pathological patterns and clinical presentation such as Amyotrophic Lateral Sclerosis (ALS), Alzheimer Disease (AD) and Parkinson's disease (PD). Genetic mutations have a known causative role, but the majority of cases are likely to be probably caused by a complex gene-environment interaction. Exposure to metals has been hypothesized to increase oxidative stress in brain cells leading to cell death and neurodegeneration. Neurotoxicity of metals has been demonstrated by several in vitro and in vivo experimental studies and it is likely that each metal could be toxic through specific pathways. The possible pathogenic role of different metals has been supported by some epidemiological evidences coming from occupational and ecological studies. In order to assess the possible association between metals and neurodegenerative disorders, several case-control studies have also been carried out evaluating the metals concentration in different biological specimens such as blood/serum/plasma, cerebrospinal fluid (CSF), nail and hair, often reporting conflicting results. This review provides an overview of our current knowledge on the possible association between metals and ALS, AD and PD as main neurodegenerative disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Early noninvasive diagnosis of neurodegenerative diseases.

    Science.gov (United States)

    Danev, Stoyan I; St Stoyanov, Drozdstoy

    2010-01-01

    This paper reviews the contemporary trends in the pathobiochemistry of neurodegenerative disorders with respect to their early predictive diagnosis and possible treatment interventions. If we consider the current epidemiological data related to neurodegenerative disorders, medicine is going to face in the near future latent pandemic situations. The introduction puts an emphasis on the emerging importance of one major cluster of neurodegenerative disorders: diseases of the abnormal protein beta-conformation. The cluster includes such significant diseases as Alzheimer, Pick, Huntington, Parkinson disease, as well as the transmissible spongiform encephalopathies (Creuzfeldt-Jakob disease). The pathogenetic mechanisms in the determination of this group of disorders are explored with an emphasis on the impairment of post-synthetic chaperone correction. The central role of a number of such protein products is discussed. In particular the pathobiochemical mechanisms concerning the formation of beta-amyloid, alpha and beta synucleins, scrapie isoform of the prion protein are presented. A new diagnostic principle allowing the early and specific diagnosis of the conformation diseases protein via amplification techniques is presented. These methods compete in sensitivity with the PCR methods and shows promises for effective treatment. In conclusion, beta-pathies are considered a suitable example for the modern concept of cluster and prototype diagnosis in medicine and especially in clinical neurosciences.

  2. Sleep disturbance in mental health problems and neurodegenerative disease

    National Research Council Canada - National Science Library

    Anderson, Kirstie N; Bradley, Andrew J

    2013-01-01

    ... and neurodegenerative disorders. The role of primary sleep disorders such as insomnia, obstructive sleep apnea, and REM sleep behavior disorder as potential causes or risk factors for particular mental health or neurodegenerative...

  3. Pain in Neurodegenerative Disease : Current Knowledge and Future Perspectives

    NARCIS (Netherlands)

    de Tommaso, Marina; Arendt-Nielsen, Lars; Defrin, Ruth; Kunz, Miriam; Pickering, Gisele; Valeriani, Massimiliano

    2016-01-01

    Neurodegenerative diseases are going to increase as the life expectancy is getting longer. The management of neurodegenerative diseases such as Alzheimer's disease (AD) and other dementias, Parkinson's disease (PD) and PD related disorders, motor neuron diseases (MND), Huntington's disease (HD),

  4. Mutation detection in glycogen storage disease type II by RT-PCR and automated sequencing

    NARCIS (Netherlands)

    M.M.P. Hermans (Monique); D. van Leenen (Dik); M.A. Kroos (Marian); A.J.J. Reuser (Arnold)

    1997-01-01

    textabstractA new method is described for detection of mutations in the lysosomal a-glucosidase gene (GAA) leading to Glycogen Storage Disease type II (GSDII). A key feature of the method is isolation and reverse transcription of mRNA followed by PCR amplification of lysosomal a-glucosidase cDNA

  5. Intracellular transport of acid beta-glucosidase and lysosome-associated membrane proteins is affected in Gaucher's disease (G202R mutation)

    NARCIS (Netherlands)

    Zimmer, K. P.; le Coutre, P.; Aerts, H. M.; Harzer, K.; Fukuda, M.; O'Brien, J. S.; Naim, H. Y.

    1999-01-01

    Gaucher's disease (GD) is caused by an inherited deficiency of acid beta-glucosidase with storage of glucosylceramides in the lysosomes of macrophages. This study identifies a G202R mutation in the acid beta-glucosidase gene in an infant with severe neuronopathic (type 2) GD and only slightly

  6. Autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity

    Directory of Open Access Journals (Sweden)

    Stern Stephan T

    2012-06-01

    Full Text Available Abstract The study of the potential risks associated with the manufacture, use, and disposal of nanoscale materials, and their mechanisms of toxicity, is important for the continued advancement of nanotechnology. Currently, the most widely accepted paradigms of nanomaterial toxicity are oxidative stress and inflammation, but the underlying mechanisms are poorly defined. This review will highlight the significance of autophagy and lysosomal dysfunction as emerging mechanisms of nanomaterial toxicity. Most endocytic routes of nanomaterial cell uptake converge upon the lysosome, making the lysosomal compartment the most common intracellular site of nanoparticle sequestration and degradation. In addition to the endo-lysosomal pathway, recent evidence suggests that some nanomaterials can also induce autophagy. Among the many physiological functions, the lysosome, by way of the autophagy (macroautophagy pathway, degrades intracellular pathogens, and damaged organelles and proteins. Thus, autophagy induction by nanoparticles may be an attempt to degrade what is perceived by the cell as foreign or aberrant. While the autophagy and endo-lysosomal pathways have the potential to influence the disposition of nanomaterials, there is also a growing body of literature suggesting that biopersistent nanomaterials can, in turn, negatively impact these pathways. Indeed, there is ample evidence that biopersistent nanomaterials can cause autophagy and lysosomal dysfunctions resulting in toxicological consequences.

  7. Splice donor site mutation in the lysosomal neuraminidase gene causing exon skipping and complete loss of enzyme activity in a sialidosis patient.

    Science.gov (United States)

    Penzel, R; Uhl, J; Kopitz, J; Beck, M; Otto, H F; Cantz, M

    2001-07-20

    Sialidosis is a lysosomal storage disease caused by the deficiency of alpha-N-acetylneuraminidase (NEU1; sialidase), the key enzyme for the intralysosomal catabolism of sialylated glycoconjugates. We have identified a homozygous transversion in the last intron (IVSE +1 G>C) in neu1 of a sialidosis patient. Sequencing of the truncated cDNA revealed an alternatively spliced neu1 transcript which lacks the complete sequence of exon 5. Skipping of exon 5 leads to a frameshift and results in a premature termination codon. This is the first description of an intronic point mutation causing a complete deficiency of the lysosomal neuraminidase activity.

  8. Sleep-disordered breathing in neurodegenerative diseases.

    Science.gov (United States)

    Gaig, Carles; Iranzo, Alex

    2012-04-01

    Sleep disorders are common in neurodegenerative diseases such as Parkinson's disease (PD), multiple system atrophy (MSA), amyotrophic lateral sclerosis (ALS), hereditary ataxias, and Alzheimer's disease (AD). Type, frequency, and severity of sleep disturbances vary depending on each of these diseases. Cell loss of the brainstem nuclei that modulates respiration, and dysfunction of bulbar and diaphragmatic muscles increase the risk for sleep-disordered breathing (SDB) in MSA and ALS. The most relevant SDB in MSA is stridor, whereas in ALS nocturnal hypoventilation due to diaphragmatic weakness is the most common sleep breathing abnormality. Stridor and nocturnal hypoventilation are associated with reduced survival in MSA and ALS. In contrast, sleep apnea seems not to be more prevalent in PD than in the general population. In some PD patients, however, coincidental obstructive sleep apnea (OSA) can be the cause of excessive daytime sleepiness (EDS). SDB can also occur in some hereditary ataxias, such as stridor in spinocerebellar ataxia type 3 (Machado-Joseph disease). The presence of concomitant OSA in patients with AD can have deleterious effects on nocturnal sleep, may result in EDS, and might aggravate the cognitive deficits inherent to the disease. However, whether OSA is more frequent in patients with AD than in the general population is uncertain. Recognition of SDB in neurodegenerative disease is important because they are associated with significant morbidity and potential effective treatments are available.

  9. Engineering enhanced protein disaggregases for neurodegenerative disease.

    Science.gov (United States)

    Jackrel, Meredith E; Shorter, James

    2015-01-01

    Protein misfolding and aggregation underpin several fatal neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD). There are no treatments that directly antagonize the protein-misfolding events that cause these disorders. Agents that reverse protein misfolding and restore proteins to native form and function could simultaneously eliminate any deleterious loss-of-function or toxic gain-of-function caused by misfolded conformers. Moreover, a disruptive technology of this nature would eliminate self-templating conformers that spread pathology and catalyze formation of toxic, soluble oligomers. Here, we highlight our efforts to engineer Hsp104, a protein disaggregase from yeast, to more effectively disaggregate misfolded proteins connected with PD, ALS, and FTD. Remarkably subtle modifications of Hsp104 primary sequence yielded large gains in protective activity against deleterious α-synuclein, TDP-43, FUS, and TAF15 misfolding. Unusually, in many cases loss of amino acid identity at select positions in Hsp104 rather than specific mutation conferred a robust therapeutic gain-of-function. Nevertheless, the misfolding and toxicity of EWSR1, an RNA-binding protein with a prion-like domain linked to ALS and FTD, could not be buffered by potentiated Hsp104 variants, indicating that further amelioration of disaggregase activity or sharpening of substrate specificity is warranted. We suggest that neuroprotection is achievable for diverse neurodegenerative conditions via surprisingly subtle structural modifications of existing chaperones.

  10. Polyphenols: Multipotent Therapeutic Agents in Neurodegenerative Diseases

    Science.gov (United States)

    Bhullar, Khushwant S.; Rupasinghe, H. P. Vasantha

    2013-01-01

    Aging leads to numerous transitions in brain physiology including synaptic dysfunction and disturbances in cognition and memory. With a few clinically relevant drugs, a substantial portion of aging population at risk for age-related neurodegenerative disorders require nutritional intervention. Dietary intake of polyphenols is known to attenuate oxidative stress and reduce the risk for related neurodegenerative diseases such as Alzheimer's disease (AD), stroke, multiple sclerosis (MS), Parkinson's disease (PD), and Huntington's disease (HD). Polyphenols exhibit strong potential to address the etiology of neurological disorders as they attenuate their complex physiology by modulating several therapeutic targets at once. Firstly, we review the advances in the therapeutic role of polyphenols in cell and animal models of AD, PD, MS, and HD and activation of drug targets for controlling pathological manifestations. Secondly, we present principle pathways in which polyphenol intake translates into therapeutic outcomes. In particular, signaling pathways like PPAR, Nrf2, STAT, HIF, and MAPK along with modulation of immune response by polyphenols are discussed. Although current polyphenol researches have limited impact on clinical practice, they have strong evidence and testable hypothesis to contribute clinical advances and drug discovery towards age-related neurological disorders. PMID:23840922

  11. MRI features of neurodegenerative Langerhans cell histiocytosis

    Energy Technology Data Exchange (ETDEWEB)

    Martin-Duverneuil, N.; Guillevin, R.; Chiras, J. [GH Pitie-Salpetriere, 47 Bd de l' Hopital, Department of Neuroradiology, Paris (France); Idbaih, A.; Hoang-Xuan, K. [GH Pitie-Salpetriere, 47 Bd de l' Hopital, Department of Neurology, Paris (France); Donadieu, J. [GH Trousseau, Department of Hematology/Oncology Pediatrics, Paris (France); Genereau, T. [Groupe d' etude des Histiocytoses langerhansiennes, Nantes (France)

    2006-09-15

    CNS complications of LCH include ''space occupying'' lesions corresponding to histiocytic granulomas and ''neurodegenerative'' presentation (ND-LCH) characterized by a progressive cerebellar ataxia. Studies analyzing specifically the MRI presentation of ND-LCH are scarce. We present here the MRIs of 13 patients registered as isolated ND-LCH. Posterior fossa was involved in 12 patients (92%), showing a symmetrical T2 hyperintensity of the cerebellar white matter areas in seven cases with a circumscribed T1 hyperintensity of the dentate nuclei in five cases, definite hyperintense T2 areas in the adjacent pontine tegmentum white matter in nine cases associated with a hyperintensity of the pontine pyramidal tracts in four cases. A cerebellar atrophy was noted in eight cases. The supratentorial region was involved in 11 patients, showing T2 hyperintense lesions in the cerebral white matter in eight cases and a discrete symmetrical T1 hyperintense signal in the globus pallidus in eight patients. A diffuse cortical atrophy was present in three cases and a marked focal atrophy of the corpus callosum in three cases. This series allows us to establish a not previously reported evocative semeiologic MR presentation to precisely orientate to the diagnosis of the pure neurodegenerative form of LCH. (orig.)

  12. Biology of Mitochondria in Neurodegenerative Diseases

    Science.gov (United States)

    Martin, Lee J.

    2012-01-01

    Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal degeneration in these familial diseases, and in the more common idiopathic (sporadic) diseases, are unresolved. Genetic, biochemical, and morphological analyses of human AD, PD, and ALS, as well as their cell and animal models, reveal that mitochondria could have roles in this neurodegeneration. The varied functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and the overlying genetic variations. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial programmed cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This chapter reviews several aspects of mitochondrial biology and how mitochondrial pathobiology might contribute to the mechanisms of neurodegeneration in AD, PD, and ALS. PMID:22482456

  13. Chronic traumatic encephalopathy and other neurodegenerative proteinopathies

    Directory of Open Access Journals (Sweden)

    Maria Carmela Tartaglia

    2014-01-01

    Full Text Available Chronic traumatic encephalopathy (CTE is described as a slowly progressive neurodegenerative disease believed to result from multiple concussions. Traditionally, concussions were considered benign events and although most people recover fully, about 10% develop a post-concussive syndrome with persisting neurological, cognitive and neuropsychiatric symptoms. CTE was once thought to be unique to boxers, but it has now been observed in many different athletes having suffered multiple concussions as well as in military personal after repeated blast injuries. Much remains unknown about the development of CTE but its pathological substrate is usually tau, similar to that seen in Alzheimer’s disease and frontotemporal lobar degeneration. The aim of this perspective is to compare and contrast clinical and pathological CTE with the other neurodegenerative proteinopathies and highlight that there is an urgent need for understanding the relationship between concussion and the development of CTE as it may provide a window into the development of a proteinopathy and thus new avenues for treatment.

  14. The role of thiamine in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Irena Bubko

    2015-09-01

    Full Text Available Vitamin B1 (thiamine plays an important role in metabolism. It is indispensable for normal growth and development of the organism. Thiamine has a favourable impact on a number of systems, including the digestive, cardiovascular and nervous systems. It also stimulates the brain and improves the psycho-emotional state. Hence it is often called the vitamin of “reassurance of the spirit”. Thiamine is a water-soluble vitamin. It can be present in the free form as thiamine or as its phosphate esters: mono-, di- or triphosphate. The main source of thiamine as an exogenous vitamin is certain foodstuffs, but trace amounts can be synthesised by microorganisms of the large intestine. The recommended daily intake of thiamine is about 2.0 mg. Since vitamin B1 has no ability to accumulate in the organism, manifestations of its deficiency begin to appear very quickly. The chronic state of thiamine deficiency, to a large extent, because of its function, contributes to the development of neurodegenerative diseases. It was proved that supporting vitamin B1 therapy not only constitutes neuroprotection but can also have a favourable impact on advanced neurodegenerative diseases. This article presents the current state of knowledge as regards the effects of thiamine exerted through this vitamin in a number of diseases such as Parkinson’s disease, Alzheimer’s disease, Wernicke’s encephalopathy or Wernicke-Korsakoff syndrome and Huntington’s disease.

  15. Ghrelin and Neurodegenerative Disorders-a Review.

    Science.gov (United States)

    Shi, Limin; Du, Xixun; Jiang, Hong; Xie, Junxia

    2017-03-01

    Ghrelin, the endogenous ligand of the growth hormone secretagogue receptor 1a (GHS-R1a), is a gut-derived, orexigenic peptide hormone that primarily regulates growth hormone secretion, food intake, and energy homeostasis. With the wide expression of GHS-R1a in extra-hypothalamic regions, the physiological role of ghrelin is more extensive than solely its involvement in metabolic function. Ghrelin has been shown to be involved in numerous higher brain functions, such as memory, reward, mood, and sleep. Some of these functions are disrupted in neurodegenerative disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). This link between ghrelin and these neurodegenerative diseases is supported by numerous studies. This review aims to provide a comprehensive overview of the most recent evidence of the novel neuromodulatory role of ghrelin in PD, AD, and HD. Moreover, the changes in circulating and/or central ghrelin levels that are associated with disease progression are also postulated to be a biomarker for clinical diagnosis and therapy.

  16. Heat shock protein 90 in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Rodina Anna

    2010-06-01

    Full Text Available Abstract Hsp90 is a molecular chaperone with important roles in regulating pathogenic transformation. In addition to its well-characterized functions in malignancy, recent evidence from several laboratories suggests a role for Hsp90 in maintaining the functional stability of neuronal proteins of aberrant capacity, whether mutated or over-activated, allowing and sustaining the accumulation of toxic aggregates. In addition, Hsp90 regulates the activity of the transcription factor heat shock factor-1 (HSF-1, the master regulator of the heat shock response, mechanism that cells use for protection when exposed to conditions of stress. These biological functions therefore propose Hsp90 inhibition as a dual therapeutic modality in neurodegenerative diseases. First, by suppressing aberrant neuronal activity, Hsp90 inhibitors may ameliorate protein aggregation and its associated toxicity. Second, by activation of HSF-1 and the subsequent induction of heat shock proteins, such as Hsp70, Hsp90 inhibitors may redirect neuronal aggregate formation, and protect against protein toxicity. This mini-review will summarize our current knowledge on Hsp90 in neurodegeneration and will focus on the potential beneficial application of Hsp90 inhibitors in neurodegenerative diseases.

  17. Precision newborn screening for lysosomal disorders.

    Science.gov (United States)

    Minter Baerg, Melissa M; Stoway, Stephanie D; Hart, Jeremy; Mott, Lea; Peck, Dawn S; Nett, Stephanie L; Eckerman, Jason S; Lacey, Jean M; Turgeon, Coleman T; Gavrilov, Dimitar; Oglesbee, Devin; Raymond, Kimiyo; Tortorelli, Silvia; Matern, Dietrich; Mørkrid, Lars; Rinaldo, Piero

    2017-11-09

    PurposeThe implementation of newborn screening for lysosomal disorders has uncovered overall poor specificity, psychosocial harm experienced by caregivers, and costly follow-up testing of false-positive cases. We report an informatics solution proven to minimize these issues.MethodsThe Kentucky Department for Public Health outsourced testing for mucopolysaccharidosis type I (MPS I) and Pompe disease, conditions recently added to the recommended uniform screening panel, plus Krabbe disease, which was added by legislative mandate. A total of 55,161 specimens were collected from infants born over 1 year starting from February 2016. Testing by tandem mass spectrometry was integrated with multivariate pattern recognition software (Collaborative Laboratory Integrated Reports), which is freely available to newborn screening programs for selection of cases for which a biochemical second-tier test is needed.ResultsOf five presumptive positive cases, one was affected with infantile Krabbe disease, two with Pompe disease, and one with MPS I. The remaining case was a heterozygote for the latter condition. The false-positive rate was 0.0018% and the positive predictive value was 80%.ConclusionPostanalytical interpretive tools can drastically reduce false-positive outcomes, with preliminary evidence of no greater risk of false-negative events, still to be verified by long-term surveillance.GENETICS in MEDICINE advance online publication, 9 November 2017; doi:10.1038/gim.2017.194.

  18. Lysosome-related organelles: Unusual compartments become mainstream

    OpenAIRE

    Marks, Michael S.; Heijnen, Harry F. G.; Raposo, Graça

    2013-01-01

    Lysosome-related organelles (LROs) comprise a group of cell type-specific subcellular compartments with unique composition, morphology and structure that share some features with endosomes and lysosomes and that function in varied processes such as pigmentation, hemostasis, lung plasticity and immunity. In recent years, studies of genetic diseases in which LRO functions are compromised have provided new insights into the mechanisms of LRO biogenesis and the regulated secretion of LRO contents...

  19. Modulation of the transport of a lysosomal enzyme by PDGF

    OpenAIRE

    1990-01-01

    The major excreted protein (MEP) of transformed mouse fibroblasts is the lysosomal protease, cathepsin L. MEP is also secreted by untransformed mouse cells in response to growth factors and tumor promoters, and is thought to play a role in cell growth and transformation. To determine the relationship between MEP synthesis and MEP secretion, we have examined these events in PDGF-treated NIH 3T3 cells. PDGF enhanced MEP synthesis and caused the diversion of MEP from the lysosomal delivery pathw...

  20. Ragulator-a multifaceted regulator of lysosomal signaling and trafficking.

    Science.gov (United States)

    Colaço, Alexandria; Jäättelä, Marja

    2017-12-04

    The lysosomal Ragulator complex regulates cell metabolism and growth by coordinating the activities of metabolic signaling pathways with nutrient availability. In this issue, Filipek et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201703061) and Pu et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201703094) introduce a role for Ragulator in growth factor- and nutrient-regulated lysosomal trafficking. © 2017 Colaço and Jäättelä.

  1. Acidic nanoparticles are trafficked to lysosomes and restore an acidic lysosomal pH and degradative function to compromised ARPE-19 cells.

    Directory of Open Access Journals (Sweden)

    Gabriel C Baltazar

    Full Text Available Lysosomal enzymes function optimally in acidic environments, and elevation of lysosomal pH can impede their ability to degrade material delivered to lysosomes through autophagy or phagocytosis. We hypothesize that abnormal lysosomal pH is a key aspect in diseases of accumulation and that restoring lysosomal pH will improve cell function. The propensity of nanoparticles to end up in the lysosome makes them an ideal method of delivering drugs to lysosomes. This study asked whether acidic nanoparticles could traffic to lysosomes, lower lysosomal pH and enhance lysosomal degradation by the cultured human retinal pigmented epithelial cell line ARPE-19. Acidic nanoparticles composed of poly (DL-lactide-co-glycolide (PLGA 502 H, PLGA 503 H and poly (DL-lactide (PLA colocalized to lysosomes of ARPE-19 cells within 60 min. PLGA 503 H and PLA lowered lysosomal pH in cells compromised by the alkalinizing agent chloroquine when measured 1 hr. after treatment, with acidification still observed 12 days later. PLA enhanced binding of Bodipy-pepstatin-A to the active site of cathepsin D in compromised cells. PLA also reduced the cellular levels of opsin and the lipofuscin-like autofluorescence associated with photoreceptor outer segments. These observations suggest the acidification produced by the nanoparticles was functionally effective. In summary, acid nanoparticles lead to a rapid and sustained lowering of lysosomal pH and improved degradative activity.

  2. Lysosomal enzymes and their receptors in invertebrates: an evolutionary perspective.

    Science.gov (United States)

    Kumar, Nadimpalli Siva; Bhamidimarri, Poorna M

    2015-01-01

    Lysosomal biogenesis is an important process in eukaryotic cells to maintain cellular homeostasis. The key components that are involved in the biogenesis such as the lysosomal enzymes, their modifications and the mannose 6-phosphate receptors have been well studied and their evolutionary conservation across mammalian and non-mammalian vertebrates is clearly established. Invertebrate lysosomal biogenesis pathway on the other hand is not well studied. Although, details on mannose 6-phosphate receptors and enzymes involved in lysosomal enzyme modifications were reported earlier, a clear cut pathway has not been established. Recent research on the invertebrate species involving biogenesis of lysosomal enzymes suggests a possible conserved pathway in invertebrates. This review presents certain observations based on these processes that include biochemical, immunological and functional studies. Major conclusions include conservation of MPR-dependent pathway in higher invertebrates and recent evidence suggests that MPR-independent pathway might have been more prominent among lower invertebrates. The possible components of MPR-independent pathway that may play a role in lysosomal enzyme targeting are also discussed here.

  3. Enzymatic reduction of disulfide bonds in lysosomes: Characterization of a Gamma-interferon-inducible lysosomal thiol reductase (GILT)

    Science.gov (United States)

    Arunachalam, Balasubramanian; Phan, Uyen T.; Geuze, Hans J.; Cresswell, Peter

    2000-01-01

    Proteins internalized into the endocytic pathway are usually degraded. Efficient proteolysis requires denaturation, induced by acidic conditions within lysosomes, and reduction of inter- and intrachain disulfide bonds. Cytosolic reduction is mediated enzymatically by thioredoxin, but the mechanism of lysosomal reduction is unknown. We describe here a lysosomal thiol reductase optimally active at low pH and capable of catalyzing disulfide bond reduction both in vivo and in vitro. The active site, determined by mutagenesis, consists of a pair of cysteine residues separated by two amino acids, similar to other enzymes of the thioredoxin family. The enzyme is a soluble glycoprotein that is synthesized as a precursor. After delivery into the endosomal/lysosomal system by the mannose 6-phosphate receptor, N- and C-terminal prosequences are removed. The enzyme is expressed constitutively in antigen-presenting cells and induced by IFN-γ in other cell types, suggesting a potentially important role in antigen processing.

  4. Determination of frequencies of alleles, associated with the pseudodeficiency of lysosomal hydrolases, in population of Ukraine.

    Science.gov (United States)

    Olkhovych, N V; Gorovenko, N G

    2016-01-01

    The pseudodeficiency of lysosomal hydrolases described as a significant reduction in enzyme activi­ty in vitro in clinically healthy individuals, can lead to diagnostic errors in the process of biochemical analysis of lysosomal storage disease in case of its combination with pathology of another origin. Pseudodeficiency is mostly caused by some non-pathogenic changes in the corresponding gene. These changes lead to the in vitro lability of the enzyme molecule, whereas in vivo the enzyme retains its functional activity. To assess the prevalence of the most common lysosomal hydrolases pseudodeficiency alleles in Ukraine, we have determined the frequency of alleles c.1055A>G and c.* 96A>G in the ARSA gene, substitutions c.739C>T (R247W) and c.745C>T (R249W) in the HEXA gene, c.1726G>A (G576S) and c.2065G>A (E689K) in the GAA gene, c.937G>T (D313Y) in the GLA1 gene and c.898G>A (A300T) in the IDUA gene in a group of 117 healthy individuals from different regions of the country and 14 heterozygous carriers of pathogenic mutations in the HEXA gene (parents of children with confirmed diagnosis of Tay-Sachs disease). The total frequency of haplotypes, associated with arylsulfatase A pseudodeficiency, in healthy people in Ukraine (c.1055G/c.*96G and c.1055G/c.*96A haplotypes) was 10.3%. The frequency of c.739C>T (R247W) allele, associated with hexo­saminidase A pseudodeficiency, among Tay-Sachs carriers from Ukraine was 7.1%. The total frequency of α-glucosidase pseudodeficiency haplotypes in healthy individuals in Ukraine (c.1726A/c.2065A and c.1726G/c.2065A haplotypes) was 2.6%. No person among examined individuals with the substitution c.937G>T (D313Y) in the GLA1 gene and c.898G>A (A300T) in the IDUA gene was found. The differential diagnostics of lysosomal storage diseases requires obligatory determination of the presence of the pseudodeficiency alleles, particularly the ones with high incidence in the total population. Ignoring phenomenon of pseudodeficiency may

  5. Ketogenic Diet in Neuromuscular and Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Antonio Paoli

    2014-01-01

    Full Text Available An increasing number of data demonstrate the utility of ketogenic diets in a variety of metabolic diseases as obesity, metabolic syndrome, and diabetes. In regard to neurological disorders, ketogenic diet is recognized as an effective treatment for pharmacoresistant epilepsy but emerging data suggests that ketogenic diet could be also useful in amyotrophic lateral sclerosis, Alzheimer, Parkinson’s disease, and some mitochondriopathies. Although these diseases have different pathogenesis and features, there are some common mechanisms that could explain the effects of ketogenic diets. These mechanisms are to provide an efficient source of energy for the treatment of certain types of neurodegenerative diseases characterized by focal brain hypometabolism; to decrease the oxidative damage associated with various kinds of metabolic stress; to increase the mitochondrial biogenesis pathways; and to take advantage of the capacity of ketones to bypass the defect in complex I activity implicated in some neurological diseases. These mechanisms will be discussed in this review.

  6. Ketogenic Diet in Neuromuscular and Neurodegenerative Diseases

    Science.gov (United States)

    Damiani, Ernesto; Bosco, Gerardo

    2014-01-01

    An increasing number of data demonstrate the utility of ketogenic diets in a variety of metabolic diseases as obesity, metabolic syndrome, and diabetes. In regard to neurological disorders, ketogenic diet is recognized as an effective treatment for pharmacoresistant epilepsy but emerging data suggests that ketogenic diet could be also useful in amyotrophic lateral sclerosis, Alzheimer, Parkinson's disease, and some mitochondriopathies. Although these diseases have different pathogenesis and features, there are some common mechanisms that could explain the effects of ketogenic diets. These mechanisms are to provide an efficient source of energy for the treatment of certain types of neurodegenerative diseases characterized by focal brain hypometabolism; to decrease the oxidative damage associated with various kinds of metabolic stress; to increase the mitochondrial biogenesis pathways; and to take advantage of the capacity of ketones to bypass the defect in complex I activity implicated in some neurological diseases. These mechanisms will be discussed in this review. PMID:25101284

  7. Transgenic nonhuman primates for neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Chan Anthony WS

    2004-06-01

    Full Text Available Abstract Animal models that represent human diseases constitute an important tool in understanding the pathogenesis of the diseases, and in developing effective therapies. Neurodegenerative diseases are complex disorders involving neuropathologic and psychiatric alterations. Although transgenic and knock-in mouse models of Alzheimer's disease, (AD, Parkinson's disease (PD and Huntington's disease (HD have been created, limited representation in clinical aspects has been recognized and the rodent models lack true neurodegeneration. Chemical induction of HD and PD in nonhuman primates (NHP has been reported, however, the role of intrinsic genetic factors in the development of the diseases is indeterminable. Nonhuman primates closely parallel humans with regard to genetic, neuroanatomic, and cognitive/behavioral characteristics. Accordingly, the development of NHP models for neurodegenerative diseases holds greater promise for success in the discovery of diagnoses, treatments, and cures than approaches using other animal species. Therefore, a transgenic NHP carrying a mutant gene similar to that of patients will help to clarify our understanding of disease onset and progression. Additionally, monitoring disease onset and development in the transgenic NHP by high resolution brain imaging technology such as MRI, and behavioral and cognitive testing can all be carried out simultaneously in the NHP but not in other animal models. Moreover, because of the similarity in motor repertoire between NHPs and humans, it will also be possible to compare the neurologic syndrome observed in the NHP model to that in patients. Understanding the correlation between genetic defects and physiologic changes (e.g. oxidative damage will lead to a better understanding of disease progression and the development of patient treatments, medications and preventive approaches for high risk individuals. The impact of the transgenic NHP model in understanding the role which

  8. Neurodegenerative diseases: exercising towards neurogenesis and neuroregeneration

    Directory of Open Access Journals (Sweden)

    Eng-Tat Ang

    2010-07-01

    Full Text Available Currently, there is still no effective therapy for neurodegenerative diseases (NDD such as Alzheimer’s disease (AD and Parkinson’s disease (PD despite intensive research and on-going clinical trials. Collectively, these diseases account for the bulk of health care burden associated with age-related neurodegenerative disorders. There is therefore an urgent need to further research into the molecular pathogenesis, histological differentiation, and clinical management of NDD. Importantly, there is also an urgency to understand the similarities and differences between these two diseases so as to identify the common or different upstream and downstream signaling pathways. In this review, the role iron play in NDD will be highlighted, as iron is key to a common underlying pathway in the production of oxidative stress. There is increasing evidence to suggest that oxidative stress predisposed cells to undergo damage to DNA, protein and lipid, and as such a common factor involved in the pathogenesis of AD and PD. The challenge then is to minimize elevated and uncontrolled oxidative stress levels while not affecting basal iron metabolism, as iron plays vital roles in sustaining cellular function. However, overload of iron results in increased oxidative stress due to the Fenton reaction. We discuss evidence to suggest that sustained exercise and diet restriction may be ways to slow the rate of neurodegeneration, by perhaps promoting neurogenesis or antioxidant-related pathways. It is also our intention to cover NDD in a broad sense, in the context of basic and clinical sciences to cater for both clinician’s and the scientist’s needs, and to highlight current research investigating exercise as a therapeutic or preventive measure.

  9. Neurodegenerative Diseases: Exercising Toward Neurogenesis and Neuroregeneration

    Science.gov (United States)

    Ang, Eng-Tat; Tai, Yee-Kit; Lo, Shun-Qiang; Seet, Raymond; Soong, Tuck-Wah

    2010-01-01

    Currently, there is still no effective therapy for neurodegenerative diseases (NDD) such as Alzheimer's disease (AD) and Parkinson's disease (PD) despite intensive research and on-going clinical trials. Collectively, these diseases account for the bulk of health care burden associated with age-related neurodegenerative disorders. There is therefore an urgent need to further research into the molecular pathogenesis, histological differentiation, and clinical management of NDD. Importantly, there is also an urgency to understand the similarities and differences between these two diseases so as to identify the common or different upstream and downstream signaling pathways. In this review, the role iron play in NDD will be highlighted, as iron is key to a common underlying pathway in the production of oxidative stress. There is increasing evidence to suggest that oxidative stress predisposed cells to undergo damage to DNA, protein and lipid, and as such a common factor involved in the pathogenesis of AD and PD. The challenge then is to minimize elevated and uncontrolled oxidative stress levels while not affecting basal iron metabolism, as iron plays vital roles in sustaining cellular function. However, overload of iron results in increased oxidative stress due to the Fenton reaction. We discuss evidence to suggest that sustained exercise and diet restriction may be ways to slow the rate of neurodegeneration, by perhaps promoting neurogenesis or antioxidant-related pathways. It is also our intention to cover NDD in a broad sense, in the context of basic and clinical sciences to cater for both clinician's and the scientist's needs, and to highlight current research investigating exercise as a therapeutic or preventive measure. PMID:20725635

  10. A mouse model suggests two mechanisms for thyroid alterations in infantile cystinosis: decreased thyroglobulin synthesis due to endoplasmic reticulum stress/unfolded protein response and impaired lysosomal processing.

    Science.gov (United States)

    Gaide Chevronnay, H P; Janssens, V; Van Der Smissen, P; Liao, X H; Abid, Y; Nevo, N; Antignac, C; Refetoff, S; Cherqui, S; Pierreux, C E; Courtoy, P J

    2015-06-01

    Thyroid hormones are released from thyroglobulin (Tg) in lysosomes, which are impaired in infantile/nephropathic cystinosis. Cystinosis is a lysosomal cystine storage disease due to defective cystine exporter, cystinosin. Cystinotic children develop subclinical and then overt hypothyroidism. Why hypothyroidism is the most frequent and earliest endocrine complication of cystinosis is unknown. We here defined early alterations in Ctns(-/-) mice thyroid and identified subcellular and molecular mechanisms. At 9 months, T4 and T3 plasma levels were normal and TSH was moderately increased (∼4-fold). By histology, hyperplasia and hypertrophy of most follicles preceded colloid exhaustion. Increased immunolabeling for thyrocyte proliferation and apoptotic shedding indicated accelerated cell turnover. Electron microscopy revealed endoplasmic reticulum (ER) dilation, apical lamellipodia indicating macropinocytic colloid uptake, and lysosomal cystine crystals. Tg accumulation in dilated ER contrasted with mRNA down-regulation. Increased expression of ER chaperones, glucose-regulated protein of 78 kDa and protein disulfide isomerase, associated with alternative X-box binding protein-1 splicing, revealed unfolded protein response (UPR) activation by ER stress. Decreased Tg mRNA and ER stress suggested reduced Tg synthesis. Coordinated increase of UPR markers, activating transcription factor-4 and C/EBP homologous protein, linked ER stress to apoptosis. Hormonogenic cathepsins were not altered, but lysosome-associated membrane protein-1 immunolabeling disclosed enlarged vesicles containing iodo-Tg and impaired lysosomal fusion. Isopycnic fractionation showed iodo-Tg accumulation in denser lysosomes, suggesting defective lysosomal processing and hormone release. In conclusion, Ctns(-/-) mice showed the following alterations: 1) compensated primary hypothyroidism and accelerated thyrocyte turnover; 2) impaired Tg production linked to ER stress/UPR response; and 3) altered

  11. Obstructive sleep apnea and neurodegenerative diseases: A bidirectional relation

    OpenAIRE

    Christianne Martins Corrêa da Silva Bahia; João Santos Pereira

    2015-01-01

    Sleep disorders are common during the clinical course of the main neurodegenerative diseases. Among these disorders, obstructive sleep apnea has been extensively studied in the last decade and recent knowledge regarding its relationship with the neurodegenerative process points a bidirectional relationship. Neurodegenerative diseases can lead to functional changes in the respiratory system that facilitate the emergence of apnea. On the other hand, obstructive sleep apnea itself can lead to ac...

  12. Effects of Ashwagandha (roots of Withania somnifera) on neurodegenerative diseases.

    Science.gov (United States)

    Kuboyama, Tomoharu; Tohda, Chihiro; Komatsu, Katsuko

    2014-01-01

    Neurodegenerative diseases commonly induce irreversible destruction of central nervous system (CNS) neuronal networks, resulting in permanent functional impairments. Effective medications against neurodegenerative diseases are currently lacking. Ashwagandha (roots of Withania somnifera Dunal) is used in traditional Indian medicine (Ayurveda) for general debility, consumption, nervous exhaustion, insomnia, and loss of memory. In this review, we summarize various effects and mechanisms of Ashwagandha extracts and related compounds on in vitro and in vivo models of neurodegenerative diseases such as Alzheimer's disease and spinal cord injury.

  13. Obstructive sleep apnea and neurodegenerative diseases: A bidirectional relation

    Directory of Open Access Journals (Sweden)

    Christianne Martins Corrêa da Silva Bahia

    Full Text Available Sleep disorders are common during the clinical course of the main neurodegenerative diseases. Among these disorders, obstructive sleep apnea has been extensively studied in the last decade and recent knowledge regarding its relationship with the neurodegenerative process points a bidirectional relationship. Neurodegenerative diseases can lead to functional changes in the respiratory system that facilitate the emergence of apnea. On the other hand, obstructive sleep apnea itself can lead to acceleration of neuronal death due to intermittent hypoxia. Considering that obstructive sleep apnea is a potentially treatable condition, its early identification and intervention could have a positive impact on the management of patients with neurodegenerative diseases.

  14. Three-layer poly(methyl methacrylate) microsystem for analysis of lysosomal enzymes for diagnostic purposes

    Energy Technology Data Exchange (ETDEWEB)

    Kwapiszewski, Radoslaw, E-mail: r.kwapiszewski@gmail.com [Department of Microbioanalytics, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw (Poland); Kwapiszewska, Karina [Department of Microbioanalytics, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw (Poland); Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw (Poland); Kutter, Jörg P. [Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen (Denmark); Brzozka, Zbigniew [Department of Microbioanalytics, Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw (Poland)

    2015-01-01

    Highlights: • New approach for measuring the activity of lysosomal enzymes. • Determination of a protonated form of 4-MU directly in the enzymatic mixture. • Elimination of a long incubation step. • Significant reduction of the processing time and simplification of the procedure. - Abstract: Lysosomal storage diseases are chronic, progressive and typically have a devastating impact on the patient and the family. The diagnosis of these diseases is still a challenge, however, even for trained specialists. Accurate diagnostic methods and high-throughput tools that could be readily incorporated into existing screening laboratories are urgently required. We propose a new method for measuring the activity of lysosomal enzymes using a microfluidic device. The principle of the method is the fluorometric determination of a protonated form of 4-methylumbelliferone directly in the enzymatic mixture. Compared to the standard diagnostic protocols, the method eliminates the necessity to add alkaline buffer to stop the enzymatic reaction, and thus, the number of analytical steps is reduced. The system allows for on-chip short-term incubation of the enzymatic reagents, leading to a much simplified analytical procedure and a significantly shortened processing time. We measured the activity of β-galactosidase in RPMI-1788 human B lymphocytes and in isolated leukocytes from healthy adults. The method shows a good agreement with the standard diagnostic method. The agreement was confirmed by statistical analysis including construction of a Bland–Altman plot. The approach presented can be an alternative for the currently used diagnostic procedures. The method developed has a potential for the implementation into complex microfluidic devices thus becoming a powerful tool for a high-throughput and multiplex screening of newborns.

  15. Structure of a human lysosomal sulfatase.

    Science.gov (United States)

    Bond, C S; Clements, P R; Ashby, S J; Collyer, C A; Harrop, S J; Hopwood, J J; Guss, J M

    1997-02-15

    . Sulfatases catalyze the hydrolysis of sulfuric acid esters from a wide variety of substrates including glycosaminoglycans, glycolipids and steroids. There is sufficient common sequence similarity within the class of sulfatase enzymes to indicate that they have a common structure. Deficiencies of specific lysosomal sulfatases that are involved in the degradation of glycosamino-glycans lead to rare inherited clinical disorders termed mucopolysaccharidoses. In sufferers of multiple sulfatase deficiency, all sulfatases are inactive because an essential post-translational modification of a specific active-site cysteine residue to oxo-alanine does not occur. Studies of this disorder have contributed to location and characterization of the sulfatase active site. To understand the catalytic mechanism of sulfatases, and ultimately the determinants of their substrate specificities, we have determined the structure of N-acetylgalactosamine-4-sulfatase. . The crystal structure of the enzyme has been solved and refined at 2.5 resolution using data recorded at both 123K and 273K. The structure has two domains, the larger of which belongs to the alpha/beta class of proteins and contains the active site. The enzyme active site in the crystals contains several hitherto undescribed features. The active-site cysteine residue, Cys91, is found as the sulfate derivative of the aldehyde species, oxo-alanine. The sulfate is bound to a previously undetected metal ion, which we have identified as calcium. The structure of a vanadate-inhibited form of the enzyme has also been solved, and this structure shows that vanadate has replaced sulfate in the active site and that the vanadate is covalently linked to the protein. Preliminary data is presented for crystals soaked in the monosaccharide N-acetylgalactosamine, the structure of which forms a product complex of the enzyme. . The structure of N-acetylgalactosamine-4-sulfatase reveals that residues conserved amongst the sulfatase family are

  16. The Role of Copper in Neurodegenerative Disease

    Science.gov (United States)

    Rose, Francis M.

    My research concerns the fundamental atomistic mechanisms of neurodegenerative diseases and the methodologies by which they may be discerned. This thesis consists of three primary parts. The introductory material is the raison d'etre for this work and a critical overview of the specific physics, mathematics and algorithms used in this research. The methods are presented along with specific details in order to facilitate future replication and enhancement. With the groundwork of mechanisms and methods out of the way, we then explore a nouveau atomistic mechanism describing the onset of Parkinson's disease, a disease that has been closely linked to misfolded metalloproteins. Further exploration of neurodegeneration takes place in the following chapter, where a remedial approach to Alzheimer's disease via a simulated chelation of a metalloprotein is undertaken. Altogether, the methods and techniques applied here allow for simulated exploration of both the atomistic mechanisms of neurodegeneration and their potential remediation strategies. The beginning portion of the research efforts explore protein misfolding dynamics in the presence a copper ion. Misfolding of the human alpha-synuclein (aS) protein has been implicated as a central constituent in neurodegenerative disease. In Parkinson's disease (PD) in particular, aS is thought to be the causative participant when found concentrated into neuritic plaques. Here we propose a scenario involving the metal ion Cu2+ as the protein misfolding initiator of fibrillized aS, the chief component of neuritic plaques. From experimental results we know these misfolded proteins have a rich beta--sheet signature, a marker that we reproduce with our simulated model. This model identifies a process of structural modifications to a natively unfolded alpha-synuclein resulting in a partially folded intermediate with a well defined nucleation site. It serves as a precursor to the fully misfolded protein. Understanding the nucleation

  17. Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation.

    Science.gov (United States)

    Rong, Yueguang; McPhee, Christina K; McPhee, Christina; Deng, Shuangshen; Huang, Lei; Chen, Lilian; Liu, Mei; Tracy, Kirsten; Baehrecke, Eric H; Baehreck, Eric H; Yu, Li; Lenardo, Michael J

    2011-05-10

    Autophagy is a conserved cellular process to degrade and recycle cytoplasmic components. During autophagy, lysosomes fuse with an autophagosome to form an autolysosome. Sequestered components are degraded by lysosomal hydrolases and presumably released into the cytosol by lysosomal efflux permeases. Following starvation-induced autophagy, lysosome homeostasis is restored by autophagic lysosome reformation (ALR) requiring activation of the "target of rapamycin" (TOR) kinase. Spinster (Spin) encodes a putative lysosomal efflux permease with the hallmarks of a sugar transporter. Drosophila spin mutants accumulate lysosomal carbohydrates and enlarged lysosomes. Here we show that defects in spin lead to the accumulation of enlarged autolysosomes. We find that spin is essential for mTOR reactivation and lysosome reformation following prolonged starvation. Further, we demonstrate that the sugar transporter activity of Spin is essential for ALR.

  18. Comparative Incidence of Conformational, Neurodegenerative Disorders.

    Directory of Open Access Journals (Sweden)

    Jesús de Pedro-Cuesta

    Full Text Available The purpose of this study was to identify incidence and survival patterns in conformational neurodegenerative disorders (CNDDs.We identified 2563 reports on the incidence of eight conditions representing sporadic, acquired and genetic, protein-associated, i.e., conformational, NDD groups and age-related macular degeneration (AMD. We selected 245 papers for full-text examination and application of quality criteria. Additionally, data-collection was completed with detailed information from British, Swedish, and Spanish registries on Creutzfeldt-Jakob disease (CJD forms, amyotrophic lateral sclerosis (ALS, and sporadic rapidly progressing neurodegenerative dementia (sRPNDd. For each condition, age-specific incidence curves, age-adjusted figures, and reported or calculated median survival were plotted and examined.Based on 51 valid reported and seven new incidence data sets, nine out of eleven conditions shared specific features. Age-adjusted incidence per million person-years increased from ≤1.5 for sRPNDd, different CJD forms and Huntington's disease (HD, to 1589 and 2589 for AMD and Alzheimer's disease (AD respectively. Age-specific profiles varied from (a symmetrical, inverted V-shaped curves for low incidences to (b those increasing with age for late-life sporadic CNDDs and for sRPNDd, with (c a suggested, intermediate, non-symmetrical inverted V-shape for fronto-temporal dementia and Parkinson's disease. Frequently, peak age-specific incidences from 20-24 to ≥90 years increased with age at onset and survival. Distinct patterns were seen: for HD, with a low incidence, levelling off at middle age, and long median survival, 20 years; and for sRPNDd which displayed the lowest incidence, increasing with age, and a short median disease duration.These results call for a unified population view of NDDs, with an age-at-onset-related pattern for acquired and sporadic CNDDs. The pattern linking age at onset to incidence magnitude and survival might

  19. α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models.

    Science.gov (United States)

    Mazzulli, Joseph R; Zunke, Friederike; Isacson, Ole; Studer, Lorenz; Krainc, Dimitri

    2016-02-16

    Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of α-synuclein (α-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with α-syn remains unclear. Here, we find that α-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of α-syn at the cell body resulted in aberrant association with cis-Golgi-tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological α-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders.

  20. Involvement of oxidative stress and impaired lysosomal degradation in amiodarone-induced schwannopathy.

    Science.gov (United States)

    Niimi, Naoko; Yako, Hideji; Tsukamoto, Masami; Takaku, Shizuka; Yamauchi, Junji; Kawakami, Emiko; Yanagisawa, Hiroko; Watabe, Kazuhiko; Utsunomiya, Kazunori; Sango, Kazunori

    2016-07-01

    Amiodarone hydrochloride (AMD), an anti-arrhythmic agent, has been shown to cause peripheral neuropathy; however, its pathogenesis remains unknown. We examined the toxic effects of AMD on an immortalized adult rat Schwann cell line, IFRS1, and cocultures of IFRS1 cells and adult rat dorsal root ganglion neurons or nerve growth factor-primed PC12 cells. Treatment with AMD (1, 5, and 10 μm) induced time- and dose-dependent cell death, accumulation of phospholipids and neutral lipids, upregulation of the expression of gangliosides, and oxidative stress (increased nuclear factor E2-related factor in nuclear extracts and reduced GSH/GSSG ratios) in IFRS1 cells. It also induced the upregulation of LC3-II and p62 expression, with phosphorylation of p62, suggesting that deficient autolysosomal degradation is involved in AMD-induced IFRS1 cell death. Furthermore, treatment of the cocultures with AMD induced detachment of IFRS1 cells from neurite networks in a time- and dose-dependent manner. These findings suggest that AMD-induced lysosomal storage accompanied by enhanced oxidative stress and impaired lysosomal degradation in Schwann cells might be a cause of demyelination in the peripheral nervous system. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  1. Quantitative Interaction Proteomics of Neurodegenerative Disease Proteins

    Directory of Open Access Journals (Sweden)

    Fabian Hosp

    2015-05-01

    Full Text Available Several proteins have been linked to neurodegenerative disorders (NDDs, but their molecular function is not completely understood. Here, we used quantitative interaction proteomics to identify binding partners of Amyloid beta precursor protein (APP and Presenilin-1 (PSEN1 for Alzheimer’s disease (AD, Huntingtin (HTT for Huntington’s disease, Parkin (PARK2 for Parkinson’s disease, and Ataxin-1 (ATXN1 for spinocerebellar ataxia type 1. Our network reveals common signatures of protein degradation and misfolding and recapitulates known biology. Toxicity modifier screens and comparison to genome-wide association studies show that interaction partners are significantly linked to disease phenotypes in vivo. Direct comparison of wild-type proteins and disease-associated variants identified binders involved in pathogenesis, highlighting the value of differential interactome mapping. Finally, we show that the mitochondrial protein LRPPRC interacts preferentially with an early-onset AD variant of APP. This interaction appears to induce mitochondrial dysfunction, which is an early phenotype of AD.

  2. Health benefits of methylxanthines in neurodegenerative diseases.

    Science.gov (United States)

    Oñatibia-Astibia, Ainhoa; Franco, Rafael; Martínez-Pinilla, Eva

    2017-06-01

    Methylxanthines (MTXs) are consumed by almost everybody in almost every area of the world. Caffeine, theophylline and theobromine are the most well-known members of this family of compounds; they are present, inter alia, in coffee, tea, cacao, yerba mate and cola drinks. MTXs are readily absorbed in the gastrointestinal tract and are able to penetrate into the central nervous system, where they exert significant psychostimulant actions, which are more evident in acute intake. Coffee has been paradigmatic, as its use was forbidden in many diseases, however, this negative view has radically changed; evidence shows that MTXs display health benefits in diseases involving cell death in the nervous system. This paper reviews data that appraise the preventive and even therapeutic potential of MTXs in a variety of neurodegenerative diseases. Future perspectives include the use of MTXs to advance the understanding the pathophysiology of, inter alia, Alzheimer's disease (AD) and Parkinson's disease (PD), and the use of the methylxanthine chemical moiety as a basis for the development of new and more efficacious drugs. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Unconventional Trafficking of Mammalian Phospholipase D3 to Lysosomes

    Directory of Open Access Journals (Sweden)

    Adriana Carolina Gonzalez

    2018-01-01

    Full Text Available Variants in the phospholipase D3 (PLD3 gene have genetically been linked to late-onset Alzheimer's disease. We present a detailed biochemical analysis of PLD3 and reveal its endogenous localization in endosomes and lysosomes. PLD3 reaches lysosomes as a type II transmembrane protein via a (for mammalian cells uncommon intracellular biosynthetic route that depends on the ESCRT (endosomal sorting complex required for transport machinery. PLD3 is sorted into intraluminal vesicles of multivesicular endosomes, and ESCRT-dependent sorting correlates with ubiquitination. In multivesicular endosomes, PLD3 is subjected to proteolytic cleavage, yielding a stable glycosylated luminal polypeptide and a rapidly degraded N-terminal membrane-bound fragment. This pathway closely resembles the delivery route of carboxypeptidase S to the yeast vacuole. Our experiments reveal a biosynthetic route of PLD3 involving proteolytic processing and ESCRT-dependent sorting for its delivery to lysosomes in mammalian cells.

  4. Salinomycin kills cancer stem cells by sequestering iron in lysosomes

    Science.gov (United States)

    Mai, Trang Thi; Hamaï, Ahmed; Hienzsch, Antje; Cañeque, Tatiana; Müller, Sebastian; Wicinski, Julien; Cabaud, Olivier; Leroy, Christine; David, Amandine; Acevedo, Verónica; Ryo, Akihide; Ginestier, Christophe; Birnbaum, Daniel; Charafe-Jauffret, Emmanuelle; Codogno, Patrice; Mehrpour, Maryam; Rodriguez, Raphaël

    2017-10-01

    Cancer stem cells (CSCs) represent a subset of cells within tumours that exhibit self-renewal properties and the capacity to seed tumours. CSCs are typically refractory to conventional treatments and have been associated to metastasis and relapse. Salinomycin operates as a selective agent against CSCs through mechanisms that remain elusive. Here, we provide evidence that a synthetic derivative of salinomycin, which we named ironomycin (AM5), exhibits a more potent and selective activity against breast CSCs in vitro and in vivo, by accumulating and sequestering iron in lysosomes. In response to the ensuing cytoplasmic depletion of iron, cells triggered the degradation of ferritin in lysosomes, leading to further iron loading in this organelle. Iron-mediated production of reactive oxygen species promoted lysosomal membrane permeabilization, activating a cell death pathway consistent with ferroptosis. These findings reveal the prevalence of iron homeostasis in breast CSCs, pointing towards iron and iron-mediated processes as potential targets against these cells.

  5. Lysosomal Regulation of mTORC1 by Amino Acids in Mammalian Cells.

    Science.gov (United States)

    Yao, Yao; Jones, Edith; Inoki, Ken

    2017-07-07

    The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth in eukaryotic cells. The active mTORC1 promotes cellular anabolic processes including protein, pyrimidine, and lipid biosynthesis, and inhibits catabolic processes such as autophagy. Consistent with its growth-promoting functions, hyper-activation of mTORC1 signaling is one of the important pathomechanisms underlying major human health problems including diabetes, neurodegenerative disorders, and cancer. The mTORC1 receives multiple upstream signals such as an abundance of amino acids and growth factors, thus it regulates a wide range of downstream events relevant to cell growth and proliferation control. The regulation of mTORC1 by amino acids is a fast-evolving field with its detailed mechanisms currently being revealed as the precise picture emerges. In this review, we summarize recent progress with respect to biochemical and biological findings in the regulation of mTORC1 signaling on the lysosomal membrane by amino acids.

  6. Analyzing Lysosome-Related Organelles by Electron Microscopy

    KAUST Repository

    Hurbain, Ilse

    2017-04-29

    Intracellular organelles have a particular morphological signature that can only be appreciated by ultrastructural analysis at the electron microscopy level. Optical imaging and associated methodologies allow to explore organelle localization and their dynamics at the cellular level. Deciphering the biogenesis and functions of lysosomes and lysosome-related organelles (LROs) and their dysfunctions requires their visualization and detailed characterization at high resolution by electron microscopy. Here, we provide detailed protocols for studying LROs by transmission electron microscopy. While conventional electron microscopy and its recent improvements is the method of choice to investigate organelle morphology, immunoelectron microscopy allows to localize organelle components and description of their molecular make up qualitatively and quantitatively.

  7. Biogenesis of the lysosome-derived vacuole containing Coxiella burnetii.

    Science.gov (United States)

    Kohler, Lara J; Roy, Craig R

    2015-01-01

    Coxiella burnetii utilizes a Type IV Secretion System (T4SS) to modify host endomembrane transport systems to form a unique lysosome-derived niche called the Coxiella-containing vacuole (CCV). Although the CCV has lysosomal properties, this organelle displays distinct characteristics such as homotypic fusion and a cholesterol enriched limiting membrane, in addition to robustly interacting with autophagosomes. This review describes recent advances in understanding CCV biogenesis and the mechanisms C. burnetii employs to maintain this unique compartment. Copyright © 2015 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

  8. Epigenetics and etiology of neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Beata M. Gruber

    2011-08-01

    Full Text Available Determination of specific gene profile expression is essential for morphological and functional differentiation of cells in the human organism. The human genome consists of 25–30 thousands genes but only some of them are expressed in each cell. Epigenetic modifications such as DNA methylation, histone and chromatin modifications or non-coding RNA functions are also responsible for the unique gene expression patterns. It is suggested that transcriptional gene activation is related to hypomethylation and the transcriptionally non-active sequences are hypermethylated. Covalent histone modifications and DNA methylation are correlated and interacting. Chromatin modeling is regulated not only by specific enzymes but also by protein kinases or phosphatases and coactivators, such as CBP. Such interaction makes the “histone code” which with the chromatin proteins determines gene expression patterns as the response to external agents. Evidence of a major role for epigenetic modifications in neurological disease has come from three converging lines of enquiry: high conservation throughout evolution of the histone residues that are the target for epigenetic modifications; association between mutations in epigenetic components and multisystem disease syndrome in the nervous system; and broad efficacy of small-molecule epigenetic modulators, e.g. histone deacetylase inhibitors, in models of neurological diseases incurable up to now, such as Huntington’s disease, (HD, Parkinson’s disease (PD and Alzheimer’s disease (AD. This article is a survey of the literature concerning the characterization of gene expression patterns correlated with some neurodegenerative diseases. The processes of DNA hypomethylation and histone acetylation are emphasized. The histone deacetylases are indicated as the basis for design of potential drugs.

  9. Cholestane-3β,5α,6β-triol: high levels in Niemann-Pick type C, cerebrotendinous xanthomatosis, and lysosomal acid lipase deficiency[S

    Science.gov (United States)

    Pajares, Sonia; Arias, Angela; García-Villoria, Judit; Macías-Vidal, Judit; Ros, Emilio; de las Heras, Javier; Girós, Marisa; Coll, Maria J.; Ribes, Antonia

    2015-01-01

    Niemann-Pick type C (NPC) is a progressive neurodegenerative disease characterized by lysosomal/endosomal accumulation of unesterified cholesterol and glycolipids. Recent studies have shown that plasma cholestane-3β,5α,6β-triol (CT) and 7-ketocholesterol (7-KC) could be potential biomarkers for the diagnosis of NPC patients. We aimed to know the sensitivity and specificity of these biomarkers for the diagnosis of NPC compared with other diseases that can potentially lead to oxysterol alterations. We studied 107 controls and 122 patients including 16 with NPC, 3 with lysosomal acid lipase (LAL) deficiency, 8 with other lysosomal diseases, 5 with galactosemia, 11 with cerebrotendinous xanthomatosis (CTX), 3 with Smith-Lemli-Opitz, 14 with peroxisomal biogenesis disorders, 19 with unspecific hepatic diseases, 13 with familial hypercholesterolemia, and 30 with neurological involvement and no evidence of an inherited metabolic disease. CT and 7-KC were analyzed by HPLC-ESI-MS/MS as mono-dimethylglycine derivatives. Levels of 7-KC were high in most of the studied diseases, whereas those of CT were only high in NPC, LAL, and CTX patients. Consequently, although CT is a sensitive biomarker of NPC disease, including those cases with doubtful filipin staining, it is not specific. 7-KC is a very unspecific biomarker. PMID:26239048

  10. Energy Storage.

    Science.gov (United States)

    Eaton, William W.

    Described are technological considerations affecting storage of energy, particularly electrical energy. The background and present status of energy storage by batteries, water storage, compressed air storage, flywheels, magnetic storage, hydrogen storage, and thermal storage are discussed followed by a review of development trends. Included are…

  11. Renin-angiotensin system gene expression and neurodegenerative diseases.

    Science.gov (United States)

    Goldstein, Benjamin; Speth, Robert C; Trivedi, Malav

    2016-07-01

    Single nucleotide polymorphisms and altered gene expression of components of the renin-angiotensin system (RAS) are associated with neurodegenerative diseases. Drugs that interact with the RAS have been shown to affect the course of neurodegenerative disease, suggesting that abnormalities in the RAS may contribute to neurodegenerative disease. A meta-analysis of genome-wide association studies and gene expression data for 14 RAS-related proteins was carried out for five neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, narcolepsy, amyotrophic lateral sclerosis and multiple sclerosis. No single nucleotide polymorphisms in any of the 14 RAS-related protein genes were significantly associated with the five neurodegenerative diseases investigated. There was an inverse association between expression of ATP6AP2, which encodes the (pro)renin receptor, and multiple sclerosis, Alzheimer's disease and Parkinson's disease. An association of AGTR, which encodes the AT1 angiotensin II receptor, and Parkinson's disease and Alzheimer's disease was also observed. To date, no single nucleotide polymorphisms in components of the RAS can be definitively linked to the neurodegenerative diseases evaluated in this study. However, altered gene expression of several components of the RAS is associated with several neurodegenerative diseases, which may indicate that the RAS contributes to the pathology of these diseases. © The Author(s) 2016.

  12. Circadian clock disruption in neurodegenerative diseases: Cause and effect?

    Directory of Open Access Journals (Sweden)

    Erik Steven Musiek

    2015-02-01

    Full Text Available Disturbance of the circadian system, manifested as disrupted daily rhythms of physiologic parameters such as sleep, activity, and hormone secretion, has long been observed as a symptom of several neurodegenerative diseases, including Alzheimer Disease. Circadian abnormalities have generally been considered consequences of the neurodegeneration. Recent evidence suggests, however, that circadian disruption might actually contribute to the neurodegenerative process, and thus might be a modifiable cause of neural injury. Herein we will review the evidence implicating circadian rhythms disturbances and clock gene dysfunction in neurodegeneration, with an emphasis on future research directions and potential therapeutic implications for neurodegenerative diseases.

  13. TAK1 regulates resident macrophages by protecting lysosomal integrity.

    Science.gov (United States)

    Sakamachi, Yosuke; Morioka, Sho; Mihaly, September R; Takaesu, Giichi; Foley, Julie F; Fessler, Michael B; Ninomiya-Tsuji, Jun

    2017-02-09

    Hematopoietic cell survival and death is critical for development of a functional immune system. Here, we report that a protein kinase, TAK1, is selectively required for resident macrophage integrity during embryogenesis. Hematopoietic lineage-specific deletion of Tak1 gene (Tak1HKO) caused accumulation of cellular debris in the thymus in perinatal mice. Although no overt alteration in thymocytes and blood myeloid populations was observed in Tak1HKO mice, we found that thymic and lung macrophages were diminished. In the in vitro setting, Tak1 deficiency caused profound disruption of lysosomes and killed bone marrow-derived macrophages (BMDMs) without any exogenous stressors. Inhibition of the lysosomal protease, cathepsin B, partially blocked Tak1-deficient BMDM death, suggesting that leakage of the lysosomal contents is in part the cause of cell death. To identify the trigger of this cell death, we examined involvement of TNF and Toll-like receptor pathways. Among them, we found that deletion of Tnfr1 partially rescued cell death. Finally, we show that Tnfr1 deletion partially restored thymic and lung macrophages in vivo. These results suggest that autocrine and potentially paracrine TNF kills Tak1-deficient macrophages during development. Our results reveal that TAK1 signaling maintains proper macrophage populations through protecting lysosomal integrity.

  14. Degradation of nicastrin involves both proteasome and lysosome.

    Science.gov (United States)

    He, Guiqiong; Qing, Hong; Tong, Yigang; Cai, Fang; Ishiura, Shoichi; Song, Weihong

    2007-05-01

    The glycoprotein nicastrin (NCT) is an essential component of the gamma-secretase complex, a high molecular weight complex which also contains the presenilin proteins, Aph-1 and Pen-2. The gamma-secretase complex is not only involved in APP processing but also in the processing of an increasing number of other type I integral membrane proteins. As the largest subunit of the gamma-secretase complex, NCT plays a crucial role in its activation. Considerable information exists on the distribution, structure and function of NCT; however, little is known of its proteolysis. The present study is aimed at exploring the molecular mechanism of NCT degradation. We found that either proteasomal or lysosomal inhibition can significantly increase the levels of both endogenous and exogenous NCT in various cell lines, and the effect of these inhibitions on NCT was time- and dose-dependent. Immunofluorescent microscopic analysis revealed that NCT accumulates in the ER and Golgi apparatus after proteasomal inhibition, while lysosomal inhibition leads to the accumulation of NCT in the lysosomal apparatus. Co-immunoprecipitation can pull down both NCT and ubiquitin. Taken together, our results demonstrate that NCT degradation involves both the proteasome and the lysosome.

  15. Structure of human saposin A at lysosomal pH

    Energy Technology Data Exchange (ETDEWEB)

    Hill, Chris H.; Read, Randy J.; Deane, Janet E., E-mail: jed55@cam.ac.uk [University of Cambridge, Wellcome Trust/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY (United Kingdom)

    2015-06-27

    A 1.8 Å resolution structure of the sphingolipid activator protein saposin A has been determined at pH 4.8, the physiologically relevant lysosomal pH for hydrolase enzyme activation and lipid-transfer activity. The saposins are essential cofactors for the normal lysosomal degradation of complex glycosphingolipids by acid hydrolase enzymes; defects in either saposin or hydrolase function lead to severe metabolic diseases. Saposin A (SapA) activates the enzyme β-galactocerebrosidase (GALC), which catalyzes the breakdown of β-d-galactocerebroside, the principal lipid component of myelin. SapA is known to bind lipids and detergents in a pH-dependent manner; this is accompanied by a striking transition from a ‘closed’ to an ‘open’ conformation. However, previous structures were determined at non-lysosomal pH. This work describes a 1.8 Å resolution X-ray crystal structure determined at the physiologically relevant lysosomal pH 4.8. In the absence of lipid or detergent at pH 4.8, SapA is observeed to adopt a conformation closely resembling the previously determined ‘closed’ conformation, showing that pH alone is not sufficient for the transition to the ‘open’ conformation. Structural alignments reveal small conformational changes, highlighting regions of flexibility.

  16. Assessments of lysosomal membrane responses to stresses with ...

    African Journals Online (AJOL)

    In marine bivalves, it has been demonstrated that their lysosomal membrane stability are very susceptible to many internal and external environmental changes and this physiological response can be quantified by the neutral red retention (NRR) assay. This assay has been applied in many recent studies in the areas of ...

  17. Lysosomal chymotrypsin B potentiates apoptosis via cleavage of Bid.

    Science.gov (United States)

    Zhao, Kai; Zhao, Xingyu; Tu, Yaping; Miao, Qi; Cao, Dongxu; Duan, Wenjuan; Sun, Yang; Wang, Jincheng; Wei, Taotao; Yang, Fuyu

    2010-08-01

    We have reported that chymotrypsin B (CtrB) is not just a digestive enzyme but is also stored in lysosomes. Herein, we demonstrated a broad distribution of CtrB and explored the involvement of CtrB in apoptosis. Exposure of RH-35 cells to H(2)O(2) or palmitate induced the redistribution of lysosomal CtrB into the cytoplasm as a result of lysosomal membrane permeabilization (LMP). Suppression of CtrB significantly blocked apoptosis, while overexpression of CtrB sensitized apoptosis markedly. CtrB could cleave Bid under neutral conditions. In RH-35 cells with Bid silenced, apoptosis induced by CtrB protein was attenuated, suggesting that CtrB mediates apoptosis of RH-35 cells mainly through processing Bid. Our data also suggest that LMP occurs earlier than mitochondrial outer membrane permeabilization; Bid activation initiated by caspase-8 might be reinforced by CtrB in consequence of LMP, which causes a positive feedback loop leading to the accumulation of tBid, and results in lysosome- and mitochondrion-dependent apoptosis.

  18. Acridine orange-mediated photodamage of microsomal- and lysosomal fractions.

    Science.gov (United States)

    Olsson, G M; Brunmark, A; Brunk, U T

    1989-01-01

    Irradiation of microsomes with visible light in the presence of externally-added acridine orange results in O2 uptake, malondialdehyde accumulation, and inactivation of the microsomal drug-metabolizing system. The latter effect is reflected by a decrease in NADPH-cytochrome P450- and NADH-cytochrome b5 reductase activities and cytochromes P450 and b5 content by 88-, 85-, 60-, and 34%, respectively, after 5-min irradiation. Anoxia prevented inactivation of both reductases by 70-90%, whereas it prevented completely cytochrome b5 destruction. The presence of reducing equivalents, at the expense of NADPH and NADH, exert a partial protection (40-54% residual activities) against photosensitization damage on both reductase activities, whereas it almost fully protected cytochrome b5. Photosensitization of lipid peroxidation, as well as inactivation of the microsomal drug-metabolizing system, appears to involve both a type I and type II process. Products of lipid peroxidation might also play a role in enzyme inactivation and cytochrome destruction, as suggested by kinetic and time course studies and the redox state of microsomes. The uptake of acridine orange by isolated lysosomes is linearly dependent on the concentration of added dye and the distribution between extra- and intralysosomal acridine orange is strongly dependent on the amount of lysosomes. Irradiation of acridine orange-loaded lysosomes (light intensity at the sample position approximately 320 mW/cm2) produces an impairment of the membrane which leads to a rapid release of enzyme (N-acetyl-beta-glucosaminidase activity) into the medium, accompanied by a loss of activity in the lysosome-containing pellet and a partial photodamage of the enzyme. Concomitantly, thiobarbituric acid-reactive material accumulation increases in the reaction mixture with increasing irradiation time. When light intensity at the position was reduced to approximately 3.6 mW/cm2, photodamage of lysosomes was of a lesser magnitude

  19. Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis.

    Science.gov (United States)

    Sreetama, S C; Takano, T; Nedergaard, M; Simon, S M; Jaiswal, J K

    2016-04-01

    Astrocytes are known to facilitate repair following brain injury; however, little is known about how injured astrocytes repair themselves. Repair of cell membrane injury requires Ca(2+)-triggered vesicle exocytosis. In astrocytes, lysosomes are the main Ca(2+)-regulated exocytic vesicles. Here we show that astrocyte cell membrane injury results in a large and rapid calcium increase. This triggers robust lysosome exocytosis where the fusing lysosomes release all luminal contents and merge fully with the plasma membrane. In contrast to this, receptor stimulation produces a small sustained calcium increase, which is associated with partial release of the lysosomal luminal content, and the lysosome membrane does not merge into the plasma membrane. In most cells, lysosomes express the synaptotagmin (Syt) isoform Syt VII; however, this isoform is not present on astrocyte lysosomes and exogenous expression of Syt VII on lysosome inhibits their exocytosis. Deletion of one of the most abundant Syt isoform in astrocyte--Syt XI--suppresses astrocyte lysosome exocytosis. This identifies lysosome as Syt XI-regulated exocytic vesicle in astrocytes. Further, inhibition of lysosome exocytosis (by Syt XI depletion or Syt VII expression) prevents repair of injured astrocytes. These results identify the lysosomes and Syt XI as the sub-cellular and molecular regulators, respectively of astrocyte cell membrane repair.

  20. Indian Herbs for the Treatment of Neurodegenerative Disease.

    Science.gov (United States)

    Mannangatti, Padmanabhan; Naidu, Kamalakkannan Narasimha

    2016-01-01

    Ayurveda, an ancient system of medicine that is indigenous to India, is believed to be the world's oldest comprehensive health-care system and is now one of the most recognized and widely practiced disciplines of alternative medicine in the world. Medicinal herbs have been in use for treating diseases since ancient times in India. Ayurvedic therapies with medicinal herbs and herbomineral products generally provide relief without much adverse effects even after prolonged administration. Neurodegenerative disorders are a major cause of mortality and disability, and increasing life spans represent one of the key challenges of medical research. Ayurvedic medicine describes most neurodegenerative diseases and has defined a number of plants with therapeutic benefits for the treatment of neurodegenerative diseases having antioxidant activities. In this chapter, the role of four important Ayurvedic medicinal plants, viz., Withania somnifera (ashwagandha), Bacopa monnieri (brahmi), Centella asiatica (gotu kola), and Mucuna pruriens (velvet bean), on neurodegenerative diseases are discussed.

  1. Environmental Pollutants as Risk Factors for Neurodegenerative Disorders

    OpenAIRE

    Miguel eChin-Chan; Juliana eNavarro-Yepes; Betzabet eQuintanilla-Vega

    2015-01-01

    Neurodegenerative diseases including Alzheimer (AD) and Parkinson (PD) have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment, from diet to the new nanomaterials as putative risk factors has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metal...

  2. Sialidosis type I carrying V217M/G243R mutations in lysosomal sialidase: an autopsy study demonstrating terminal sialic acid in lysosomal lamellar inclusions and cerebellar dysplasia.

    Science.gov (United States)

    Uchihara, Toshiki; Ohashi, Ken-ichi; Kitagawa, Masanobu; Kurata, Morito; Nakamura, Ayako; Hirokawa, Katsuiku; Kasuga, Tsutomu; Kobayashi, Takayoshi

    2010-01-01

    Autopsy findings of a patient, with sialidosis type I phenotype carrying V217M/G243R mutations in the lysosomal sialidase gene and biochemically defined isolated sialidase deficiency, who died of intractable lymphoma at the age of 32 years, are described. Perikaryal expansion of cytoplasm was evident, mostly in motor neurons (in the anterior horn and the brain stem), dorsal root ganglia, cerebellar dentate neurons and some neurons in the thalamus and nucleus basalis of Meynert. The stored material was lamellar in lysosomes and exhibited a specific affinity to wheat germ agglutinin at light and electron microscopy, which indicates the accumulation of terminal sialic acid at the non-reducing end of the sugar chain in this pathological structure. Neuronal loss in these nuclei, however, was not frequent in spite of frequent and massive cytoplasmic expansion. Neocortex exhibited a mild spongiosis with some swelling of neurons, which contained lipofuscin-like granules and small amount of lamellar structures in lysosomes. This contrast suggests a discrepancy between the storage process and vulnerability of neurons, both variable according to areas examined. In the cerebellar vermis, dysplastic features, such as abnormal layering of Purkinje cells, thinning and rarefaction of the granule cell layer, incomplete formation of synapse and disordered proliferation of Bergmann's glia, were focally accentuated, suggesting some developmental abnormality not secondary to the storage process. This is the first autopsy demonstration of sialic acid in the lamellar materials and of a developmental abnormality in isolated sialidase deficiency. Additional studies are needed to clarify how this molecular abnormality leads to these morphological and clinical manifestations.

  3. Capgras syndrome and its relationship to neurodegenerative disease.

    Science.gov (United States)

    Josephs, Keith A

    2007-12-01

    Capgras syndrome is characterized by a delusional belief that a person has been replaced by an imposter. It has been described in psychiatric and neurological (neurodegenerative and nonneurodegenerative) diseases. To determine whether the clinical and demographic features of subjects with Capgras syndrome differ when the syndrome is associated with neurodegenerative compared with nonneurodegenerative diseases, and whether features differ across different neurodegenerative diseases. Retrospective study. Tertiary care medical center. Patients Forty-seven subjects with Capgras syndrome. Thirty-eight of the subjects with Capgras syndrome (81%) had a neurodegenerative disease, most commonly Lewy body disease. Capgras syndrome occurred at a younger age of onset in those with a nonneurodegenerative disease (51 vs 72 years) (P Capgras syndrome and Lewy body disease, 100% had visual hallucinations compared with only one of those with Alzheimer disease (14%). Capgras syndrome is more commonly associated with neurodegenerative diseases, especially Lewy body disease, where visual hallucinations always coexist. In the absence of a neurodegenerative disease, the onset of Capgras syndrome occurs at a significantly younger age and can be associated with psychiatric disease, cerebrovascular events, and illicit drug use.

  4. Transcranial Direct Current Stimulation in Neurodegenerative Disease

    Directory of Open Access Journals (Sweden)

    Argye E. Hillis

    2014-04-01

    Full Text Available We review rationale, challenges, study designs, reported results, and future directions in the use of transcranial direct cranial stimulation (tDCS in neurodegenerative disease, focusing on treatment of spelling in primary progressive aphasia (PPA. Rationale Evidence from both animal studies and human studies indicates that anodal and cathodal tDCS over the brain result in a temporary change in membrane potentials, reducing the threshold for long-term potentiation of neurons in the affected area. This may allow unaffected brain regions to assume functions of diseased regions. Challenges Special challenges in treating individuals with progressive conditions include altered goals of treatment and the possibility that participants may accumulate new deficits over the course of the treatment program that interfere with their ability to understand, retain, or cooperate with aspects of the program. The most serious challenge – particularly for single case designs - is that there may be no stable baseline against which to measure change with treatment. Thus, it is essential to demonstrate that treatment results in a statistically significant change in the slope of decline or improvement. Therefore, demonstration of a significant difference between tDCS and control (sham requires either a large number of participants or a large effect size. Designs The choice of a treatment design reflects these limitations. Group studies with a randomized, double-blind, sham control trial design (without cross-over provide the greatest power to detect a difference between intervention and control conditions, with the fewest participants. A cross-over design, in which all participants (from 1 to many receive both active and sham conditions, in randomized order, requires a larger effect size for the active condition relative to the control condition (or little to no maintenance of treatment gains or carry-over effect to show significant differences between treatment

  5. A lysosome-locating and acidic pH-activatable fluorescent probe for visualizing endogenous H2O2 in lysosomes.

    Science.gov (United States)

    Liu, Jun; Zhou, Shunqing; Ren, Jing; Wu, Chuanliu; Zhao, Yibing

    2017-11-20

    There is increasing evidence indicating that lysosomal H2O2 is closely related to autophagy and apoptotic pathways under both physiological and pathological conditions. Therefore, fluorescent probes that can be exploited to visualize H2O2 in lysosomes are potential tools for exploring diverse roles of H2O2 in cells. However, functional exploration of lysosomal H2O2 is limited by the lack of fluorescent probes capable of compatibly sensing H2O2 under weak acidic conditions (pH = 4.5) of lysosomes. Lower spatial resolution of the fluorescent visualization of lysosomal H2O2 might be caused by the interference of signals from cytosolic and mitochondrial H2O2, as well as the non-specific distribution of the probes in cells. In this work, we developed a lysosome-locating and acidic-pH-activatable fluorescent probe for the detection and visualization of H2O2 in lysosomes, which consists of a H2O2-responsive boronate unit, a lysosome-locating morpholine group, and a pH-activatable benzorhodol fluorophore. The response of the fluorescent probe to H2O2 is significantly more pronounced under acidic pH conditions than that under neutral pH conditions. Notably, the present probe enables the fluorescence sensing of endogenous lysosomal H2O2 in living cells without external stimulations, with signal interference from the cytoplasm and other intracellular organelles being negligible.

  6. Imaging Lysosomal pH Alteration in Stressed Cells with a Sensitive Ratiometric Fluorescence Sensor.

    Science.gov (United States)

    Xue, Zhongwei; Zhao, Hu; Liu, Jian; Han, Jiahuai; Han, Shoufa

    2017-03-24

    The organelle-specific pH is crucial for cell homeostasis. Aberrant pH of lysosomes has been manifested in myriad diseases. To probe lysosome responses to cell stress, we herein report the detection of lysosomal pH changes with a dual colored probe (CM-ROX), featuring a coumarin domain with "always-on" blue fluorescence and a rhodamine-lactam domain activatable to lysosomal acidity to give red fluorescence. With sensitive ratiometric signals upon subtle pH changes, CM-ROX enables discernment of lysosomal pH changes in cells undergoing autophagy, cell death, and viral infection.

  7. A Novel Method of Imaging Lysosomes in Living Human Mammary Epithelial Cells

    Directory of Open Access Journals (Sweden)

    Kristine Glunde

    2003-01-01

    Full Text Available Cancer cells invade by secreting degradative enzymes which, under normal conditions, are sequestered in lysosomal vesicles. The ability to noninvasively label lysosomes and track lysosomal trafficking would be extremely useful to understand the mechanisms by which degradative enzymes are secreted in the presence of pathophysiological environments, such as hypoxia and acidic extracellular pH, which are frequently encountered in solid tumors. In this study, a novel method of introducing a fluorescent label into lysosomes of human mammary epithelial cells (HMECs was evaluated. Highly glycosylated lysosomal membrane proteins were labeled with a newly synthesized compound, 5-dimethylamino-naphthalene-1-sulfonic acid 5-amino-3,4,6-trihydroxy-tetrahydro-pyran-2-ylmethyl ester (6-O-dansyl-GlcNH2. The ability to optically image lysosomes using this new probe was validated by determining the colocalization of the fluorescence from the dansyl group with immunofluorescent staining of two well-established lysosomal marker proteins, LAMP-1 and LAMP-2. The location of the dansyl group in lysosomes was also verified by using an anti-dansyl antibody in Western blots of lysosomes isolated using isopycnic density gradient centrifugation. This novel method of labeling lysosomes biosynthetically was used to image lysosomes in living HMECs perfused in a microscopy-compatible cell perfusion system.

  8. Chaperone therapy for neuronopathic lysosomal diseases: competitive inhibitors as chemical chaperones for enhancement of mutant enzyme activities.

    Science.gov (United States)

    Suzuki, Yoshiyuki; Ogawa, Seiichiro; Sakakibara, Yasubumi

    2009-05-26

    Chaperone therapy is a newly developed molecular approach to lysosomal diseases, a group of human genetic diseases causing severe brain damage. We found two valienamine derivatives, N-octyl-4-epi-beta-valienamine (NOEV) and N-octyl-beta-valienamine (NOV), as promising therapeutic agents for human beta-galactosidase deficiency disorders (mainly G(M1)-gangliosidosis) and beta-glucosidase deficiency disorders (Gaucher disease), respectively. We briefly reviewed the historical background of research in carbasugar glycosidase inhibitors. Originally NOEV and NOV had been discovered as competitive inhibitors, and then their paradoxical bioactivities as chaperones were confirmed in cultured fibroblasts from patients with these disorders. Subsequently G(M1)-gangliosidosis model mice were developed and useful for experimental studies. Orally administered NOEV entered the brain through the blood-brain barrier, enhanced beta-galactosidase activity, reduced substrate storage, and improved neurological deterioration clinically. Furthermore, we executed computational analysis for prediction of molecular interactions between beta-galactosidase and NOEV. Some preliminary results of computational analysis of molecular interaction mechanism are presented in this article. NOV also showed the chaperone effect toward several beta-glucosidase gene mutations in Gaucher disease. We hope chaperone therapy will become available for some patients with G(M1)-gangliosidosis, Gaucher disease, and potentially other lysosomal storage diseases with central nervous system involvement.

  9. Recent Patent Advances For Neurodegenerative Disorders And Its Treatment.

    Science.gov (United States)

    Kumar, Bhavna; Sharma, Deepika

    2017-10-10

    Neurodegenerative disorders are one of the common diseases that affect our society with tremendous medical and financial burdens. As a whole, neurodegeneration affects individuals of all ages, but becomes increasingly frequent with age, coming to affect a very large share of our elderly population which is severely affecting the patient, caregivers, and enormously increasing the financial burden of the nation. These diseases share a very complex nature, which often result from combined genetic, environment and pathogenic factors. Various challenges are faced by the scientific community that researches on the pathogenesis and the therapy of neurodegenerative disorder. The review has been analysed for recent patent documents and treatment approaches for neurodegenerative disorders. The study design is based on updating the international and national literatures and an exhaustive patent search and compiling of various patented documents for the treatment of neurodegenerative disorders (EP2282779 A1, US20110229555 A1) to provide information in the state of technological innovation in terms of research and development. In the present review, the authors described various neurodegenerative diseases, there treatment strategies and emphasized on various patented approaches for age-related neurodegenerative disorders such as New therapeutic approaches for treating Alzheimer disease and related disorders through a modulation of cell stress response EP2282779 A1, through combined therapies that modulate angiogenesis US20120058992 A1. The review will attract the interest of academics, researchers, students and pharmaceutical companies in the recent on-going activities in neurodegenerative disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Lysosome-related organelles: unusual compartments become mainstream.

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    Marks, Michael S; Heijnen, Harry F G; Raposo, Graça

    2013-08-01

    Lysosome-related organelles (LROs) comprise a group of cell type-specific subcellular compartments with unique composition, morphology and structure that share some features with endosomes and lysosomes and that function in varied processes such as pigmentation, hemostasis, lung plasticity and immunity. In recent years, studies of genetic diseases in which LRO functions are compromised have provided new insights into the mechanisms of LRO biogenesis and the regulated secretion of LRO contents. These insights have revealed previously unappreciated specialized endosomal sorting processes in all cell types, and are expanding our views of the plasticity of the endosomal and secretory systems in adapting to cell type-specific needs. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Lysosomal and vacuolar sorting: not so different after all!

    Science.gov (United States)

    de Marcos Lousa, Carine; Denecke, Jurgen

    2016-06-15

    Soluble hydrolases represent the main proteins of lysosomes and vacuoles and are essential to sustain the lytic properties of these organelles typical for the eukaryotic organisms. The sorting of these proteins from ER residents and secreted proteins is controlled by highly specific receptors to avoid mislocalization and subsequent cellular damage. After binding their soluble cargo in the early stage of the secretory pathway, receptors rely on their own sorting signals to reach their target organelles for ligand delivery, and to recycle back for a new round of cargo recognition. Although signals in cargo and receptor molecules have been studied in human, yeast and plant model systems, common denominators and specific examples of diversification have not been systematically explored. This review aims to fill this niche by comparing the structure and the function of lysosomal/vacuolar sorting receptors (VSRs) from these three organisms. © 2016 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

  12. Group XV phospholipase A2, a lysosomal phospholipase A2

    OpenAIRE

    Shayman, James A.; Kelly, Robert; Kollmeyer, Jessica; He, Yongqun; Abe, Akira

    2011-01-01

    A phospholipase A2 was identified from MDCK cell homogenates with broad specificity toward glycerophospholipids including phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylglycerol. The phospholipase has the unique ability to transacylate short chain ceramides. This phospholipase is calcium-independent, localized to lysosomes, and has an acidic pH optimum. The enzyme was purified from bovine brain and found to be a water-soluble glycoprotein consisting of a si...

  13. Alterations in ROS activity and lysosomal pH account for distinct patterns of macroautophagy in LINCL and JNCL fibroblasts.

    Science.gov (United States)

    Vidal-Donet, José Manuel; Cárcel-Trullols, Jaime; Casanova, Bonaventura; Aguado, Carmen; Knecht, Erwin

    2013-01-01

    Neuronal ceroid lipofuscinoses (NCL) are lysosomal storage disorders characterized by the accumulation of lipofuscin within lysosomes. Late infantile (LINCL) and juvenile (JNCL) are their most common forms and are caused by loss-of-function mutations in tripeptidyl peptidase 1 (TPP1), a lysosomal endopeptidase, and CLN3 protein (CLN3p), whose location and function is still controversial. LINCL patients suffer more severely from NCL consequences than JNCL patients, in spite of having in common an abnormal accumulation of material with a similar composition in the lysosomes. To identify distinctive characteristics that could explain the differences in the severity of LINCL and JNCL pathologies, we compared the protein degradation mechanisms in patientś fibroblasts. Pulse-chase experiments show a significant decrease in protein degradation by macroautophagy in fibroblasts bearing TPP1 (CLN2) and CLN3p (CLN3) mutations. In CLN2 fibroblasts, LC3-II levels and other procedures indicate an impaired formation of autophagosomes, which confirms the pulse-chase experiments. This defect is linked to an accumulation of reactive oxygen species (ROS), an upregulation of the Akt-mTOR signalling pathway and increased activities of the p38α and ERK1/2 MAPKs. In CLN3 fibroblasts, LC3-II analysis indicates impairment in autophagosome maturation and there is also a defect in fluid phase endocytosis, two alterations that can be related to an observed increase of 0.5 units in lysosomal pH. CLN3 fibroblasts also accumulate ROS but to a lower extent than CLN2. TPP1 activity is completely abrogated in CLN2 and partially diminished in CLN3 fibroblasts. TPP1 cleaves small hydrophobic proteins like subunit c of mitochondrial ATP synthase and the lack or a lower activity of this enzyme can contribute to lipofuscin accumulation. These alterations in TPP1 activity lead to an increased ROS production, especially in CLN2 in which it is aggravated by a decrease in catalase activity. This could

  14. Alterations in ROS activity and lysosomal pH account for distinct patterns of macroautophagy in LINCL and JNCL fibroblasts.

    Directory of Open Access Journals (Sweden)

    José Manuel Vidal-Donet

    Full Text Available Neuronal ceroid lipofuscinoses (NCL are lysosomal storage disorders characterized by the accumulation of lipofuscin within lysosomes. Late infantile (LINCL and juvenile (JNCL are their most common forms and are caused by loss-of-function mutations in tripeptidyl peptidase 1 (TPP1, a lysosomal endopeptidase, and CLN3 protein (CLN3p, whose location and function is still controversial. LINCL patients suffer more severely from NCL consequences than JNCL patients, in spite of having in common an abnormal accumulation of material with a similar composition in the lysosomes. To identify distinctive characteristics that could explain the differences in the severity of LINCL and JNCL pathologies, we compared the protein degradation mechanisms in patientś fibroblasts. Pulse-chase experiments show a significant decrease in protein degradation by macroautophagy in fibroblasts bearing TPP1 (CLN2 and CLN3p (CLN3 mutations. In CLN2 fibroblasts, LC3-II levels and other procedures indicate an impaired formation of autophagosomes, which confirms the pulse-chase experiments. This defect is linked to an accumulation of reactive oxygen species (ROS, an upregulation of the Akt-mTOR signalling pathway and increased activities of the p38α and ERK1/2 MAPKs. In CLN3 fibroblasts, LC3-II analysis indicates impairment in autophagosome maturation and there is also a defect in fluid phase endocytosis, two alterations that can be related to an observed increase of 0.5 units in lysosomal pH. CLN3 fibroblasts also accumulate ROS but to a lower extent than CLN2. TPP1 activity is completely abrogated in CLN2 and partially diminished in CLN3 fibroblasts. TPP1 cleaves small hydrophobic proteins like subunit c of mitochondrial ATP synthase and the lack or a lower activity of this enzyme can contribute to lipofuscin accumulation. These alterations in TPP1 activity lead to an increased ROS production, especially in CLN2 in which it is aggravated by a decrease in catalase activity

  15. Lysosomal multienzymatic complex-related diseases: a genetic study among Portuguese patients.

    Science.gov (United States)

    Coutinho, M F; Lacerda, L; Macedo-Ribeiro, S; Baptista, E; Ribeiro, H; Prata, M J; Alves, S

    2012-04-01

    The functional activity of lysosomal enzymes sialidase, β-galactosidase and N-acetylaminogalacto-6-sulfate-sulfatase in the cell depends on their association in a multienzyme complex with cathepsin A. Mutations in any of the components of this complex result in functional deficiency thereby causing severe lysosomal storage disorders. Here, we report the molecular defects underlying sialidosis (mutations in sialidase; gene NEU1), galactosialidosis (mutations in cathepsin A; gene PPGB) and GM1 gangliosidosis (mutations in β-galactosidase; gene GLB1) in Portuguese patients. We performed molecular studies of the PPGB, NEU1 and GLB1 genes in biochemically diagnosed Portuguese patients. Gene expression was determined and the effect of each mutation predicted at protein levels. In the NEU1 gene, we found three novel missense mutations (p.P200L, p.D234N and p.Q282H) and one nonsense mutation (p.R341X). In the PPGB gene, we identified two missense mutations, one novel (p.G86V) and one already described (p.V104M), as well as two new deletions (c.230delC and c.991-992delT) that give rise to non-functional proteins. We also present the first molecular evidence of a causal missense mutation localized to the cathepsin A active site. Finally, in the GLB1 gene, we found six different mutations, all of them previously described (p.R59H, p.R201H, p.H281Y, p.W527X, c.1572-1577InsG and c.845-846delC). Seven novel mutations are reported here, contributing to our knowledge of the mutational spectrum of these diseases and to a better understanding of the genetics of the lysosomal multienzymatic complex. The results of this study will allow carrier detection in affected families and prenatal molecular diagnosis, leading to the improvement of genetic counseling. © 2011 John Wiley & Sons A/S.

  16. Discriminating lysosomal membrane protein types using dynamic neural network.

    Science.gov (United States)

    Tripathi, Vijay; Gupta, Dwijendra Kumar

    2014-01-01

    This work presents a dynamic artificial neural network methodology, which classifies the proteins into their classes from their sequences alone: the lysosomal membrane protein classes and the various other membranes protein classes. In this paper, neural networks-based lysosomal-associated membrane protein type prediction system is proposed. Different protein sequence representations are fused to extract the features of a protein sequence, which includes seven feature sets; amino acid (AA) composition, sequence length, hydrophobic group, electronic group, sum of hydrophobicity, R-group, and dipeptide composition. To reduce the dimensionality of the large feature vector, we applied the principal component analysis. The probabilistic neural network, generalized regression neural network, and Elman regression neural network (RNN) are used as classifiers and compared with layer recurrent network (LRN), a dynamic network. The dynamic networks have memory, i.e. its output depends not only on the input but the previous outputs also. Thus, the accuracy of LRN classifier among all other artificial neural networks comes out to be the highest. The overall accuracy of jackknife cross-validation is 93.2% for the data-set. These predicted results suggest that the method can be effectively applied to discriminate lysosomal associated membrane proteins from other membrane proteins (Type-I, Outer membrane proteins, GPI-Anchored) and Globular proteins, and it also indicates that the protein sequence representation can better reflect the core feature of membrane proteins than the classical AA composition.

  17. Unconventional Trafficking of Mammalian Phospholipase D3 to Lysosomes.

    Science.gov (United States)

    Gonzalez, Adriana Carolina; Schweizer, Michaela; Jagdmann, Sebastian; Bernreuther, Christian; Reinheckel, Thomas; Saftig, Paul; Damme, Markus

    2018-01-23

    Variants in the phospholipase D3 (PLD3) gene have genetically been linked to late-onset Alzheimer's disease. We present a detailed biochemical analysis of PLD3 and reveal its endogenous localization in endosomes and lysosomes. PLD3 reaches lysosomes as a type II transmembrane protein via a (for mammalian cells) uncommon intracellular biosynthetic route that depends on the ESCRT (endosomal sorting complex required for transport) machinery. PLD3 is sorted into intraluminal vesicles of multivesicular endosomes, and ESCRT-dependent sorting correlates with ubiquitination. In multivesicular endosomes, PLD3 is subjected to proteolytic cleavage, yielding a stable glycosylated luminal polypeptide and a rapidly degraded N-terminal membrane-bound fragment. This pathway closely resembles the delivery route of carboxypeptidase S to the yeast vacuole. Our experiments reveal a biosynthetic route of PLD3 involving proteolytic processing and ESCRT-dependent sorting for its delivery to lysosomes in mammalian cells. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  18. In silico studies in drug research against neurodegenerative diseases.

    Science.gov (United States)

    Makhouri, Farahnaz Rezaei; Ghasemi, Jahan B

    2017-08-22

    Neurodegenerative diseases such as Alzheimer's disease (AD), progressive neurodegenerative forms of Huntington's disease, Parkinson's disease (PD), amyotrophic lateral sclerosis, spinal cerebellar ataxias, and spinal and bulbar muscular atrophy are described by slow and selective dysfunction and degeneration of neurons and axons in the central nervous system (CNS). Computer-aided or in silico design methods have matured into powerful tools for reducing the number of ligands that should be screened in experimental assays. In the present review, the authors provide a basic background about neurodegenerative diseases and in silico techniques in the drug research. Furthermore, they review the various in silico studies reported against various targets in neurodegenerative diseases, including homology modeling, molecular docking, virtual high-throughput screening, quantitative structure activity relationship (QSAR), hologram quantitative structure activity relationship (HQSAR), 3D pharmacophore mapping, proteochemometrics modeling (PCM), fingerprints, fragment-based drug discovery, Monte Carlo simulation, molecular dynamic (MD) simulation, quantum-mechanical methods for drug design, support vector machines, and machine learning approaches. Neurodegenerative diseases have a multifactorial pathoetiological origin, so scientists have become persuaded that a multi-target therapeutic strategy aimed at the simultaneous targeting of multiple proteins (and therefore etiologies) involved in the development of a disease is recommended in future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Preventive and therapeutic potential of ascorbic acid in neurodegenerative diseases.

    Science.gov (United States)

    Moretti, Morgana; Fraga, Daiane Bittencourt; Rodrigues, Ana Lúcia S

    2017-12-01

    In this review, we summarize the involvement of ascorbic acid in neurodegenerative diseases by presenting available evidence on the behavioral and biochemical effects of this compound in animal models of neurodegeneration as well as the use of ascorbic acid as a therapeutic approach to alleviate neurodegenerative progression in clinical studies. Ascorbate, a reduced form of vitamin C, has gained interest for its multiple functions and mechanisms of action, contributing to the homeostasis of normal tissues and organs as well as to tissue regeneration. In the brain, ascorbate exerts neuromodulatory functions and scavenges reactive oxygen species generated during synaptic activity and neuronal metabolism. These are important properties as redox imbalance and abnormal protein aggregation constitute central mechanisms implicated in the pathogenesis of neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases, multiple sclerosis, and amyotrophic lateral sclerosis. Indeed, several studies have indicated an association between low serum ascorbate concentrations and neurodegeneration. Moreover, ascorbic acid is a suitable candidate for supplying either antioxidant defense or modulation of neuronal and astrocytic metabolism under neurodegenerative conditions. Ascorbic acid acts mainly by decreasing oxidative stress and reducing the formation of protein aggregates, which may contribute to the reduction of cognitive and/or motor impairments observed in neurodegenerative processes. Although several studies support a possible role of ascorbic acid administration against neurodegeneration, more researches are essential to substantiate the existing results and accelerate the knowledge in this field. © 2017 John Wiley & Sons Ltd.

  20. Neurodegenerative Diseases: Multifactorial Conformational Diseases and Their Therapeutic Interventions

    Directory of Open Access Journals (Sweden)

    Saba Sheikh

    2013-01-01

    Full Text Available Neurodegenerative diseases are multifactorial debilitating disorders of the nervous system that affect approximately 30 millionindividuals worldwide. Neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and amyotrophic lateral sclerosis diseases are the consequence of misfolding and dysfunctional trafficking of proteins. Beside that, mitochondrial dysfunction, oxidative stress, and/or environmental factors strongly associated with age have also been implicated in causing neurodegeneration. After years of intensive research, considerable evidence has accumulated that demonstrates an important role of these factors in the etiology of common neurodegenerative diseases. Despite the extensive efforts that have attempted to define the molecular mechanisms underlying neurodegeneration, many aspects of these pathologies remain elusive. However, in order to explore the therapeutic interventions directed towards treatment of neurodegenerative diseases, neuroscientists are now fully exploiting the data obtained from studies of these basic mechanisms that have gone awry. The novelty of these mechanisms represents a challenge to the identification of viable drug targets and biomarkers for early diagnosis of the diseases. In this paper, we are reviewing various aspects associated with the disease and the recent trends that may have an application for the treatment of the neurodegenerative disorders.

  1. VCP-dependent muscle degeneration is linked to defects in a dynamic tubular lysosomal network in vivo.

    Science.gov (United States)

    Johnson, Alyssa E; Shu, Huidy; Hauswirth, Anna G; Tong, Amy; Davis, Graeme W

    2015-07-13

    Lysosomes are classically viewed as vesicular structures to which cargos are delivered for degradation. Here, we identify a network of dynamic, tubular lysosomes that extends throughout Drosophila muscle, in vivo. Live imaging reveals that autophagosomes merge with tubular lysosomes and that lysosomal membranes undergo extension, retraction, fusion and fission. The dynamics and integrity of this tubular lysosomal network requires VCP, an AAA-ATPase that, when mutated, causes degenerative diseases of muscle, bone and neurons. We show that human VCP rescues the defects caused by loss of Drosophila VCP and overexpression of disease relevant VCP transgenes dismantles tubular lysosomes, linking tubular lysosome dysfunction to human VCP-related diseases. Finally, disruption of tubular lysosomes correlates with impaired autophagosome-lysosome fusion, increased cytoplasmic poly-ubiquitin aggregates, lipofuscin material, damaged mitochondria and impaired muscle function. We propose that VCP sustains sarcoplasmic proteostasis, in part, by controlling the integrity of a dynamic tubular lysosomal network.

  2. Melatonin for Sleep Disorders in Patients with Neurodegenerative Diseases.

    Science.gov (United States)

    Trotti, Lynn Marie; Karroum, Elias G

    2016-07-01

    In patients with neurodegenerative diseases, sleep disorders are common; they impair the quality of life for patients and caregivers and are associated with poorer clinical outcomes. Melatonin has circadian, hypnotic, and free radical-scavenging effects, and preclinical data suggest benefits of melatonin on neurodegeneration. However, randomized, controlled trials of melatonin in patients with neurodegenerative diseases have not shown strong effects. Trials in Alzheimer's patients demonstrate a lack of benefit on sleep quantity. Subjective measures of sleep quality are mixed, with possible symptomatic improvements seen only on some measures or at some time points. Benefits on cognition have not been observed across several studies. In Parkinson's patients, there may be minimal benefit on objective sleep measures, but a suggestion of subjective benefit in few, small studies. Effective treatments for the sleep disorders associated with neurodegenerative diseases are urgently needed, but current data are insufficient to establish melatonin as such a treatment.

  3. Redox Imbalance and Viral Infections in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Dolores Limongi

    2016-01-01

    Full Text Available Reactive oxygen species (ROS are essential molecules for many physiological functions and act as second messengers in a large variety of tissues. An imbalance in the production and elimination of ROS is associated with human diseases including neurodegenerative disorders. In the last years the notion that neurodegenerative diseases are accompanied by chronic viral infections, which may result in an increase of neurodegenerative diseases progression, emerged. It is known in literature that enhanced viral infection risk, observed during neurodegeneration, is partly due to the increase of ROS accumulation in brain cells. However, the molecular mechanisms of viral infection, occurring during the progression of neurodegeneration, remain unclear. In this review, we discuss the recent knowledge regarding the role of influenza, herpes simplex virus type-1, and retroviruses infection in ROS/RNS-mediated Parkinson’s disease (PD, Alzheimer’s disease (AD, and amyotrophic lateral sclerosis (ALS.

  4. Interaction between -Synuclein and Other Proteins in Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Kurt A. Jellinger

    2011-01-01

    Full Text Available Protein aggregation is a common characteristic of many neurodegenerative disorders, and the interaction between pathological/toxic proteins to cause neurodegeneration is a hot topic of current neuroscience research. Despite clinical, genetic, and experimental differences, evidence increasingly indicates considerable overlap between synucleinopathies and tauopathies or other protein-misfolding diseases. Inclusions, characteristics of these disorders, also occurring in other neurodegenerative diseases, suggest interactions of pathological proteins engaging common downstream pathways. Novel findings that have shifted our understanding in the role of pathologic proteins in the pathogenesis of Parkinson and Alzheimer diseases have confirmed correlations/overlaps between these and other neurodegenerative disorders. The synergistic effects of α-synuclein, hyperphosphorylated tau, amyloid-β, and other pathologic proteins, and the underlying molecular pathogenic mechanisms, including induction and spread of protein aggregates, are critically reviewed, suggesting a dualism or triad of neurodegeneration in protein-misfolding disorders, although the etiology of most of these processes is still mysterious.

  5. The Function of the Mitochondrial Calcium Uniporter in Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Yajin Liao

    2017-02-01

    Full Text Available The mitochondrial calcium uniporter (MCU—a calcium uniporter on the inner membrane of mitochondria—controls the mitochondrial calcium uptake in normal and abnormal situations. Mitochondrial calcium is essential for the production of adenosine triphosphate (ATP; however, excessive calcium will induce mitochondrial dysfunction. Calcium homeostasis disruption and mitochondrial dysfunction is observed in many neurodegenerative disorders. However, the role and regulatory mechanism of the MCU in the development of these diseases are obscure. In this review, we summarize the role of the MCU in controlling oxidative stress-elevated mitochondrial calcium and its function in neurodegenerative disorders. Inhibition of the MCU signaling pathway might be a new target for the treatment of neurodegenerative disorders.

  6. Sleep disturbance in mental health problems and neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    Anderson KN

    2013-05-01

    Full Text Available Kirstie N Anderson1 Andrew J Bradley2,3 1Department of Neurology, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, UK; 2Eli Lilly and Company Limited, Lilly House, Basingstoke, UK; 3Institute of Neuroscience, Newcastle University, Newcastle Upon Tyne, UK Abstract: Sleep has been described as being of the brain, by the brain, and for the brain. This fundamental neurobiological behavior is controlled by homeostatic and circadian (24-hour processes and is vital for normal brain function. This review will outline the normal sleep–wake cycle, the changes that occur during aging, and the specific patterns of sleep disturbance that occur in association with both mental health disorders and neurodegenerative disorders. The role of primary sleep disorders such as insomnia, obstructive sleep apnea, and REM sleep behavior disorder as potential causes or risk factors for particular mental health or neurodegenerative problems will also be discussed. Keywords: sleep, mental health, neurodegenerative disorders, cognition

  7. Stem Cells for the Treatment of Neurodegenerative Diseases

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    Ning Zhang

    2010-09-01

    Full Text Available Neurodegenerative diseases are characterized by neurodegenerative changes or apoptosis of neurons involved in networks, leading to permanent paralysis and loss of sensation below the site of the injury. Cell replacement therapy has provided the basis for the development of potentially powerful new therapeutic strategies for a broad spectrum of human neurological diseases. In recent years, neurons and glial cells have successfully been generated from stem cells, and extensive efforts by investigators to develop stem cell-based brain transplantation therapies have been carried out. We review here notable previously published experimental and preclinical studies involving stem cell-based cell for neurodegenerative diseases and discuss the future prospects for stem cell therapy of neurological disorders in the clinical setting. Steady and solid progress in stem cell research in both basic and preclinical settings should support the hope for development of stem cell-based cell therapies for neurological diseases.

  8. Eyelid Dysfunction in Neurodegenerative, Neurogenetic, and Neurometabolic Disease

    Directory of Open Access Journals (Sweden)

    Ali G. Hamedani

    2017-07-01

    Full Text Available Eye movement abnormalities are among the earliest clinical manifestations of inherited and acquired neurodegenerative diseases and play an integral role in their diagnosis. Eyelid movement is neuroanatomically linked to eye movement, and thus eyelid dysfunction can also be a distinguishing feature of neurodegenerative disease and complements eye movement abnormalities in helping us to understand their pathophysiology. In this review, we summarize the various eyelid abnormalities that can occur in neurodegenerative, neurogenetic, and neurometabolic diseases. We discuss eyelid disorders, such as ptosis, eyelid retraction, abnormal spontaneous and reflexive blinking, blepharospasm, and eyelid apraxia in the context of the neuroanatomic pathways that are affected. We also review the literature regarding the prevalence of eyelid abnormalities in different neurologic diseases as well as treatment strategies (Table 1.

  9. Nanomedicine and neurodegenerative disorders: so close yet so far.

    Science.gov (United States)

    Tosi, Giovanni; Vandelli, Maria Angela; Forni, Flavio; Ruozi, Barbara

    2015-07-01

    This editorial provides an overview of the main advantages of the use of nanomedicine-based approach for innovation in the treatment of neurodegenerative diseases. Besides these aspects, a critical analysis on the main causes that slow the application of nanomedicine to brain disorders is given along with the identification of possible solutions and possible interventions. Better communication between the main players of research in this field and a detailed understanding of the most critical issues to be addressed should help in defining future directions towards the improvement and, finally, the clinical application of nanomedicine to neurodegenerative diseases.

  10. Sleep disturbance in mental health problems and neurodegenerative disease.

    Science.gov (United States)

    Anderson, Kirstie N; Bradley, Andrew J

    2013-01-01

    Sleep has been described as being of the brain, by the brain, and for the brain. This fundamental neurobiological behavior is controlled by homeostatic and circadian (24-hour) processes and is vital for normal brain function. This review will outline the normal sleep-wake cycle, the changes that occur during aging, and the specific patterns of sleep disturbance that occur in association with both mental health disorders and neurodegenerative disorders. The role of primary sleep disorders such as insomnia, obstructive sleep apnea, and REM sleep behavior disorder as potential causes or risk factors for particular mental health or neurodegenerative problems will also be discussed.

  11. Apocynin, a Low Molecular Oral Treatment for Neurodegenerative Disease

    Directory of Open Access Journals (Sweden)

    Bert A. ‘t Hart

    2014-01-01

    Full Text Available Accumulating evidence suggests that inflammatory mediators secreted by activated resident or infiltrated innate immune cells have a significant impact on the pathogenesis of neurodegenerative diseases. This may imply that patients affected by a neurodegenerative disease may benefit from treatment with selective inhibitors of innate immune activity. Here we review the therapeutic potential of apocynin, an essentially nontoxic phenolic compound isolated from the medicinal plant Jatropha multifida. Apocynin is a selective inhibitor of the phagocyte NADPH oxidase Nox2 that can be applied orally and is remarkably effective at low dose.

  12. Global warming and neurodegenerative disorders: speculations on their linkage.

    Science.gov (United States)

    Habibi, Laleh; Perry, George; Mahmoudi, Morteza

    2014-01-01

    Climate change is having considerable impact on biological systems. Eras of ice ages and warming shaped the contemporary earth and origin of creatures including humans. Warming forces stress conditions on cells. Therefore, cells evolved elaborate defense mechanisms, such as creation of heat shock proteins, to combat heat stress. Global warming is becoming a crisis and this process would yield an undefined increasing rate of neurodegenerative disorders in future decades. Since heat stress is known to have a degenerative effects on neurons and, conversely, cold conditions have protective effect on these cells, we hypothesize that persistent heat stress forced by global warming might play a crucial role in increasing neurodegenerative disorders.

  13. Lysosomal membrane permeabilization by targeted magnetic nanoparticles in alternating magnetic fields.

    Science.gov (United States)

    Domenech, Maribella; Marrero-Berrios, Ileana; Torres-Lugo, Madeline; Rinaldi, Carlos

    2013-06-25

    Lysosomal death pathways are being explored as alternatives of overcoming cancer tumor resistance to traditional forms of treatment. Nanotechnologies that can selectively target and induce permeabilization of lysosomal compartments in cells could become powerful medical tools. Here we demonstrate that iron oxide magnetic nanoparticles (MNPs) targeted to the epidermal growth factor receptor (EGFR) can selectively induce lysosomal membrane permeabilization (LMP) in cancer cells overexpressing the EGFR under the action of an alternating magnetic field (AMF). LMP was observed to correlate with the production of reactive oxygen species (ROS) and a decrease in tumor cell viability. Confocal microscopy images showed an increase in the cytosolic activity of the lysosomal protease cathepsin B. These observations suggest the possibility of remotely triggering lysosomal death pathways in cancer cells through the administration of MNPs which target lysosomal internalization pathways and the application of AMFs.

  14. The formation of primary and secondary lysosomes in Balantidium coli, Ciliata.

    Science.gov (United States)

    Skotarczak, B

    1999-01-01

    Trophozoites, vegetative forms of Balantidum coli isolated from pigs affected by acute and asymptomatic balantidiasis were studied. Lysosomes and food vacuoles were revealed by cytochemical detection of lysosomal marker, acid phosphatase. The cytoplasm of all the B. coli trophozoites examined was found to contain numerous structures which differed widely in shape, size and location in the cells. One of them was located among the rough endoplasmic reticulum membranes and another one in the vicinity of endosomes. Those structures were regarded as the primary lysosomes. The two types of vesicular structures most probably represent two stages of the primary lysosome formation. Trophozoites were also found to contain secondary lysosomes which are formed by fusion of several primary lysosomes with phagosomes. The ultrathin sections of B. coli trohozoites showed the presence of two types of phagosomes. They were divided, based on their contents, into auto- and heterophagosomes.

  15. Detection of Lysosomal Exocytosis by Surface Exposure of Lamp1 Luminal Epitopes.

    Science.gov (United States)

    Andrews, Norma W

    2017-01-01

    Elevation in the cytosolic Ca 2+ concentration triggers exocytosis of lysosomes in many cell types. This chapter describes a method to detect lysosomal exocytosis in mammalian cells, which takes advantage of the presence of an abundant glycoprotein, Lamp1, on the membrane of lysosomes. Lamp1 is a transmembrane protein with a large, heavily glycosylated region that faces the lumen of lysosomes. When lysosomes fuse with the plasma membrane, epitopes present on the luminal domain of Lamp1 are exposed on the cell surface. The Lamp1 luminal epitopes can then be detected on the surface of live, unfixed cells using highly specific monoclonal antibodies and fluorescence microscopy. The main advantage of this method is its sensitivity, and the fact that it provides spatial information on lysosomal exocytosis at the single cell level.

  16. TFEB and TFE3: Linking Lysosomes to Cellular Adaptation to Stress.

    Science.gov (United States)

    Raben, Nina; Puertollano, Rosa

    2016-10-06

    In recent years, our vision of lysosomes has drastically changed. Formerly considered to be mere degradative compartments, they are now recognized as key players in many cellular processes. The ability of lysosomes to respond to different stimuli revealed a complex and coordinated regulation of lysosomal gene expression. This review discusses the participation of the transcription factors TFEB and TFE3 in the regulation of lysosomal function and biogenesis, as well as the role of the lysosomal pathway in cellular adaptation to a variety of stress conditions, including nutrient deprivation, mitochondrial dysfunction, protein misfolding, and pathogen infection. We also describe how cancer cells make use of TFEB and TFE3 to promote their own survival and highlight the potential of these transcription factors as therapeutic targets for the treatment of neurological and lysosomal diseases.

  17. Altered Met receptor phosphorylation and LRP1-mediated uptake in cells lacking carbohydrate-dependent lysosomal targeting.

    Science.gov (United States)

    Aarnio-Peterson, Megan; Zhao, Peng; Yu, Seok-Ho; Christian, Courtney; Flanagan-Steet, Heather; Wells, Lance; Steet, Richard

    2017-09-08

    Acid hydrolases utilize a carbohydrate-dependent mechanism for lysosomal targeting. These hydrolases acquire a mannose 6-phosphate tag by the action of the GlcNAc-1-phosphotransferase enzyme, allowing them to bind receptors and traffic to endosomes. Loss of GlcNAc-1-phosphotransferase results in hydrolase hypersecretion and profound lysosomal storage. Little, however, is known about how these cellular phenotypes affect the trafficking, activity, and localization of surface glycoproteins. To address this question, we profiled the abundance of surface glycoproteins in WT and CRISPR-mediated GNPTAB-/- HeLa cells and identified changes in numerous glycoproteins, including the uptake receptor LRP1 and multiple receptor tyrosine kinases. Decreased cell surface LRP1 in GNPTAB-/- cells corresponded with a reduction in its steady-state level and less amyloid-β-40 (Aβ40) peptide uptake. GNPTAB-/- cells displayed elevated activation of several kinases including Met receptor. We found increased Met phosphorylation within both the kinase and the docking domains and observed that lower concentrations of pervanadate were needed to cause an increase in phospho-Met in GNPTAB-/- cells. Together, these data suggested a decrease in the activity of the receptor and non-receptor protein-tyrosine phosphatases that down-regulate Met phosphorylation. GNPTAB-/- cells exhibited elevated levels of reactive oxygen species, known to inactivate cell surface and cytosolic phosphatases by oxidation of active site cysteine residues. Consistent with this mode of action, peroxide treatment of parental HeLa cells elevated phospho-Met levels whereas antioxidant treatment of GNPTAB-/- cells reduced phospho-Met levels. Collectively, these findings identify new mechanisms whereby impaired lysosomal targeting can impact the activity and recycling of receptors.

  18. Disruption of Lysosome Function Promotes Tumor Growth and Metastasis in Drosophila *

    OpenAIRE

    Chi, Congwu; Zhu, Huanhu; Han, Min; Zhuang, Yuan; Wu, Xiaohui; Xu, Tian

    2010-01-01

    Lysosome function is essential to many physiological processes. It has been suggested that deregulation of lysosome function could contribute to cancer. Through a genetic screen in Drosophila, we have discovered that mutations disrupting lysosomal degradation pathway components contribute to tumor development and progression. Loss-of-function mutations in the Class C vacuolar protein sorting (VPS) gene, deep orange (dor), dramatically promote tumor overgrowth and invasion of the RasV12 cells....

  19. Circadian clocks and neurodegenerative diseases: time to aggregate?

    Science.gov (United States)

    Hastings, Michael H; Goedert, Michel

    2013-10-01

    The major neurodegenerative diseases are characterised by a disabling loss of the daily pattern of sleep and wakefulness, which may be reflective of a compromise to the underlying circadian clock that times the sleep cycle. At a molecular level, the canonical property of neurodegenerative diseases is aberrant aggregation of otherwise soluble neuronal proteins. They can thus be viewed as disturbances of proteostasis, raising the question whether the two features - altered daily rhythms and molecular aggregation - are related. Recent discoveries have highlighted the fundamental contribution of circadian clocks to the correct ordering of daily cellular metabolic cycles, imposing on peripheral organs such as the liver a strict programme that alternates between anabolic and catabolic states. The discovery that circadian mechanisms are active in local brain regions suggests that they may impinge upon physiological and pathological elements that influence pro-neurodegenerative aggregation. This review explores how introducing the dimension of circadian time and the circadian clock might refine the analysis of aberrant aggregation, thus expanding our perspective on the cell biology common to neurodegenerative diseases. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Chronic sleep disturbance and neural injury: links to neurodegenerative disease.

    Science.gov (United States)

    Abbott, Sabra M; Videnovic, Aleksandar

    2016-01-01

    Sleep-wake disruption is frequently observed and often one of the earliest reported symptoms of many neurodegenerative disorders. This provides insight into the underlying pathophysiology of these disorders, as sleep-wake abnormalities are often accompanied by neurodegenerative or neurotransmitter changes. However, in addition to being a symptom of the underlying neurodegenerative condition, there is also emerging evidence that sleep disturbance itself may contribute to the development and facilitate the progression of several of these disorders. Due to its impact both as an early symptom and as a potential factor contributing to ongoing neurodegeneration, the sleep-wake cycle is an ideal target for further study for potential interventions not only to lessen the burden of these diseases but also to slow their progression. In this review, we will highlight the sleep phenotypes associated with some of the major neurodegenerative disorders, focusing on the circadian disruption associated with Alzheimer's disease, the rapid eye movement behavior disorder and sleep fragmentation associated with Parkinson's disease, and the insomnia and circadian dysregulation associated with Huntington's disease.

  1. NSAIDs and cardiovascular drugs in neurodegenerative and cerebrovascular diseases

    NARCIS (Netherlands)

    M.D.M. Haag (Mendel)

    2009-01-01

    textabstractNeurodegenerative and cerebrovascular diseases are frequent in elderly populations and comprise primarily of dementia (mainly Alzheimer disease (AD)), Parkinson disease (PD) and stroke. The prevalence of these neurological disorders rises with older age. From 55 years to 90 years and

  2. Absence of consensus in diagnostic criteria for familial neurodegenerative diseases.

    LENUS (Irish Health Repository)

    Byrne, Susan

    2012-04-01

    A small proportion of cases seen in neurodegenerative conditions such as amyotrophic lateral sclerosis (ALS), Parkinson\\'s disease and Alzheimer disease are familial. These familial cases are usually clinically indistinguishable from sporadic cases. Identifying familial cases is important both in terms of clinical guidance for family members and for gene discovery.

  3. Neurotrophin Therapy of Neurodegenerative Disorders with Mitochondrial Dysfunction

    Science.gov (United States)

    2007-09-01

    TELEPHONE NUMBER (include area code) Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 Table of Contents 1 Narrative...neurodegenerative disorders including Wernicke -Korsakoff syndrome (reviewed in Martin et al., 2005). 2. Results At E15.5, Ts16 brains are slightly

  4. Memory in neurodegenerative disease: biological, cognitive, and clinical perspectives

    National Research Council Canada - National Science Library

    Tröster, Alexander I

    1998-01-01

    ... associated with Huntington's disease  .   .   21 3 Neuropathology and memory dysfunction in neurodegenerative disease...

  5. Rescue strategies in Drosophila models of neurodegenerative diseases

    NARCIS (Netherlands)

    Baratashvili, Madina Baratovna

    2016-01-01

    In the past decades advances in medicine have led to an extended life span of the general population, which, as a negative consequence, increased the occurrence of age-related neurodegenerative diseases. The necessity to improve the quality of life together with the urge to decrease the economic

  6. Predictive gene testing for Huntington disease and other neurodegenerative disorders.

    Science.gov (United States)

    Wedderburn, S; Panegyres, P K; Andrew, S; Goldblatt, J; Liebeck, T; McGrath, F; Wiltshire, M; Pestell, C; Lee, J; Beilby, J

    2013-12-01

    Controversies exist around predictive testing (PT) programmes in neurodegenerative disorders. This study sets out to answer the following questions relating to Huntington disease (HD) and other neurodegenerative disorders: differences between these patients in their PT journeys, why and when individuals withdraw from PT, and decision-making processes regarding reproductive genetic testing. A case series analysis of patients having PT from the multidisciplinary Western Australian centre for PT over the past 20 years was performed using internationally recognised guidelines for predictive gene testing in neurodegenerative disorders. Of 740 at-risk patients, 518 applied for PT: 466 at risk of HD, 52 at risk of other neurodegenerative disorders - spinocerebellar ataxias, hereditary prion disease and familial Alzheimer disease. Thirteen percent withdrew from PT - 80.32% of withdrawals occurred during counselling stages. Major withdrawal reasons related to timing in the patients' lives or unknown as the patient did not disclose the reason. Thirty-eight HD individuals had reproductive genetic testing: 34 initiated prenatal testing (of which eight withdrew from the process) and four initiated pre-implantation genetic diagnosis. There was no recorded or other evidence of major psychological reactions or suicides during PT. People withdrew from PT in relation to life stages and reasons that are unknown. Our findings emphasise the importance of: (i) adherence to internationally recommended guidelines for PT; (ii) the role of the multidisciplinary team in risk minimisation; and (iii) patient selection. © 2013 The Authors; Internal Medicine Journal © 2013 Royal Australasian College of Physicians.

  7. Chronic sleep disturbance and neural injury: links to neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    Abbott SM

    2016-01-01

    Full Text Available Sabra M Abbott,1 Aleksandar Videnovic21Department of Neurology, Northwestern Feinberg School of Medicine, Chicago, IL, USA; 2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Abstract: Sleep–wake disruption is frequently observed and often one of the earliest reported symptoms of many neurodegenerative disorders. This provides insight into the underlying pathophysiology of these disorders, as sleep–wake abnormalities are often accompanied by neurodegenerative or neurotransmitter changes. However, in addition to being a symptom of the underlying neurodegenerative condition, there is also emerging evidence that sleep disturbance itself may contribute to the development and facilitate the progression of several of these disorders. Due to its impact both as an early symptom and as a potential factor contributing to ongoing neurodegeneration, the sleep–wake cycle is an ideal target for further study for potential interventions not only to lessen the burden of these diseases but also to slow their progression. In this review, we will highlight the sleep phenotypes associated with some of the major neurodegenerative disorders, focusing on the circadian disruption associated with Alzheimer’s disease, the rapid eye movement behavior disorder and sleep fragmentation associated with Parkinson’s disease, and the insomnia and circadian dysregulation associated with Huntington’s disease. Keywords: sleep, neurodegeneration, Alzheimer's disease, Parkinson's disease, Huntington's disease

  8. Pharmacological Modulation of Functional Phenotypes of Microglia in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Gyun Jee Song

    2017-05-01

    Full Text Available Microglia are the resident innate immune cells of the central nervous system that mediate brain homeostasis maintenance. Microglia-mediated neuroinflammation is a hallmark shared by various neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Numerous studies have shown microglial activation phenotypes to be heterogeneous; however, these microglial phenotypes can largely be categorized as being either M1 or M2 type. Although the specific classification of M1 and M2 functionally polarized microglia remains a topic for debate, the use of functional modulators of microglial phenotypes as potential therapeutic approaches for the treatment of neurodegenerative diseases has garnered considerable attention. This review discusses M1 and M2 microglial phenotypes and their relevance in neurodegenerative disease models, as described in recent literature. The modulation of microglial polarization toward the M2 phenotype may lead to development of future therapeutic and preventive strategies for neuroinflammatory and neurodegenerative diseases. Thus, we focus on recent studies of microglial polarization modulators, with a particular emphasis on the small-molecule compounds and their intracellular target proteins.

  9. Gene Therapy-Based Modeling of Neurodegenerative Disorders: Huntington's Disease.

    Science.gov (United States)

    Young, Deborah

    2016-01-01

    Huntington's disease is a fatal neurodegenerative disease characterized by impairments in motor control, and cognitive and psychiatric disturbances. In this chapter, viral vector-mediated approaches used in modeling the key neuropathological features of the disease including the production of abnormal intracellular protein aggregates, neuronal dysfunction and degeneration and motor impairments in rodents are described.

  10. Epigenetic programming of neurodegenerative diseases by an adverse environment.

    Science.gov (United States)

    Babenko, Olena; Kovalchuk, Igor; Metz, Gerlinde A

    2012-03-20

    Experience and environment can critically influence the risk and progression of neurodegenerative disorders. Epigenetic mechanisms, such as miRNA expression, DNA methylation, and histone modifications, readily respond to experience and environmental factors. Here we propose that epigenetic regulation of gene expression and environmental modulation thereof may play a key role in the onset and course of common neurological conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. For example, epigenetic mechanisms may mediate long-term responses to adverse experience, such as stress, to affect disease susceptibility and the course of neurodegenerative events. This review introduces the epigenetic components and their possible role in mediating neuropathological processes in response to stress. We argue that epigenetic modifications will affect neurodegenerative events through altered gene function. The study of epigenetic states in neurodegenerative diseases presents an opportunity to gain new insights into risk factors and pathogenic mechanisms. Moreover, research into epigenetic regulation of disease may revolutionize health care by opening new avenues of personalized, preventive and curative medicine. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. The role of extracellular vesicles in neurodegenerative diseases.

    Science.gov (United States)

    Quek, Camelia; Hill, Andrew F

    2017-02-19

    Extracellular vesicles, including exosomes, are small membranous vesicles released from many biotypes, contributing to the disease progression and spreading. These extracellular vesicles provide an important mode of cell-to-cell communication by delivering proteins, lipids and RNA to target cells. Exosomes are found associated with neurodegenerative diseases, which are characterised by progressive degeneration of neurons and often associated with misfolded protein. The common diseases include Parkinson's disease (PD), Alzheimer's diseases (AD), amyotrophic lateral sclerosis (ALS), and the prion diseases. Of all neurodegenerative diseases, prion diseases are classified as the distinctive group owing to its transmissible and infectious nature of misfolded prion protein. The infectious prion particles have been demonstrated to be present in exosomes to spread prion infectivity within cells. Similarly, misfolded proteins involved in other neurodegenerative diseases such as Amyloid-β and tau in AD, α-synuclein in PD, and superoxide dismutase 1 in ALS have been demonstrated to exploit exosomes for induced spreading of misfolded proteins in a prion-like mechanism. Furthermore, RNA molecules can be taken up by the recipient cells as cargo in exosomes. These RNAs can module the expression of the target genes by repressing or inhibiting protein translation. Here we review the role of exosomes in prion diseases and other common neurodegenerative diseases, and discuss the potential of these vesicles for disease pathogenesis. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Ghrelin: a link between ageing, metabolism and neurodegenerative disorders

    NARCIS (Netherlands)

    Stoyanova, Irina

    2014-01-01

    Along with the increase in life expectancy over the last century comes the increased risk for development of age-related disorders, including metabolic and neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases. These chronic disorders share two main characteristics:

  13. Reporter Assay for Endo/Lysosomal Escape of Toxin-Based Therapeutics

    Directory of Open Access Journals (Sweden)

    Roger Gilabert-Oriol

    2014-05-01

    Full Text Available Protein-based therapeutics with cytosolic targets are capable of exhibiting their therapeutic effect once they have escaped from the endosomes or lysosomes. In this study, the reporters—horseradish peroxidase (HRP, Alexa Fluor 488 (Alexa and ricin A-chain (RTA—were investigated for their capacity to monitor the endo/lysosomal escape of the ribosome-inactivating protein, saporin. The conjugates—saporin-HRP, Alexasaporin and saporin-KQ-RTA—were constructed, and the endo/lysosomal escape of these conjugates alone (lack of endo/lysosomal release or in combination with certain structurally-specific triterpenoidal saponins (efficient endo/lysosomal escape was characterized. HRP failed in reporting the endo/lysosomal escape of saporin. Contrastingly, Alexa Fluor 488 successfully allowed the report of the process at a toxin concentration of 1000 nM. In addition, single endo/lysosome analysis facilitated the determination of the amount of Alexasaporin released from each vesicle. RTA was also successful in reporting the endo/lysosomal escape of the enzymatically inactive mutant, saporin-KQ, but in this case, the sensitivity of the method reached a toxin concentration of 10 nM. In conclusion, the simultaneous usage of Alexa Fluor 488 and RTA as reporters may provide the possibility of monitoring the endo/lysosomal escape of protein-based therapeutics in the concentration range of 10–1000 nM.

  14. Cathepsin inhibition-induced lysosomal dysfunction enhances pancreatic beta-cell apoptosis in high glucose.

    Directory of Open Access Journals (Sweden)

    Minjeong Jung

    Full Text Available Autophagy is a lysosomal degradative pathway that plays an important role in maintaining cellular homeostasis. We previously showed that the inhibition of autophagy causes pancreatic β-cell apoptosis, suggesting that autophagy is a protective mechanism for the survival of pancreatic β-cells. The current study demonstrates that treatment with inhibitors and knockdown of the lysosomal cysteine proteases such as cathepsins B and L impair autophagy, enhancing the caspase-dependent apoptosis of INS-1 cells and islets upon exposure to high concentration of glucose. Interestingly, treatment with cathepsin B and L inhibitors prevented the proteolytic processing of cathepsins B, D and L, as evidenced by gradual accumulation of the respective pro-forms. Of note, inhibition of aspartic cathepsins had no effect on autophagy and cell viability, suggesting the selective role of cathepsins B and L in the regulation of β-cell autophagy and apoptosis. Lysosomal localization of accumulated pro-cathepsins in the presence of cathepsin B and L inhibitors was verified via immunocytochemistry and lysosomal fractionation. Lysotracker staining indicated that cathepsin B and L inhibitors led to the formation of severely enlarged lysosomes in a time-dependent manner. The abnormal accumulation of pro-cathepsins following treatment with inhibitors of cathepsins B and L suppressed normal lysosomal degradation and the processing of lysosomal enzymes, leading to lysosomal dysfunction. Collectively, our findings suggest that cathepsin defects following the inhibition of cathepsin B and L result in lysosomal dysfunction and consequent cell death in pancreatic β-cells.

  15. Lysosomes serve as a platform for hepatitis A virus particle maturation and nonlytic release.

    Science.gov (United States)

    Seggewiß, Nicole; Paulmann, Dajana; Dotzauer, Andreas

    2016-01-01

    Early studies on hepatitis A virus (HAV) in cell culture demonstrated the inclusion of several viral particles in an intracellular lipid-bilayer membrane. However, the origin of these virus-associated membranes and the mechanism for the non-lytic release of HAV into bile are still unknown. Analyzing the association of this virus with cell organelles, we found that newly synthesized HAV particles accumulate in lysosomal organelles and that lysosomal enzymes are involved in the maturation cleavage of the virion. Furthermore, by inhibiting the processes of fusion of lysosomes with the plasma membrane, we found that the nonlytic release of HAV from infected cells occurs via lysosome-related organelles.

  16. Perturbation of redox balance after thioredoxin reductase deficiency interrupts autophagy-lysosomal degradation pathway and enhances cell death in nutritionally stressed SH-SY5Y cells.

    Science.gov (United States)

    Nagakannan, Pandian; Iqbal, Mohamed Ariff; Yeung, Albert; Thliveris, James A; Rastegar, Mojgan; Ghavami, Saeid; Eftekharpour, Eftekhar

    2016-12-01

    Oxidative damage and aggregation of cellular proteins is a hallmark of neuronal cell death after neurotrauma and chronic neurodegenerative conditions. Autophagy and ubiquitin protease system are involved in degradation of protein aggregates, and interruption of their function is linked to apoptotic cell death in these diseases. Oxidative modification of cysteine groups in key molecular proteins has been linked to modification of cellular systems and cell death in these conditions. Glutathione and thioredoxin systems provide reducing protons that can effectively reverse protein modifications and promote cell survival. The central role of Thioredoxin in inhibition of apoptosis is well identified. Additionally, its involvement in initiation of autophagy has been suggested recently. We therefore aimed to investigate the involvement of Thioredoxin system in autophagy-apoptosis processes. A model of serum deprivation in SH-SY5Y was used that is associated with autophagy and apoptosis. Using pharmacological and RNA-editing technology we show that Thioredoxin reductase deficiency in this model enhances oxidative stress and interrupts the early protective autophagy and promotes apoptosis. This was associated with decreased protein-degradation in lysosomes due to altered lysosomal acidification and accumulation of autophagosomes as well as impairment in proteasome pathway. We further confirmed that the extent of oxidative stress is a determining factor in autophagy- apoptosis interplay, as upregulation of cellular reducing capacity by N-acetylcysteine prevented impairment in autophagy and proteasome systems thus promoted cell viability. Our study provides evidence that excessive oxidative stress inhibits protein degradation systems and affects the final stages of autophagy by inhibiting autolysosome maturation: a novel mechanistic link between protein aggregation and conversion of autophagy to apoptosis that can be applicable to neurodegenerative diseases. Copyright © 2016

  17. Intracellular Protein Degradation: From a Vague Idea through the Lysosome and the Ubiquitin-Proteasome System and onto Human Diseases and Drug Targeting

    Directory of Open Access Journals (Sweden)

    Aaron Ciechanover

    2012-01-01

    Full Text Available Between the 1950s and 1980s, scientists were focusing mostly on how the genetic code was transcribed to RNA and translated to proteins, but how proteins were degraded had remained a neglected research area. With the discovery of the lysosome by Christian de Duve it was assumed that cellular proteins are degraded within this organelle. Yet, several independent lines of experimental evidence strongly suggested that intracellular proteolysis was largely non-lysosomal, but the mechanisms involved have remained obscure. The discovery of the ubiquitin-proteasome system resolved the enigma. We now recognize that degradation of intracellular proteins is involved in regulation of a broad array of cellular processes, such as cell cycle and division, regulation of transcription factors, and assurance of the cellular quality control. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of human disease, such as malignancies and neurodegenerative disorders, which led subsequently to an increasing effort to develop mechanism-based drugs.

  18. A mouse model for fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease.

    Science.gov (United States)

    Wolf, Heike; Damme, Markus; Stroobants, Stijn; D'Hooge, Rudi; Beck, Hans Christian; Hermans-Borgmeyer, Irm; Lüllmann-Rauch, Renate; Dierks, Thomas; Lübke, Torben

    2016-09-01

    Fucosidosis is a rare lysosomal storage disorder caused by the inherited deficiency of the lysosomal hydrolase α-L-fucosidase, which leads to an impaired degradation of fucosylated glycoconjugates. Here, we report the generation of a fucosidosis mouse model, in which the gene for lysosomal α-L-fucosidase (Fuca1) was disrupted by gene targeting. Homozygous knockout mice completely lack α-L-fucosidase activity in all tested organs leading to highly elevated amounts of the core-fucosylated glycoasparagine Fuc(α1,6)-GlcNAc(β1-N)-Asn and, to a lesser extent, other fucosylated glycoasparagines, which all were also partially excreted in urine. Lysosomal storage pathology was observed in many visceral organs, such as in the liver, kidney, spleen and bladder, as well as in the central nervous system (CNS). On the cellular level, storage was characterized by membrane-limited cytoplasmic vacuoles primarily containing water-soluble storage material. In the CNS, cellular alterations included enlargement of the lysosomal compartment in various cell types, accumulation of secondary storage material and neuroinflammation, as well as a progressive loss of Purkinje cells combined with astrogliosis leading to psychomotor and memory deficits. Our results demonstrate that this new fucosidosis mouse model resembles the human disease and thus will help to unravel underlying pathological processes. Moreover, this model could be utilized to establish diagnostic and therapeutic strategies for fucosidosis. © 2016. Published by The Company of Biologists Ltd.

  19. A mouse model for fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease

    Directory of Open Access Journals (Sweden)

    Heike Wolf

    2016-09-01

    Full Text Available Fucosidosis is a rare lysosomal storage disorder caused by the inherited deficiency of the lysosomal hydrolase α-L-fucosidase, which leads to an impaired degradation of fucosylated glycoconjugates. Here, we report the generation of a fucosidosis mouse model, in which the gene for lysosomal α-L-fucosidase (Fuca1 was disrupted by gene targeting. Homozygous knockout mice completely lack α-L-fucosidase activity in all tested organs leading to highly elevated amounts of the core-fucosylated glycoasparagine Fuc(α1,6-GlcNAc(β1-N-Asn and, to a lesser extent, other fucosylated glycoasparagines, which all were also partially excreted in urine. Lysosomal storage pathology was observed in many visceral organs, such as in the liver, kidney, spleen and bladder, as well as in the central nervous system (CNS. On the cellular level, storage was characterized by membrane-limited cytoplasmic vacuoles primarily containing water-soluble storage material. In the CNS, cellular alterations included enlargement of the lysosomal compartment in various cell types, accumulation of secondary storage material and neuroinflammation, as well as a progressive loss of Purkinje cells combined with astrogliosis leading to psychomotor and memory deficits. Our results demonstrate that this new fucosidosis mouse model resembles the human disease and thus will help to unravel underlying pathological processes. Moreover, this model could be utilized to establish diagnostic and therapeutic strategies for fucosidosis.

  20. Klebsiella pneumoniae survives within macrophages by avoiding delivery to lysosomes.

    Science.gov (United States)

    Cano, Victoria; March, Catalina; Insua, Jose Luis; Aguiló, Nacho; Llobet, Enrique; Moranta, David; Regueiro, Verónica; Brennan, Gerard P; Millán-Lou, Maria Isabel; Martín, Carlos; Garmendia, Junkal; Bengoechea, José A

    2015-11-01

    Klebsiella pneumoniae is an important cause of community-acquired and nosocomial pneumonia. Evidence indicates that Klebsiella might be able to persist intracellularly within a vacuolar compartment. This study was designed to investigate the interaction between Klebsiella and macrophages. Engulfment of K. pneumoniae was dependent on host cytoskeleton, cell plasma membrane lipid rafts and the activation of phosphoinositide 3-kinase (PI3K). Microscopy studies revealed that K. pneumoniae resides within a vacuolar compartment, the Klebsiella-containing vacuole (KCV), which traffics within vacuoles associated with the endocytic pathway. In contrast to UV-killed bacteria, the majority of live bacteria did not co-localize with markers of the lysosomal compartment. Our data suggest that K. pneumoniae triggers a programmed cell death in macrophages displaying features of apoptosis. Our efforts to identify the mechanism(s) whereby K. pneumoniae prevents the fusion of the lysosomes to the KCV uncovered the central role of the PI3K-Akt-Rab14 axis to control the phagosome maturation. Our data revealed that the capsule is dispensable for Klebsiella intracellular survival if bacteria were not opsonized. Furthermore, the environment found by Klebsiella within the KCV triggered the down-regulation of the expression of cps. Altogether, this study proves evidence that K. pneumoniae survives killing by macrophages by manipulating phagosome maturation that may contribute to Klebsiella pathogenesis. © 2015 John Wiley & Sons Ltd.

  1. Affinity purification of soluble lysosomal proteins for mass spectrometric identification.

    Science.gov (United States)

    Jaquinod, Sylvie Kieffer-; Chapel, Agnès; Garin, Jérôme; Journet, Agnøs

    2008-01-01

    This chapter describes the process of production, purification, separation, and mass spectrometry identification of soluble lysosomal proteins. The rationale for purification of these proteins resides in their characteristic sugar, the mannose-6-phosphate (M6P), which allows an easy purification by affinity chromatography on immobilized M6P receptor (MPR). The secretion of M6P proteins (essentially soluble lysosomal proteins) from cells in culture is induced by adding a weak base in the culture medium. Secreted proteins are ammonium sulfate precipitated, dialyzed, and loaded onto the immobilized MPR column. After specific elution and collection of the M6P proteins, these are resolved by either bidimensional or monodimensional gel electrophoresis (designated as 2-DE or 1-DE, respectively). Mass spectrometry analysis is performed on spots excised from the 2-DE gel, or on discrete bands covering altogether the whole length of the 1-DE gel lane: these spots or bands are in-gel digested with trypsin and protein identification is obtained, thanks to peptide mass fingerprints [provided by analysis of the digests by matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS)] or peptide amino acid sequences (provided by analysis of the digests by the coupling between liquid chromatography and tandem mass spectrometry, LC-MS/MS).

  2. Engaging the lysosomal compartment to combat B cell malignancies

    DEFF Research Database (Denmark)

    Gronbaek, K.; Jaattela, M.

    2009-01-01

    The combination of rituximab, a type I anti-CD20 mAb, with conventional chemotherapy has significantly improved the outcome of patients with B cell malignancies. Regardless of this success, many patients still relapse with therapy-resistant disease, highlighting the need for the development of m......Abs with higher capacity to induce programmed cell death. The so-called type II anti-CD20 mAbs (e.g., tositumomab) that trigger caspase-independent B cell lymphoma cell death in vitro and show superior efficacy as compared with rituximab in eradicating target cells in mouse models are emerging as the next...... generation of therapeutic anti-CD20 mAbs. In this issue of the JCI, Ivanov and colleagues identify the lysosomal compartment as a target for type II mAbs (see the related article beginning on page 2143). These data encourage the further clinical development of type II mAbs as well as other lysosome...

  3. Noxa couples lysosomal membrane permeabilization and apoptosis during oxidative stress.

    Science.gov (United States)

    Eno, Colins O; Zhao, Guoping; Venkatanarayan, Avinashnarayan; Wang, Bing; Flores, Elsa R; Li, Chi

    2013-12-01

    The exact roles of lysosomal membrane permeabilization (LMP) in oxidative stress-triggered apoptosis are not completely understood. Here, we first studied the temporal relation between LMP and mitochondrial outer membrane permeabilization (MOMP) during the initial stage of apoptosis caused by the oxidative stress inducer H2O2. Despite its essential role in mediating apoptosis, the expression of the BH3-only Bcl-2 protein Noxa was dispensable for LMP. In contrast, MOMP was dependent on Noxa expression and occurred downstream of LMP. When lysosomal membranes were stabilized by the iron-chelating agent desferrioxamine, H2O2-induced increase in DNA damage, Noxa expression, and subsequent apoptosis were abolished by the inhibition of LMP. Importantly, LMP-induced Noxa expression increase was mediated by p53 and seems to be a unique feature of apoptosis caused by oxidative stress. Finally, exogenous iron loading recapitulated the effects of H2O2 on the expression of BH3-only Bcl-2 proteins. Overall, these data reveal a Noxa-mediated signaling pathway that couples LMP with MOMP and ultimate apoptosis during oxidative stress. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Limitations of drug registries to evaluate orphan medicinal products for the treatment of lysosomal storage disorders

    NARCIS (Netherlands)

    Hollak, Carla E. M.; Aerts, Johannes M. F. G.; Aymé, Ségolène; Manuel, Jeremy

    2011-01-01

    Orphan drugs are often approved under exceptional circumstances, requiring submission of additional data on safety and effectiveness through registries. These registries are mainly focused on one drug only and data is frequently incomplete. Some registries also address phenotypic heterogeneity and

  5. Influence of Corneal Opacity on Intraocular Pressure Assessment in Patients with Lysosomal Storage Diseases.

    Science.gov (United States)

    Wasielica-Poslednik, Joanna; Politino, Giuseppe; Schmidtmann, Irene; Lorenz, Katrin; Bell, Katharina; Pfeiffer, Norbert; Pitz, Susanne

    2017-01-01

    To investigate an influence of mucopolysaccharidosis (MPS)- and Morbus Fabry-associated corneal opacities on intraocular pressure (IOP) measurements and to evaluate the concordance of the different tonometry methods. 25 MPS patients with or without corneal clouding, 25 Fabry patients with cornea verticillata ≥ grade 2 and 25 healthy age matched controls were prospectively included into this study. Outcome measures: Goldmann applanation tonometry (GAT); palpatory assessment of IOP; Goldmann-correlated intraocular pressure (IOPg), corneal-compensated intraocular pressure (IOPcc), corneal resistance factor (CRF) and corneal hysteresis (CH) assessed by Ocular Response Analyzer (ORA); central corneal thickness (CCT) and density assessed with Pentacam. Statistical analysis was performed using linear mixed effect models and Spearman correlation coefficients. The concordance between tonometry methods was assessed using Bland-Altman analysis. There was no relevant difference between study groups regarding median GAT, IOPg, IOPcc and CCT measurements. The limits of agreement between GAT and IOPcc/IOPg/palpatory IOP in MPS were: [-11.7 to 12.1mmHg], [-8.6 to 15.5 mmHg] and [- 5.4 to 10.1 mmHg] respectively. Limits of agreement were less wide in healthy subjects and Fabry patients. Palpatory IOP was higher in MPS than in healthy controls and Fabry patients. Corneal opacity correlated more strongly with GAT, IOPg, CH, CRF, CCT and corneal density in MPS (r = 0.4, 0.5, 0.5, 0.7, 0.6, 0.6 respectively) than in Fabry patients (r = 0.3, 0.2, -0.03, 0.1, 0.3, -0.2 respectively). In contrast, IOPcc revealed less correlation with corneal opacity than GAT in MPS (r = 0.2 vs. 0.4). ORA and GAT render less comparable IOP-values in patients suffering from MPS-associated corneal opacity in comparison to Fabry and healthy controls. The IOP seems to be overestimated in opaque MPS-affected corneas. GAT, IOPg and biomechanical parameters of the cornea correlate more strongly with the corneal clouding than IOPcc in MPS patients. ClinicalTrials.gov NCT01695161.

  6. Transposable elements in TDP-43-mediated neurodegenerative disorders.

    Directory of Open Access Journals (Sweden)

    Wanhe Li

    Full Text Available Elevated expression of specific transposable elements (TEs has been observed in several neurodegenerative disorders. TEs also can be active during normal neurogenesis. By mining a series of deep sequencing datasets of protein-RNA interactions and of gene expression profiles, we uncovered extensive binding of TE transcripts to TDP-43, an RNA-binding protein central to amyotrophic lateral sclerosis (ALS and frontotemporal lobar degeneration (FTLD. Second, we find that association between TDP-43 and many of its TE targets is reduced in FTLD patients. Third, we discovered that a large fraction of the TEs to which TDP-43 binds become de-repressed in mouse TDP-43 disease models. We propose the hypothesis that TE mis-regulation contributes to TDP-43 related neurodegenerative diseases.

  7. Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease.

    Science.gov (United States)

    Wulff, Katharina; Gatti, Silvia; Wettstein, Joseph G; Foster, Russell G

    2010-08-01

    Sleep and circadian rhythm disruption are frequently observed in patients with psychiatric disorders and neurodegenerative disease. The abnormal sleep that is experienced by these patients is largely assumed to be the product of medication or some other influence that is not well defined. However, normal brain function and the generation of sleep are linked by common neurotransmitter systems and regulatory pathways. Disruption of sleep alters sleep-wake timing, destabilizes physiology and promotes a range of pathologies (from cognitive to metabolic defects) that are rarely considered to be associated with abnormal sleep. We propose that brain disorders and abnormal sleep have a common mechanistic origin and that many co-morbid pathologies that are found in brain disease arise from a destabilization of sleep mechanisms. The stabilization of sleep may be a means by which to reduce the symptoms of--and permit early intervention of--psychiatric and neurodegenerative disease.

  8. Sleep-wake changes and cognition in neurodegenerative disease.

    Science.gov (United States)

    Naismith, Sharon L; Lewis, Simon J G; Rogers, Naomi L

    2011-01-01

    With the increasing aging population, neurodegenerative disorders will become more common in clinical practice. These disorders involve multiple pathophysiological mechanisms that differentially affect cognition, mood, and physical functions. Possibly due to the involvement of common underlying neurobiological circuits, sleep and/or circadian (sleep-wake) changes are also common in this disease group. Of significance, sleep-wake changes are often a prodromal feature and are predictive of cognitive decline, psychiatric symptoms, quality of life, need for institutional care, and caregiver burden. Unfortunately, in neurodegenerative disease, few studies have included detailed polysomnography or neuropsychological assessments although some data indicate that sleep and neurocognitive features are related. Further studies are also required to address the effects of pharmacological and nonpharmacological treatments on cognitive functioning. Such research will hopefully lead to targeted early intervention approaches for cognitive decline in older people. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. Need to improve clinical trials in rare neurodegenerative disorders.

    Science.gov (United States)

    Puopolo, Maria; Pocchiari, Maurizio

    2011-01-01

    Rare neurodegenerative diseases are fatal and no therapy is available to cure or slow down the progression of disease. We report possibly weaknesses in the management of clinical studies in these diseases, ranging from poor preclinical studies, difficulties in the recruitment of patients, delay in the onset of treatment because of lack in early disease-specific biomarkers, and suboptimal design of Phase II clinical trials. The adoption of innovative statistical approaches in early Phase II trials might improve the screening of drugs in rare neurodegenerative disorders, but this implicates efforts from clinical researchers, statisticians, and regulatory people to the development of new strategies that should maintain rigorous scientific integrity together with a more ethical approach to human experimentations.

  10. Need to improve clinical trials in rare neurodegenerative disorders

    Directory of Open Access Journals (Sweden)

    Maria Puopolo

    2011-01-01

    Full Text Available Rare neurodegenerative diseases are fatal and no therapy is available to cure or slow down the progression of disease. We report possibly weaknesses in the management of clinical studies in these diseases, ranging from poor preclinical studies, difficulties in the recruitment of patients, delay in the onset of treatment because of lack in early disease-specific biomarkers, and suboptimal design of Phase II clinical trials. The adoption of innovative statistical approaches in early Phase II trials might improve the screening of drugs in rare neurodegenerative disorders, but this implicates efforts from clinical researchers, statisticians, and regulatory people to the development of new strategies that should maintain rigorous scientific integrity together with a more ethical approach to human experimentations.

  11. Astrocytes in neurodegenerative diseases (I): function and molecular description.

    Science.gov (United States)

    Guillamón-Vivancos, T; Gómez-Pinedo, U; Matías-Guiu, J

    2015-03-01

    Astrocytes have been considered mere supporting cells in the CNS. However, we now know that astrocytes are actively involved in many of the functions of the CNS and may play an important role in neurodegenerative diseases. This article reviews the roles astrocytes play in CNS development and plasticity; control of synaptic transmission; regulation of blood flow, energy, and metabolism; formation of the blood-brain barrier; regulation of the circadian rhythms, lipid metabolism and secretion of lipoproteins; and in neurogenesis. Astrocyte markers and the functions of astrogliosis are also described. Astrocytes play an active role in the CNS. A good knowledge of astrocytes is essential to understanding the mechanisms of neurodegenerative diseases. Copyright © 2012 Sociedad Española de Neurología. Published by Elsevier Espana. All rights reserved.

  12. Olfaction in Neurologic and Neurodegenerative Diseases: A Literature Review

    Directory of Open Access Journals (Sweden)

    Godoy, Maria Dantas Costa Lima

    2015-01-01

    Full Text Available Introduction Loss of smell is involved in various neurologic and neurodegenerative diseases, such as Parkinson disease and Alzheimer disease. However, the olfactory test is usually neglected by physicians at large. Objective The aim of this study was to review the current literature about the relationship between olfactory dysfunction and neurologic and neurodegenerative diseases. Data Synthesis Twenty-seven studies were selected for analysis, and the olfactory system, olfaction, and the association between the olfactory dysfunction and dementias were reviewed. Furthermore, is described an up to date in olfaction. Conclusion Otolaryngologist should remember the importance of olfaction evaluation in daily practice. Furthermore, neurologists and physicians in general should include olfactory tests in the screening of those at higher risk of dementia.

  13. Maillard reaction versus other nonenzymatic modifications in neurodegenerative processes.

    Science.gov (United States)

    Pamplona, Reinald; Ilieva, Ekaterina; Ayala, Victoria; Bellmunt, Maria Josep; Cacabelos, Daniel; Dalfo, Esther; Ferrer, Isidre; Portero-Otin, Manuel

    2008-04-01

    Nonenzymatic protein modifications are generated from direct oxidation of amino acid side chains and from reaction of the nucleophilic side chains of specific amino acids with reactive carbonyl species. These reactions give rise to specific markers that have been analyzed in different neurodegenerative diseases sharing protein aggregation, such as Alzheimer's disease, Pick's disease, Parkinson's disease, dementia with Lewy bodies, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis. Collectively, available data demonstrate that oxidative stress homeostasis, mitochondrial function, and energy metabolism are key factors in determining the disease-specific pattern of protein molecular damage. In addition, these findings suggest the lack of a "gold marker of oxidative stress," and, consequently, they strengthen the need for a molecular dissection of the nonenzymatic reactions underlying neurodegenerative processes.

  14. Potential future neuroprotective therapies for neurodegenerative disorders and stroke.

    Science.gov (United States)

    Tarawneh, Rawan; Galvin, James E

    2010-02-01

    The cellular mechanisms underlying neuronal loss and neurodegeneration have been an area of interest in the last decade. Although neurodegenerative diseases such as Alzheimer disease, Parkinson disease, and Huntington disease each have distinct clinical symptoms and pathologies, they all share common mechanisms such as protein aggregation, oxidative injury, inflammation, apoptosis, and mitochondrial injury that contribute to neuronal loss. Although cerebrovascular disease has different causes from the neurodegenerative disorders, many of the same common disease mechanisms come into play following a stroke. Novel therapies that target each of these mechanisms may be effective in decreasing the risk of disease, abating symptoms, or slowing down their progression. Although most of these therapies are experimental, and require further investigation, a few seem to offer promise.

  15. Searching for MIND: MicroRNAs in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Christian Barbato

    2009-01-01

    Full Text Available In few years our understanding of microRNA (miRNA biogenesis, molecular mechanisms by which miRNAs regulate gene expression, and the functional roles of miRNAs has been expanded. Interestingly, numerous miRNAs are expressed in a spatially and temporally controlled manner in the nervous system, suggesting that their posttrascriptional regulation may be particularly relevant in neural development and function. MiRNA studies in neurobiology showed their involvement in synaptic plasticity and brain diseases. In this review ,correlations between miRNA-mediated gene silencing and Alzheimer's, Parkinson's, and other neurodegenerative diseases will be discussed. Molecular and cellular neurobiological studies of the miRNAs in neurodegeneration represent the exploration of a new Frontier of miRNAs biology and the potential development of new diagnostic tests and genetic therapies for neurodegenerative diseases.

  16. Widespread Aggregation and Neurodegenerative Diseases Are Associated with Supersaturated Proteins

    Directory of Open Access Journals (Sweden)

    Prajwal Ciryam

    2013-11-01

    Full Text Available The maintenance of protein solubility is a fundamental aspect of cellular homeostasis because protein aggregation is associated with a wide variety of human diseases. Numerous proteins unrelated in sequence and structure, however, can misfold and aggregate, and widespread aggregation can occur in living systems under stress or aging. A crucial question in this context is why only certain proteins appear to aggregate readily in vivo, whereas others do not. We identify here the proteins most vulnerable to aggregation as those whose cellular concentrations are high relative to their solubilities. We find that these supersaturated proteins represent a metastable subproteome involved in pathological aggregation during stress and aging and are overrepresented in biochemical processes associated with neurodegenerative disorders. Consequently, such cellular processes become dysfunctional when the ability to keep intrinsically supersaturated proteins soluble is compromised. Thus, the simultaneous analysis of abundance and solubility can rationalize the diverse cellular pathologies linked to neurodegenerative diseases and aging.

  17. Outdoor Ambient Air Pollution and Neurodegenerative Diseases: the Neuroinflammation Hypothesis.

    Science.gov (United States)

    Jayaraj, Richard L; Rodriguez, Eric A; Wang, Yi; Block, Michelle L

    2017-06-01

    Accumulating research indicates that ambient outdoor air pollution impacts the brain and may affect neurodegenerative diseases, yet the potential underlying mechanisms are poorly understood. The neuroinflammation hypothesis holds that elevation of cytokines and reactive oxygen species in the brain mediates the deleterious effects of urban air pollution on the central nervous system (CNS). Studies in human and animal research document that neuroinflammation occurs in response to several inhaled pollutants. Microglia are a prominent source of cytokines and reactive oxygen species in the brain, implicated in the progressive neuron damage in diverse neurodegenerative diseases, and activated by inhaled components of urban air pollution through both direct and indirect pathways. The MAC1-NOX2 pathway has been identified as a mechanism through which microglia respond to different forms of air pollution, suggesting a potential common deleterious pathway. Multiple direct and indirect pathways in response to air pollution exposure likely interact in concert to exert CNS effects.

  18. Pathophysiology of language, speech and emotions in neurodegenerative disease.

    Science.gov (United States)

    Graff-Radford, Jonathan; Jones, David T; Graff-Radford, Neill R

    2014-01-01

    Studying neurodegenerative diseases has greatly expanded our knowledge of language, speech and emotion as these diseases can affect areas not typically seen with stroke or tumor. Newer imaging techniques such as voxel based morphometry), fluorodeoxyglucose (F18) positron emission tomography and functional magnetic resonance imaging have allowed localization of these deficits and a greater understanding of the language network targeted by these progressive neurodegenerative illnesses. This review illustrates these important points by describing five syndromes, using clinical cases and then noting the anatomy, typical pathology, and proposed pathophysiology. The syndromes are Progressive Nonfluent Aphasia, Semantic Dementia, Logopenic Aphasia, Primary Progressive Apraxia of Speech and Dysprosody of Speech. Clinicians recognizing these syndromes using the associated clinico-anatomic patterns will lead to more accurate diagnosis and improved patient counseling and management. Further, patients may be included in appropriate clinical trials when their doctors are aware of the most likely pathology. Copyright © 2013 Elsevier Ltd. All rights reserved.

  19. Neurodegenerative diseases and widespread aggregation are associated with supersaturated proteins

    Science.gov (United States)

    Ciryam, Prajwal; Tartaglia, Gian Gaetano; Morimoto, Richard I.; Dobson, Christopher M.; Vendruscolo, Michele

    2013-01-01

    Summary The maintenance of protein solubility is a fundamental aspect of protein homeostasis, as aggregation is associated with cytotoxicity and a variety of human diseases. Numerous proteins unrelated in sequence and structure, however, can misfold and aggregate, and widespread aggregation can occur in living systems under stress or ageing. A crucial question in this context is why only certain proteins aggregate in vivo while others do not. We identify here the proteins most vulnerable to aggregation as those whose cellular concentrations are high relative to their solubilities. These supersaturated proteins represent a metastable sub-proteome involved in pathological aggregation during stress and ageing, and are overrepresented in biochemical processes associated with neurodegenerative disorders. Consequently, such cellular processes become dysfunctional when the ability to keep intrinsically supersaturated proteins soluble is compromised. Thus, the simultaneous analysis of abundance and solubility can rationalize the diverse cellular pathologies linked to neurodegenerative diseases and aging. PMID:24183671

  20. Advances in epigenetics and epigenomics for neurodegenerative diseases.

    Science.gov (United States)

    Qureshi, Irfan A; Mehler, Mark F

    2011-10-01

    In the post-genomic era, epigenetic factors-literally those that are "over" or "above" genetic ones and responsible for controlling the expression and function of genes-have emerged as important mediators of development and aging; gene-gene and gene-environmental interactions; and the pathophysiology of complex disease states. Here, we provide a brief overview of the major epigenetic mechanisms (ie, DNA methylation, histone modifications and chromatin remodeling, and non-coding RNA regulation). We highlight the nearly ubiquitous profiles of epigenetic dysregulation that have been found in Alzheimer's and other neurodegenerative diseases. We also review innovative methods and technologies that enable the characterization of individual epigenetic modifications and more widespread epigenomic states at high resolution. We conclude that, together with complementary genetic, genomic, and related approaches, interrogating epigenetic and epigenomic profiles in neurodegenerative diseases represent important and increasingly practical strategies for advancing our understanding of and the diagnosis and treatment of these disorders.

  1. Yeast buddies helping to unravel the complexity of neurodegenerative disorders.

    Science.gov (United States)

    Fruhmann, Gernot; Seynnaeve, David; Zheng, Ju; Ven, Karen; Molenberghs, Sofie; Wilms, Tobias; Liu, Beidong; Winderickx, Joris; Franssens, Vanessa

    2017-01-01

    Neurodegenerative disorders have a profound effect on the quality of life of patients and their environment. However, the development of adequate therapies requires accurate understanding of the underlying disease pathogenesis. On that account, yeast models can play an important role, as they enable the elucidation of the mechanisms leading to neurodegenerative disorders. Furthermore, by using so-called humanized yeast systems, the findings in yeast can be interpolated to humans. In this review, we will give an overview of the current body of knowledge on the use of yeast models with regard to Huntington's, Parkinson's and Alzheimer's disease. In addition to the results, obtained with the baker's yeast Saccharomyces cerevisiae, we also consider the existing literature on the less common but promising fission yeast Schizosaccharomyces pombe. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Protein Modification by Dicarbonyl Molecular Species in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Wesley M. Williams

    2011-01-01

    Full Text Available Neurodegeneration results from abnormalities in cerebral metabolism and energy balance within neurons, astrocytes, microglia, or microvascular endothelial cells of the blood-brain barrier. In Alzheimer's disease, -amyloid is considered the primary contributor to neuropathology and neurodegeneration. It now is believed that certain systemic diseases, such as diabetes mellitus, can contribute to neurodegeneration through the effects of chronic hyperglycemia/insulin resistance resulting in protein glycation, oxidative stress and inflammation within susceptible brain regions. Here, we present an overview of research focusing on the role of protein glycation, oxidative stress, and inflammation in the neurodegenerative process. Of special interest in this paper is the effect of methylglyoxal (MGO, a cytotoxic byproduct of glucose metabolism, elevated in neurodegenerative disease, and diabetes mellitus, on cerebral protein function and oxidative stress. How MGO interacts with amino acid residues within -amyloid, and small peptides within the brain, is also discussed in terms of the affect on protein function.

  3. The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes

    NARCIS (Netherlands)

    Schwenk, B.M.; Lang, C.M.; Hogl, S.; Tahirovic, S.; Orozco, D.; Rentzsch, K.; Lichtenthaler, S.F.; Hoogenraad, Casper; Capell, A.; Haass, C.; Edbauer, D.

    2014-01-01

    TMEM106B is a major risk factor for frontotemporal lobar degeneration with TDP‐43 pathology. TMEM106B localizes to lysosomes, but its function remains unclear. We show that TMEM106B knockdown in primary neurons affects lysosomal trafficking and blunts dendritic arborization. We identify

  4. The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes.

    Science.gov (United States)

    Schwenk, Benjamin M; Lang, Christina M; Hogl, Sebastian; Tahirovic, Sabina; Orozco, Denise; Rentzsch, Kristin; Lichtenthaler, Stefan F; Hoogenraad, Casper C; Capell, Anja; Haass, Christian; Edbauer, Dieter

    2014-03-03

    TMEM106B is a major risk factor for frontotemporal lobar degeneration with TDP-43 pathology. TMEM106B localizes to lysosomes, but its function remains unclear. We show that TMEM106B knockdown in primary neurons affects lysosomal trafficking and blunts dendritic arborization. We identify microtubule-associated protein 6 (MAP6) as novel interacting protein for TMEM106B. MAP6 over-expression inhibits dendritic branching similar to TMEM106B knockdown. MAP6 knockdown fully rescues the dendritic phenotype of TMEM106B knockdown, supporting a functional interaction between TMEM106B and MAP6. Live imaging reveals that TMEM106B knockdown and MAP6 overexpression strongly increase retrograde transport of lysosomes in dendrites. Downregulation of MAP6 in TMEM106B knockdown neurons restores the balance of anterograde and retrograde lysosomal transport and thereby prevents loss of dendrites. To strengthen the link, we enhanced anterograde lysosomal transport by expressing dominant-negative Rab7-interacting lysosomal protein (RILP), which also rescues the dendrite loss in TMEM106B knockdown neurons. Thus, TMEM106B/MAP6 interaction is crucial for controlling dendritic trafficking of lysosomes, presumably by acting as a molecular brake for retrograde transport. Lysosomal misrouting may promote neurodegeneration in patients with TMEM106B risk variants.

  5. Imidazoacridinone-dependent lysosomal photodestruction: a pharmacological Trojan horse approach to eradicate multidrug-resistant cancers.

    Science.gov (United States)

    Adar, Y; Stark, M; Bram, E E; Nowak-Sliwinska, P; van den Bergh, H; Szewczyk, G; Sarna, T; Skladanowski, A; Griffioen, A W; Assaraf, Y G

    2012-04-05

    Multidrug resistance (MDR) remains a primary hindrance to curative cancer therapy. Thus, introduction of novel strategies to overcome MDR is of paramount therapeutic significance. Sequestration of chemotherapeutics in lysosomes is an established mechanism of drug resistance. Here, we show that MDR cells display a marked increase in lysosome number. We further demonstrate that imidazoacridinones (IAs), which are cytotoxic fluorochromes, undergo a dramatic compartmentalization in lysosomes because of their hydrophobic weak base nature. We hence developed a novel photoactivation-based pharmacological Trojan horse approach to target and eradicate MDR cancer cells based on photo-rupture of IA-loaded lysosomes and tumor cell lysis via formation of reactive oxygen species. Illumination of IA-loaded cells resulted in lysosomal photodestruction and restoration of parental cell drug sensitivity. Lysosomal photodestruction of MDR cells overexpressing the key MDR efflux transporters ABCG2, ABCB1 or ABCC1 resulted in 10- to 52-fold lower IC(50) values of various IAs, thereby restoring parental cell sensitivity. Finally, in vivo application of this photodynamic therapy strategy after i.v. injection of IAs in human ovarian tumor xenografts in the chorioallantoic membrane model revealed selective destruction of tumors and their associated vasculature. These findings identify lysosomal sequestration of IAs as an Achilles heel of MDR cells that can be harnessed to eradicate MDR tumor cells via lysosomal photodestruction.

  6. Drug-drug interactions involving lysosomes: mechanisms and potential clinical implications.

    Science.gov (United States)

    Logan, Randall; Funk, Ryan S; Axcell, Erick; Krise, Jeffrey P

    2012-08-01

    Many commercially available, weakly basic drugs have been shown to be lysosomotropic, meaning they are subject to extensive sequestration in lysosomes through an ion trapping-type mechanism. The extent of lysosomal trapping of a drug is an important therapeutic consideration because it can influence both activity and pharmacokinetic disposition. The administration of certain drugs can alter lysosomes such that their accumulation capacity for co-administered and/or secondarily administered drugs is altered. In this review the authors explore what is known regarding the mechanistic basis for drug-drug interactions involving lysosomes. Specifically, the authors address the influence of drugs on lysosomal pH, volume and lipid processing. Many drugs are known to extensively accumulate in lysosomes and significantly alter their structure and function; however, the therapeutic and toxicological implications of this remain controversial. The authors propose that drug-drug interactions involving lysosomes represent an important potential source of variability in drug activity and pharmacokinetics. Most evaluations of drug-drug interactions involving lysosomes have been performed in cultured cells and isolated tissues. More comprehensive in vivo evaluations are needed to fully explore the impact of this drug-drug interaction pathway on therapeutic outcomes.

  7. Plasma Membrane Repair Is Regulated Extracellularly by Proteases Released from Lysosomes.

    Directory of Open Access Journals (Sweden)

    Thiago Castro-Gomes

    Full Text Available Eukaryotic cells rapidly repair wounds on their plasma membrane. Resealing is Ca(2+-dependent, and involves exocytosis of lysosomes followed by massive endocytosis. Extracellular activity of the lysosomal enzyme acid sphingomyelinase was previously shown to promote endocytosis and wound removal. However, whether lysosomal proteases released during cell injury participate in resealing is unknown. Here we show that lysosomal proteases regulate plasma membrane repair. Extracellular proteolysis is detected shortly after cell wounding, and inhibition of this process blocks repair. Conversely, surface protein degradation facilitates plasma membrane resealing. The abundant lysosomal cysteine proteases cathepsin B and L, known to proteolytically remodel the extracellular matrix, are rapidly released upon cell injury and are required for efficient plasma membrane repair. In contrast, inhibition of aspartyl proteases or RNAi-mediated silencing of the lysosomal aspartyl protease cathepsin D enhances resealing, an effect associated with the accumulation of active acid sphingomyelinase on the cell surface. Thus, secreted lysosomal cysteine proteases may promote repair by facilitating membrane access of lysosomal acid sphingomyelinase, which promotes wound removal and is subsequently downregulated extracellularly by a process involving cathepsin D.

  8. The Octyl Ester of Ginsenoside Rh2 Induces Lysosomal Membrane Permeabilization via Bax Translocation

    Directory of Open Access Journals (Sweden)

    Fang Chen

    2016-04-01

    Full Text Available Ginsenoside Rh2 is a potential pharmacologically active metabolite of ginseng. Previously, we have reported that an octyl ester derivative of ginsenoside Rh2 (Rh2-O, has been confirmed to possess higher bioavailability and anticancer effect than Rh2 in vitro. In order to better assess the possibility that Rh2-O could be used as an anticancer compound, the underlying mechanism was investigated in this study. The present results revealed that lysosomal destabilization was involved in the early stage of cell apoptosis in HepG2 cells induced by Rh2-O. Rh2-O could induce an early lysosomal membrane permeabilization with the release of lysosomal protease cathepsins to the cytosol in HepG2 cells. The Cat B inhibitor (leu and Cat D inhibitor (pepA inhibited Rh2-O-induced HepG2 apoptosis as well as tBid production and Δφm depolarization, indicating that lysosomal permeabilization occurred upstream of mitochondrial dysfunction. In addition, Rh2-O induced a significant increase in the protein levels of DRAM1 and Bax (p < 0.05 in lysosomes of HepG2 cells. Knockdown of Bax partially inhibited Rh2-O-induced Cat D release from lysosomes. Thus it was concluded that Rh2-O induced apoptosis of HepG2 cells through activation of the lysosomal-mitochondrial apoptotic pathway involving the translocation of Bax to the lysosome.

  9. Epidemiology of mild traumatic brain injury and neurodegenerative disease

    OpenAIRE

    Gardner, Raquel C.; Yaffe, Kristine

    2015-01-01

    Every year an estimated 42 million people worldwide suffer a mild traumatic brain injury (MTBI) or concussion. More severe traumatic brain injury (TBI) is a well-established risk factor for a variety of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). Recently, large epidemiological studies have additionally identified MTBI as a risk factor for dementia. The role of MTBI in risk of PD or ALS is less well established. Repet...

  10. Chronic sleep disturbance and neural injury: links to neurodegenerative disease

    OpenAIRE

    Abbott SM; Videnovic A

    2016-01-01

    Sabra M Abbott,1 Aleksandar Videnovic21Department of Neurology, Northwestern Feinberg School of Medicine, Chicago, IL, USA; 2Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Abstract: Sleep–wake disruption is frequently observed and often one of the earliest reported symptoms of many neurodegenerative disorders. This provides insight into the underlying pathophysiology of these disorders, as sleep–wake abnormalities are ofte...

  11. Characterizing a neurodegenerative syndrome: primary progressive apraxia of speech

    OpenAIRE

    Josephs, Keith A.; Duffy, Joseph R.; Strand, Edythe A.; Machulda, Mary M.; Matthew L. Senjem; Master, Ankit V.; Lowe, Val J.; Jack, Clifford R.; Jennifer L. Whitwell

    2012-01-01

    Apraxia of speech is a disorder of speech motor planning and/or programming that is distinguishable from aphasia and dysarthria. It most commonly results from vascular insults but can occur in degenerative diseases where it has typically been subsumed under aphasia, or it occurs in the context of more widespread neurodegeneration. The aim of this study was to determine whether apraxia of speech can present as an isolated sign of neurodegenerative disease. Between July 2010 and July 2011, 37 s...

  12. Connected Speech in Neurodegenerative Language Disorders: A Review.

    Science.gov (United States)

    Boschi, Veronica; Catricalà, Eleonora; Consonni, Monica; Chesi, Cristiano; Moro, Andrea; Cappa, Stefano F

    2017-01-01

    Language assessment has a crucial role in the clinical diagnosis of several neurodegenerative diseases. The analysis of extended speech production is a precious source of information encompassing the phonetic, phonological, lexico-semantic, morpho-syntactic, and pragmatic levels of language organization. The knowledge about the distinctive linguistic variables identifying language deficits associated to different neurodegenerative diseases has progressively improved in the last years. However, the heterogeneity of such variables and of the way they are measured and classified limits any generalization and makes the comparison among studies difficult. Here we present an exhaustive review of the studies focusing on the linguistic variables derived from the analysis of connected speech samples, with the aim of characterizing the language disorders of the most prevalent neurodegenerative diseases, including primary progressive aphasia, Alzheimer's disease, movement disorders, and amyotrophic lateral sclerosis. A total of 61 studies have been included, considering only those reporting group analysis and comparisons with a group of healthy persons. This review first analyzes the differences in the tasks used to elicit connected speech, namely picture description, story narration, and interview, considering the possible different contributions to the assessment of different linguistic domains. This is followed by an analysis of the terminologies and of the methods of measurements of the variables, indicating the need for harmonization and standardization. The final section reviews the linguistic domains affected by each different neurodegenerative disease, indicating the variables most consistently impaired at each level and suggesting the key variables helping in the differential diagnosis among diseases. While a large amount of valuable information is already available, the review highlights the need of further work, including the development of automated methods, to

  13. Reliability of measuring regional callosal atrophy in neurodegenerative diseases

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    Jeroen Van Schependom, MSc Eng, PhD

    2016-01-01

    In summary, we have constructed an algorithm that reliably detects the CC in 3D T1 images in a fully automated way in healthy controls and different neurodegenerative diseases. Although the CC area and the circularity are the most reliable features (ICC > 0.97; the reliability of the thickness profile (ICC > 0.90; excluding the tip is sufficient to warrant its inclusion in future clinical studies.

  14. The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases

    OpenAIRE

    Rachel E. Lackie; Rachel E. Lackie; Andrzej Maciejewski; Andrzej Maciejewski; Valeriy G. Ostapchenko; Jose Marques-Lopes; Wing-Yiu Choy; Martin L. Duennwald; Vania F. Prado; Vania F. Prado; Vania F. Prado; Vania F. Prado; Marco A. M. Prado; Marco A. M. Prado; Marco A. M. Prado

    2017-01-01

    The accumulation of misfolded proteins in the human brain is one of the critical features of many neurodegenerative diseases, including Alzheimer's disease (AD). Assembles of beta-amyloid (Aβ) peptide—either soluble (oligomers) or insoluble (plaques) and of tau protein, which form neurofibrillary tangles, are the major hallmarks of AD. Chaperones and co-chaperones regulate protein folding and client maturation, but they also target misfolded or aggregated proteins for refolding or for degrada...

  15. Drosophila as an In Vivo Model for Human Neurodegenerative Disease

    Science.gov (United States)

    McGurk, Leeanne; Berson, Amit; Bonini, Nancy M.

    2015-01-01

    With the increase in the ageing population, neurodegenerative disease is devastating to families and poses a huge burden on society. The brain and spinal cord are extraordinarily complex: they consist of a highly organized network of neuronal and support cells that communicate in a highly specialized manner. One approach to tackling problems of such complexity is to address the scientific questions in simpler, yet analogous, systems. The fruit fly, Drosophila melanogaster, has been proven tremendously valuable as a model organism, enabling many major discoveries in neuroscientific disease research. The plethora of genetic tools available in Drosophila allows for exquisite targeted manipulation of the genome. Due to its relatively short lifespan, complex questions of brain function can be addressed more rapidly than in other model organisms, such as the mouse. Here we discuss features of the fly as a model for human neurodegenerative disease. There are many distinct fly models for a range of neurodegenerative diseases; we focus on select studies from models of polyglutamine disease and amyotrophic lateral sclerosis that illustrate the type and range of insights that can be gleaned. In discussion of these models, we underscore strengths of the fly in providing understanding into mechanisms and pathways, as a foundation for translational and therapeutic research. PMID:26447127

  16. Localization of Axonal Motor Molecules Machinery in Neurodegenerative Disorders

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    Fulvio Florenzano

    2012-04-01

    Full Text Available Axonal transport and neuronal survival depend critically on active transport and axon integrity both for supplying materials and communication to different domains of the cell body. All these actions are executed through cytoskeleton, transport and regulatory elements that appear to be disrupted in neurodegenerative diseases. Motor-driven transport both supplies and clears distal cellular portions with proteins and organelles. This transport is especially relevant in projection and motor neurons, which have long axons to reach the farthest nerve endings. Thus, any disturbance of axonal transport may have severe consequences for neuronal function and survival. A growing body of literature indicates the presence of alterations to the motor molecules machinery, not only in expression levels and phosphorylation, but also in their subcellular distribution within populations of neurons, which are selectively affected in the course of neurodegenerative diseases. The implications of this altered subcellular localization and how this affects axon survival and neuronal death still remain poorly understood, although several hypotheses have been suggested. Furthermore, cytoskeleton and transport element localization can be selectively disrupted in some disorders suggesting that specific loss of the axonal functionality could be a primary hallmark of the disorder. This can lead to axon degeneration and neuronal death either directly, through the functional absence of essential axonal proteins, or indirectly, through failures in communication among different cellular domains. This review compares the localization of cytoskeleton and transport elements in some neurodegenerative disorders to ask what aspects may be essential for axon survival and neuronal death.

  17. Vestibular Deficits in Neurodegenerative Disorders: Balance, Dizziness, and Spatial Disorientation.

    Science.gov (United States)

    Cronin, Thomas; Arshad, Qadeer; Seemungal, Barry M

    2017-01-01

    The vestibular system consists of the peripheral vestibular organs in the inner ear and the associated extensive central nervous system projections-from the cerebellum and brainstem to the thalamic relays to cortical projections. This system is important for spatial orientation and balance, both of critical ecological importance, particularly for successful navigation in our environment. Balance disorders and spatial disorientation are common presenting features of neurodegenerative diseases; however, little is known regarding central vestibular processing in these diseases. A ubiquitous aspect of central vestibular processing is its promiscuity given that vestibular signals are commonly found in combination with other sensory signals. This review discusses how impaired central processing of vestibular signals-typically in combination with other sensory and motor systems-may account for the impaired balance and spatial disorientation in common neurodegenerative conditions. Such an understanding may provide for new diagnostic tests, potentially useful in detecting early disease while a mechanistic understanding of imbalance and spatial disorientation in these patients may enable a vestibular-targeted therapy for such problems in neurodegenerative diseases. Studies with state of the art central vestibular testing are now much needed to tackle this important topic.

  18. Vestibular Deficits in Neurodegenerative Disorders: Balance, Dizziness, and Spatial Disorientation

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    Thomas Cronin

    2017-10-01

    Full Text Available The vestibular system consists of the peripheral vestibular organs in the inner ear and the associated extensive central nervous system projections—from the cerebellum and brainstem to the thalamic relays to cortical projections. This system is important for spatial orientation and balance, both of critical ecological importance, particularly for successful navigation in our environment. Balance disorders and spatial disorientation are common presenting features of neurodegenerative diseases; however, little is known regarding central vestibular processing in these diseases. A ubiquitous aspect of central vestibular processing is its promiscuity given that vestibular signals are commonly found in combination with other sensory signals. This review discusses how impaired central processing of vestibular signals—typically in combination with other sensory and motor systems—may account for the impaired balance and spatial disorientation in common neurodegenerative conditions. Such an understanding may provide for new diagnostic tests, potentially useful in detecting early disease while a mechanistic understanding of imbalance and spatial disorientation in these patients may enable a vestibular-targeted therapy for such problems in neurodegenerative diseases. Studies with state of the art central vestibular testing are now much needed to tackle this important topic.

  19. Mitochondrial Iron-Sulfur Cluster Dysfunction In Neurodegenerative Disease

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    Grazia eIsaya

    2014-03-01

    Full Text Available Growing evidence supports a role for mitochondrial iron metabolism in the pathophysiology of neurodegenerative disorders such as Friedreich ataxia and Parkinson disease as well as in the motor and cognitive decline associated with the aging process. Iron-sulfur enzyme deficits and regional iron accumulation have been observed in each of these conditions. In spite of significant etiological, clinical and pathological differences that exist between Friedreich ataxia and Parkinson disease, it is possible that defects in mitochondrial iron-sulfur clusters biogenesis represent a common underlying mechanism leading to abnormal intracellular iron distribution with mitochondrial iron accumulation, OXPHOS deficits and oxidative stress in susceptible cells and specific regions of the nervous system. Moreover, a similar mechanism may contribute to the age-dependent iron accumulation that occurs in certain brain regions such as the globus pallidus and the substantia nigra. Targeting chelatable iron and reactive oxygen species appear as possible therapeutic options for Friedreich ataxia and Parkinson disease, and possibly other age-related neurodegenerative conditions. However, new technology to interrogate iron-sulfur cluster synthesis in humans is needed to (i assess how defects in this pathway contribute to the natural history of neurodegenerative disorders and (ii develop treatments to correct those defects early in the disease process, before they cause irreversible neuronal cell damage.

  20. Sublethal RNA Oxidation as a Mechanism for Neurodegenerative Disease

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    Mark A. Smith

    2008-05-01

    Full Text Available Although cellular RNA is subjected to the same oxidative insults as DNA and other cellular macromolecules, oxidative damage to RNA has not been a major focus in investigations of the biological consequences of free radical damage. In fact, because it is largely single-stranded and its bases lack the protection of hydrogen bonding and binding by specific proteins, RNA may be more susceptible to oxidative insults than is DNA. Oxidative damage to protein-coding RNA or non-coding RNA will, in turn, potentially cause errors in proteins and/or dysregulation of gene expression. While less lethal than mutations in the genome, such sublethal insults to cells might be associated with underlying mechanisms of several chronic diseases, including neurodegenerative disease. Recently, oxidative RNA damage has been described in several neurodegenerative diseases including Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and prion diseases. Of particular interest, oxidative RNA damage can be demonstrated in vulnerable neurons early in disease, suggesting that RNA oxidation may actively contribute to the onset of the disease. An increasing body of evidence suggests that, mechanistically speaking, the detrimental effects of oxidative RNA damage to protein synthesis are attenuated, at least in part, by the existence of protective mechanisms that prevent the incorporation of the damaged ribonucleotides into the translational machinery. Further investigations aimed at understanding the processing mechanisms related to oxidative RNA damage and its consequences may provide significant insights into the pathogenesis of neurodegenerative and other degenerative diseases and lead to better therapeutic strategies.

  1. Pain in Neurodegenerative Disease: Current Knowledge and Future Perspectives

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    Marina de Tommaso

    2016-01-01

    Full Text Available Neurodegenerative diseases are going to increase as the life expectancy is getting longer. The management of neurodegenerative diseases such as Alzheimer’s disease (AD and other dementias, Parkinson’s disease (PD and PD related disorders, motor neuron diseases (MND, Huntington’s disease (HD, spinocerebellar ataxia (SCA, and spinal muscular atrophy (SMA, is mainly addressed to motor and cognitive impairment, with special care to vital functions as breathing and feeding. Many of these patients complain of painful symptoms though their origin is variable, and their presence is frequently not considered in the treatment guidelines, leaving their management to the decision of the clinicians alone. However, studies focusing on pain frequency in such disorders suggest a high prevalence of pain in selected populations from 38 to 75% in AD, 40% to 86% in PD, and 19 to 85% in MND. The methods of pain assessment vary between studies so the type of pain has been rarely reported. However, a prevalent nonneuropathic origin of pain emerged for MND and PD. In AD, no data on pain features are available. No controlled therapeutic trials and guidelines are currently available. Given the relevance of pain in neurodegenerative disorders, the comprehensive understanding of mechanisms and predisposing factors, the application and validation of specific scales, and new specific therapeutic trials are needed.

  2. Microbiome, probiotics and neurodegenerative diseases: deciphering the gut brain axis.

    Science.gov (United States)

    Westfall, Susan; Lomis, Nikita; Kahouli, Imen; Dia, Si Yuan; Singh, Surya Pratap; Prakash, Satya

    2017-10-01

    The gut microbiota is essential to health and has recently become a target for live bacterial cell biotherapies for various chronic diseases including metabolic syndrome, diabetes, obesity and neurodegenerative disease. Probiotic biotherapies are known to create a healthy gut environment by balancing bacterial populations and promoting their favorable metabolic action. The microbiota and its respective metabolites communicate to the host through a series of biochemical and functional links thereby affecting host homeostasis and health. In particular, the gastrointestinal tract communicates with the central nervous system through the gut-brain axis to support neuronal development and maintenance while gut dysbiosis manifests in neurological disease. There are three basic mechanisms that mediate the communication between the gut and the brain: direct neuronal communication, endocrine signaling mediators and the immune system. Together, these systems create a highly integrated molecular communication network that link systemic imbalances with the development of neurodegeneration including insulin regulation, fat metabolism, oxidative markers and immune signaling. Age is a common factor in the development of neurodegenerative disease and probiotics prevent many harmful effects of aging such as decreased neurotransmitter levels, chronic inflammation, oxidative stress and apoptosis-all factors that are proven aggravators of neurodegenerative disease. Indeed patients with Parkinson's and Alzheimer's diseases have a high rate of gastrointestinal comorbidities and it has be proposed by some the management of the gut microbiota may prevent or alleviate the symptoms of these chronic diseases.

  3. Role of Redox Signaling in Neuroinflammation and Neurodegenerative Diseases

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    Hsi-Lung Hsieh

    2013-01-01

    Full Text Available Reactive oxygen species (ROS, a redox signal, are produced by various enzymatic reactions and chemical processes, which are essential for many physiological functions and act as second messengers. However, accumulating evidence has implicated the pathogenesis of several human diseases including neurodegenerative disorders related to increased oxidative stress. Under pathological conditions, increasing ROS production can regulate the expression of diverse inflammatory mediators during brain injury. Elevated levels of several proinflammatory factors including cytokines, peptides, pathogenic structures, and peroxidants in the central nervous system (CNS have been detected in patients with neurodegenerative diseases such as Alzheimer’s disease (AD. These proinflammatory factors act as potent stimuli in brain inflammation through upregulation of diverse inflammatory genes, including matrix metalloproteinases (MMPs, cytosolic phospholipase A2 (cPLA2, cyclooxygenase-2 (COX-2, and adhesion molecules. To date, the intracellular signaling mechanisms underlying the expression of target proteins regulated by these factors are elusive. In this review, we discuss the mechanisms underlying the intracellular signaling pathways, especially ROS, involved in the expression of several inflammatory proteins induced by proinflammatory factors in brain resident cells. Understanding redox signaling transduction mechanisms involved in the expression of target proteins and genes may provide useful therapeutic strategies for brain injury, inflammation, and neurodegenerative diseases.

  4. Dissecting the Molecular Mechanisms of Neurodegenerative Diseases through Network Biology

    Directory of Open Access Journals (Sweden)

    Jose A. Santiago

    2017-05-01

    Full Text Available Neurodegenerative diseases are rarely caused by a mutation in a single gene but rather influenced by a combination of genetic, epigenetic and environmental factors. Emerging high-throughput technologies such as RNA sequencing have been instrumental in deciphering the molecular landscape of neurodegenerative diseases, however, the interpretation of such large amounts of data remains a challenge. Network biology has become a powerful platform to integrate multiple omics data to comprehensively explore the molecular networks in the context of health and disease. In this review article, we highlight recent advances in network biology approaches with an emphasis in brain-networks that have provided insights into the molecular mechanisms leading to the most prevalent neurodegenerative diseases including Alzheimer’s (AD, Parkinson’s (PD and Huntington’s diseases (HD. We discuss how integrative approaches using multi-omics data from different tissues have been valuable for identifying biomarkers and therapeutic targets. In addition, we discuss the challenges the field of network medicine faces toward the translation of network-based findings into clinically actionable tools for personalized medicine applications.

  5. Myeloid dendritic cells are potential players in human neurodegenerative diseases

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    Paola eBossù

    2015-12-01

    Full Text Available Alzheimer’s (AD and Parkinson’s (PD diseases are devastating neurodegenerative disturbances wherein neuroinflammation is a chronic pathogenic process with high therapeutic potential. Major mediators of AD/PD neuroimmune processes are resident immune cells, but immune cells derived from periphery may also participate and to some extent modify neuroinflammation. Specifically, blood borne myeloid cells emerge as crucial components of AD/PD progression and susceptibility. Among these, dendritic cells (DCs are key immune orchestrators and players of brain immune surveillance: we candidate them as potential mediators of both AD and PD and as relevant cell model for unraveling myeloid cell role in neurodegeneration. Hence, we recapitulate and discuss emerging data suggesting that blood-derived DCs play a role in experimental and human neurodegenerative diseases. In humans, in particular, DCs are modified by in vitro culture with neurodegeneration-associated pathogenic factors and dysregulated in AD patients, while the levels of DC precursors are decreased in AD and PD patients’ blood, possibly as an index of their recruitment to the brain. Overall, we emphasize the need to explore the impact of DCs on neurodegeneration to uncover peripheral immune mechanisms of pathogenic importance, recognize potential biomarkers and improve therapeutic approaches for neurodegenerative diseases.

  6. The transition metals copper and iron in neurodegenerative diseases.

    Science.gov (United States)

    Rivera-Mancía, Susana; Pérez-Neri, Iván; Ríos, Camilo; Tristán-López, Luis; Rivera-Espinosa, Liliana; Montes, Sergio

    2010-07-30

    Neurodegenerative diseases constitute a worldwide health problem. Metals like iron and copper are essential for life, but they are also involved in several neurodegenerative mechanisms such as protein aggregation, free radical generation and oxidative stress. The role of Fe and Cu, their pathogenic mechanisms and possible therapeutic relevance are discussed regarding four of the most common neurodegenerative diseases, Alzheimer's, Parkinson's and Huntington's diseases as well as amyotrophic lateral sclerosis. Metal-mediated oxidation by Fenton chemistry is a common feature for all those disorders and takes part of a self-amplifying damaging mechanism, leading to neurodegeneration. The interaction between metals and proteins in the nervous system seems to be a crucial factor for the development or absence of neurodegeneration. The present review also deals with the therapeutic strategies tested, mainly using metal chelating drugs. Metal accumulation within the nervous system observed in those diseases could be the result of compensatory mechanisms to improve metal availability for physiological processes. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  7. Dissecting the Molecular Mechanisms of Neurodegenerative Diseases through Network Biology.

    Science.gov (United States)

    Santiago, Jose A; Bottero, Virginie; Potashkin, Judith A

    2017-01-01

    Neurodegenerative diseases are rarely caused by a mutation in a single gene but rather influenced by a combination of genetic, epigenetic and environmental factors. Emerging high-throughput technologies such as RNA sequencing have been instrumental in deciphering the molecular landscape of neurodegenerative diseases, however, the interpretation of such large amounts of data remains a challenge. Network biology has become a powerful platform to integrate multiple omics data to comprehensively explore the molecular networks in the context of health and disease. In this review article, we highlight recent advances in network biology approaches with an emphasis in brain-networks that have provided insights into the molecular mechanisms leading to the most prevalent neurodegenerative diseases including Alzheimer's (AD), Parkinson's (PD) and Huntington's diseases (HD). We discuss how integrative approaches using multi-omics data from different tissues have been valuable for identifying biomarkers and therapeutic targets. In addition, we discuss the challenges the field of network medicine faces toward the translation of network-based findings into clinically actionable tools for personalized medicine applications.

  8. 4-hydroxytamoxifen leads to PrPSc clearance by conveying both PrPC and PrPSc to lysosomes independently of autophagy.

    Science.gov (United States)

    Marzo, Ludovica; Marijanovic, Zrinka; Browman, Duncan; Chamoun, Zeina; Caputo, Anna; Zurzolo, Chiara

    2013-03-15

    Prion diseases are fatal neurodegenerative disorders involving the abnormal folding of a native cellular protein, named PrP(C), to a malconformed aggregation-prone state, enriched in beta sheet secondary structure, denoted PrP(Sc). Recently, autophagy has garnered considerable attention as a cellular process with the potential to counteract neurodegenerative diseases of protein aggregation such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. Stimulation of autophagy by chemical compounds has also been shown to reduce PrP(Sc) in infected neuronal cells and prolong survival times in mouse models. Consistent with previous reports, we demonstrate that autophagic flux is increased in chronically infected cells. However, in contrast to recent findings we show that autophagy does not cause a reduction in scrapie burden. We report that in infected neuronal cells different compounds known to stimulate autophagy are ineffective in increasing autophagic flux and in reducing PrP(Sc). We further demonstrate that tamoxifen and its metabolite 4-hydroxytamoxifen lead to prion degradation in an autophagy-independent manner by diverting the trafficking of both PrP and cholesterol to lysosomes. Our data indicate that tamoxifen, a well-characterized, widely available pharmaceutical, may have applications in the therapy of prion diseases.

  9. Retrieval of lysosomal membrane and acid phosphatase from phagolysosomes of Paramecium caudatum

    Science.gov (United States)

    1984-01-01

    Little is known about the fate of lysosomal membrane in phagocytic cells. Because the age of the digestive vacuoles in Paramecium caudatum can be easily determined, we have been able to study the dynamic membrane events in the older vacuoles. Late in the phagolysosomal stage (DV-III) the vacuole membrane undergoes a burst of tubule formation. The tubules expand into vesicles which have characteristics resembling lysosomes in both thin sections and freeze-fracture replicas. The tubules also contain acid phosphatase activity when they arise from acid phosphatase-reactive vacuoles. We conclude that after active digestion lysosomal membrane is retrieved in whole or in part along with some membrane-associated hydrolases. A logical extension of these results is that the lysosome-like vesicles, after being recharged with hydrolases by fusing with primary lysosomes, are recycled back to DV-II for reuse. PMID:6501410

  10. PREFACE: Physics and biology of neurodegenerative diseases Physics and biology of neurodegenerative diseases

    Science.gov (United States)

    Pastore, Annalisa

    2012-06-01

    , about 15 years after the original reports, it is clear that amyloids are special structures that occur in nature under several different guises, some good, some evil [3]. The number of diseases associated with misfolding and fibrillogenesis has steadily increased. Examples of fairly common pathologies associated with fibre formation include Alzheimer's disease (currently one of the major threats for human health in our increasingly aging world), Parkinson's disease and several rare, but not less severe, pathologies. On the other hand, it is also clear that amyloid formation is a convenient mechanism for storing peptides and/or proteins in a compact and resistant way. The number of organisms/tissues in which amyloid deposits are found is thus increasing. It is also not too far-fetched to expect that the mechanical properties of amyloids could be used in biotechnology to design new materials. Because of the importance of this topic in so many scientific fields, we have dedicated this special issue of Journal of Physics: Condensed Matter to the topic of protein aggregation and disease. In the following pages we have collected two reviews and five articles that explore new and interesting developments in the field. References [1] Olby R 1994 The Path of the Double Helix: The Discovery of DNA (New York: Dover) [2] Dobson C M 2004 Principles of protein folding, misfolding and aggregation Semin. Cell Dev. Biol. 15 3-16 [3] Hammer N D, Wang X, McGuffie B A, Chapman M R 2008 Amyloids: friend or foe? J. Alzheimers Dis. 13 407-19 Physics and biology of neurodegenerative diseases contents Protein aggregation and misfolding: good or evil?Annalisa Pastore and Pierandrea Temussi Alzheimer's disease: biological aspects, therapeutic perspectives and diagnostic toolsM Di Carlo, D Giacomazza and P L San Biagio Entrapment of Aβ1-40 peptide in unstructured aggregatesC Corsale, R Carrotta, M R Mangione, S Vilasi, A Provenzano, G Cavallaro, D Bulone and P L San Biagio Elemental micro

  11. Septins as modulators of endo-lysosomal membrane traffic

    Directory of Open Access Journals (Sweden)

    Kyungyeun Song

    2016-11-01

    Full Text Available Septins constitute a family of GTP-binding proteins, which assemble into non-polar filaments in a nucleotide-dependent manner. These filaments can be recruited to negatively charged membrane surfaces. When associated with membranes septin filaments can act as diffusion barriers, which confine subdomains of distinct biological functions. In addition, they serve scaffolding roles by recruiting cytosolic proteins and other cytoskeletal elements. Septins have been implicated in a large variety of membrane-dependent processes, including cytokinesis, signaling, cell migration, and membrane traffic, and several family members have been implicated in disease. However, surprisingly little is known about the molecular mechanisms underlying their biological functions. This review summarizes evidence in support of regulatory roles of septins during endo-lysosomal sorting, with a particular focus on phosphoinositides, which serve as spatial landmarks guiding septin recruitment to distinct subcellular localizations.

  12. Unconventional secretion of FABP4 by endosomes and secretory lysosomes.

    Science.gov (United States)

    Villeneuve, Julien; Bassaganyas, Laia; Lepreux, Sebastien; Chiritoiu, Marioara; Costet, Pierre; Ripoche, Jean; Malhotra, Vivek; Schekman, Randy

    2017-12-06

    An appreciation of the functional properties of the cytoplasmic fatty acid binding protein 4 (FABP4) has advanced with the recent demonstration that an extracellular form secreted by adipocytes regulates a wide range of physiological functions. Little, however, is known about the mechanisms that mediate the unconventional secretion of FABP4. Here, we demonstrate that FABP4 secretion is mediated by a membrane-bounded compartment, independent of the conventional endoplasmic reticulum-Golgi secretory pathway. We show that FABP4 secretion is also independent of GRASP proteins, autophagy, and multivesicular bodies but involves enclosure within endosomes and secretory lysosomes. We highlight the physiological significance of this pathway with the demonstration that an increase in plasma levels of FABP4 is inhibited by chloroquine treatment of mice. These findings chart the pathway of FABP4 secretion and provide a potential therapeutic means to control metabolic disorders associated with its dysregulated secretion. © 2018 Villeneuve et al.

  13. Synergistic Anticancer Action of Lysosomal Membrane Permeabilization and Glycolysis Inhibition.

    Science.gov (United States)

    Kosic, Milica; Arsikin-Csordas, Katarina; Paunovic, Verica; Firestone, Raymond A; Ristic, Biljana; Mircic, Aleksandar; Petricevic, Sasa; Bosnjak, Mihajlo; Zogovic, Nevena; Mandic, Milos; Bumbasirevic, Vladimir; Trajkovic, Vladimir; Harhaji-Trajkovic, Ljubica

    2016-10-28

    We investigated the in vitro and in vivo anticancer effect of combining lysosomal membrane permeabilization (LMP)-inducing agent N-dodecylimidazole (NDI) with glycolytic inhibitor 2-deoxy-d-glucose (2DG). NDI-triggered LMP and 2DG-mediated glycolysis block synergized in inducing rapid ATP depletion, mitochondrial damage, and reactive oxygen species production, eventually leading to necrotic death of U251 glioma cells but not primary astrocytes. NDI/2DG-induced death of glioma cells was partly prevented by lysosomal cathepsin inhibitor E64 and antioxidant α-tocopherol, suggesting the involvement of LMP and oxidative stress in the observed cytotoxicity. LMP-inducing agent chloroquine also displayed a synergistic anticancer effect with 2DG, whereas glucose deprivation or glycolytic inhibitors iodoacetate and sodium fluoride synergistically cooperated with NDI, thus further indicating that the anticancer effect of NDI/2DG combination was indeed due to LMP and glycolysis block. The two agents synergistically induced ATP depletion, mitochondrial depolarization, oxidative stress, and necrotic death also in B16 mouse melanoma cells. Moreover, the combined oral administration of NDI and 2DG reduced in vivo melanoma growth in C57BL/6 mice by inducing necrotic death of tumor cells, without causing liver, spleen, or kidney toxicity. Based on these results, we propose that NDI-triggered LMP causes initial mitochondrial damage that is further increased by 2DG due to the lack of glycolytic ATP required to maintain mitochondrial health. This leads to a positive feedback cycle of mitochondrial dysfunction, ATP loss, and reactive oxygen species production, culminating in necrotic cell death. Therefore, the combination of LMP-inducing agents and glycolysis inhibitors seems worthy of further exploration as an anticancer strategy. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Mexican consensus on lysosomal acid lipase deficiency diagnosis.

    Science.gov (United States)

    Vázquez-Frias, R; García-Ortiz, J E; Valencia-Mayoral, P F; Castro-Narro, G E; Medina-Bravo, P G; Santillán-Hernández, Y; Flores-Calderón, J; Mehta, R; Arellano-Valdés, C A; Carbajal-Rodríguez, L; Navarrete-Martínez, J I; Urbán-Reyes, M L; Valadez-Reyes, M T; Zárate-Mondragón, F; Consuelo-Sánchez, A

    Lysosomal acid lipase deficiency (LAL-D) causes progressive cholesteryl ester and triglyceride accumulation in the lysosomes of hepatocytes and monocyte-macrophage system cells, resulting in a systemic disease with various manifestations that may go unnoticed. It is indispensable to recognize the deficiency, which can present in patients at any age, so that specific treatment can be given. The aim of the present review was to offer a guide for physicians in understanding the fundamental diagnostic aspects of LAL-D, to successfully aid in its identification. The review was designed by a group of Mexican experts and is presented as an orienting algorithm for the pediatrician, internist, gastroenterologist, endocrinologist, geneticist, pathologist, radiologist, and other specialists that could come across this disease in their patients. An up-to-date review of the literature in relation to the clinical manifestations of LAL-D and its diagnosis was performed. The statements were formulated based on said review and were then voted upon. The structured quantitative method employed for reaching consensus was the nominal group technique. A practical algorithm of the diagnostic process in LAL-D patients was proposed, based on clinical and laboratory data indicative of the disease and in accordance with the consensus established for each recommendation. The algorithm provides a sequence of clinical actions from different studies for optimizing the diagnostic process of patients suspected of having LAL-D. Copyright © 2017 Asociación Mexicana de Gastroenterología. Publicado por Masson Doyma México S.A. All rights reserved.

  15. Transformation-associated changes in sphingolipid metabolism sensitize cells to lysosomal cell death induced by inhibitors of acid sphingomyelinase

    DEFF Research Database (Denmark)

    Petersen, Nikolaj H T; Olsen, Ole D; Groth-Pedersen, Line

    2013-01-01

    Lysosomal membrane permeabilization and subsequent cell death may prove useful in cancer treatment, provided that cancer cell lysosomes can be specifically targeted. Here, we identify acid sphingomyelinase (ASM) inhibition as a selective means to destabilize cancer cell lysosomes. Lysosome-destab...... multidrug resistance. Their cancer selectivity is associated with transformation-associated reduction in ASM expression and subsequent failure to maintain sphingomyelin hydrolysis during drug exposure. Taken together, these data identify ASM as an attractive target for cancer therapy....

  16. Eucommia ulmoides Cortex, Geniposide and Aucubin Regulate Lipotoxicity through the Inhibition of Lysosomal BAX

    Science.gov (United States)

    Lee, Geum-Hwa; Lee, Mi-Rin; Lee, Hwa-Young; Kim, Seung Hyun; Kim, Hye-Kyung; Kim, Hyung-Ryong; Chae, Han-Jung

    2014-01-01

    In this study we examined the inhibition of hepatic dyslipidemia by Eucommia ulmoides extract (EUE). Using a screening assay for BAX inhibition we determined that EUE regulates BAX-induced cell death. Among various cell death stimuli tested EUE regulated palmitate-induced cell death, which involves lysosomal BAX translocation. EUE rescued palmitate-induced inhibition of lysosomal V-ATPase, α-galactosidase, α-mannosidase, and acid phosphatase, and this effect was reversed by bafilomycin, a lysosomal V-ATPase inhibitor. The active components of EUE, aucubin and geniposide, showed similar inhibition of palmitate-induced cell death to that of EUE through enhancement of lysosome activity. Consistent with these in vitro findings, EUE inhibited the dyslipidemic condition in a high-fat diet animal model by regulating the lysosomal localization of BAX. This study demonstrates that EUE regulates lipotoxicity through a novel mechanism of enhanced lysosomal activity leading to the regulation of lysosomal BAX activation and cell death. Our findings further indicate that geniposide and aucubin, active components of EUE, may be therapeutic candidates for non-alcoholic fatty liver disease. PMID:24586300

  17. Chlamydia species-dependent differences in the growth requirement for lysosomes.

    Directory of Open Access Journals (Sweden)

    Scot P Ouellette

    2011-03-01

    Full Text Available Genome reduction is a hallmark of obligate intracellular pathogens such as Chlamydia, where adaptation to intracellular growth has resulted in the elimination of genes encoding biosynthetic enzymes. Accordingly, chlamydiae rely heavily on the host cell for nutrients yet their specific source is unclear. Interestingly, chlamydiae grow within a pathogen-defined vacuole that is in close apposition to lysosomes. Metabolically-labeled uninfected host cell proteins were provided as an exogenous nutrient source to chlamydiae-infected cells, and uptake and subsequent labeling of chlamydiae suggested lysosomal degradation as a source of amino acids for the pathogen. Indeed, Bafilomycin A1 (BafA1, an inhibitor of the vacuolar H(+/ATPase that blocks lysosomal acidification and functions, impairs the growth of C. trachomatis and C. pneumoniae, and these effects are especially profound in C. pneumoniae. BafA1 induced the marked accumulation of material within the lysosomal lumen, which was due to the inhibition of proteolytic activities, and this response inhibits chlamydiae rather than changes in lysosomal acidification per se, as cathepsin inhibitors also inhibit the growth of chlamydiae. Finally, the addition of cycloheximide, an inhibitor of eukaryotic protein synthesis, compromises the ability of lysosomal inhibitors to block chlamydial growth, suggesting chlamydiae directly access free amino acids in the host cytosol as a preferred source of these nutrients. Thus, chlamydiae co-opt the functions of lysosomes to acquire essential amino acids.

  18. Impaired JIP3-dependent axonal lysosome transport promotes amyloid plaque pathology.

    Science.gov (United States)

    Gowrishankar, Swetha; Wu, Yumei; Ferguson, Shawn M

    2017-10-02

    Lysosomes robustly accumulate within axonal swellings at Alzheimer's disease (AD) amyloid plaques. However, the underlying mechanisms and disease relevance of such lysosome accumulations are not well understood. Motivated by these problems, we identified JNK-interacting protein 3 (JIP3) as an important regulator of axonal lysosome transport and maturation. JIP3 knockout mouse neuron primary cultures accumulate lysosomes within focal axonal swellings that resemble the dystrophic axons at amyloid plaques. These swellings contain high levels of amyloid precursor protein processing enzymes (BACE1 and presenilin 2) and are accompanied by elevated Aβ peptide levels. The in vivo importance of the JIP3-dependent regulation of axonal lysosomes was revealed by the worsening of the amyloid plaque pathology arising from JIP3 haploinsufficiency in a mouse model of AD. These results establish the critical role of JIP3-dependent axonal lysosome transport in regulating amyloidogenic amyloid precursor protein processing and support a model wherein Aβ production is amplified by plaque-induced axonal lysosome transport defects. © 2017 Gowrishankar et al.

  19. Subversion of a Lysosomal Pathway Regulating Neutrophil Apoptosis by a Major Bacterial Toxin, Pyocyanin1

    Science.gov (United States)

    Prince, Lynne R.; Bianchi, Stephen M.; Vaughan, Kathryn M.; Bewley, Martin A.; Marriott, Helen M.; Walmsley, Sarah R.; Taylor, Graham W.; Buttle, David J.; Sabroe, Ian; Dockrell, David H.; Whyte, Moira K. B.

    2008-01-01

    Neutrophils undergo rapid constitutive apoptosis that is accelerated following bacterial ingestion as part of effective immunity, but is also accelerated by bacterial exotoxins as a mechanism of immune evasion. The paradigm of pathogen-driven neutrophil apoptosis is exemplified by the Pseudomonas aeruginosa toxic metabolite, pyocyanin. We previously showed pyocyanin dramatically accelerates neutrophil apoptosis both in vitro and in vivo, impairs host defenses, and favors bacterial persistence. Here, we investigated the mechanisms of pyocyanin-induced neutrophil apoptosis. Pyocyanin induced early lysosomal dysfunction, shown by altered lysosomal pH, within 15 mins of exposure. Lysosomal disruption was followed by mitochondrial membrane permeabilization, caspase activation and destabilization of Mcl-1. Pharmacological inhibitors of a lysosomal protease, cathepsin D (CTSD), abrogated pyocyanin-induced apoptosis and translocation of CTSD to the cytosol followed pyocyanin treatment and lysosomal disruption. A stable analogue of cyclic AMP (dbcAMP) impeded the translocation of CTSD and prevented the destabilization of Mcl-1 by pyocyanin. Thus pyocyanin activated a co-ordinated series of events dependent upon lysosomal dysfunction and protease release, the first description of a bacterial toxin utilising a lysosomal cell death pathway. This may be a pathological pathway of cell death to which neutrophils are particularly susceptible, and could be therapeutically targeted to limit neutrophil death and preserve host responses. PMID:18292577

  20. Subversion of a lysosomal pathway regulating neutrophil apoptosis by a major bacterial toxin, pyocyanin.

    Science.gov (United States)

    Prince, Lynne R; Bianchi, Stephen M; Vaughan, Kathryn M; Bewley, Martin A; Marriott, Helen M; Walmsley, Sarah R; Taylor, Graham W; Buttle, David J; Sabroe, Ian; Dockrell, David H; Whyte, Moira K B

    2008-03-01

    Neutrophils undergo rapid constitutive apoptosis that is accelerated following bacterial ingestion as part of effective immunity, but is also accelerated by bacterial exotoxins as a mechanism of immune evasion. The paradigm of pathogen-driven neutrophil apoptosis is exemplified by the Pseudomonas aeruginosa toxic metabolite, pyocyanin. We previously showed pyocyanin dramatically accelerates neutrophil apoptosis both in vitro and in vivo, impairs host defenses, and favors bacterial persistence. In this study, we investigated the mechanisms of pyocyanin-induced neutrophil apoptosis. Pyocyanin induced early lysosomal dysfunction, shown by altered lysosomal pH, within 15 min of exposure. Lysosomal disruption was followed by mitochondrial membrane permeabilization, caspase activation, and destabilization of Mcl-1. Pharmacological inhibitors of a lysosomal protease, cathepsin D (CTSD), abrogated pyocyanin-induced apoptosis, and translocation of CTSD to the cytosol followed pyocyanin treatment and lysosomal disruption. A stable analog of cAMP (dibutyryl cAMP) impeded the translocation of CTSD and prevented the destabilization of Mcl-1 by pyocyanin. Thus, pyocyanin activated a coordinated series of events dependent upon lysosomal dysfunction and protease release, the first description of a bacterial toxin using a lysosomal cell death pathway. This may be a pathological pathway of cell death to which neutrophils are particularly susceptible, and could be therapeutically targeted to limit neutrophil death and preserve host responses.

  1. Oxidative stress and neurodegenerative diseases: a neurotrophic approach.

    Science.gov (United States)

    Espinet, Carme; Gonzalo, Hugo; Fleitas, Catherine; Menal, Maria Jose; Egea, Joaquim

    2015-01-01

    Neurotrophins are important neurotrophic factors involved in the survival, differentiation and function of a wide variety of neuron populations. A common feature for most neurotrophins is that they are synthesized as precursor proteins (pro-neurotrophins) that upon being processed by proteolysis render the mature active form responsible for most of their trophic functions. However, some of the pro-neurotrophin form of these proteins, such as the precursor form of NGF (pro-NGF), have been shown to induce opposite effects and trigger apoptosis on neurons through the p75NTR receptor. This suggests that the balance between the levels of proneurotrophin and neurotrophin must be tightly controlled. In this context, it has been shown that in conditions of oxidative stress due for instance to aging or the development of some neurodegenerative disease, neurotrophins are oxidatively modified at least by advanced glycation/lipoxidation end products (AGE/ALEs) which makes pro-NGF refractary to be processed. The lack of maturation and the imbalance in favor of the precursor form may change the pattern of active signaling pathways towards cell death, thus exacerbating the deleterious alterations, for instance during the development of neurodegenerative diseases. Besides that, AGE/ALEs also induce the processing of the pro-NGF receptor p75NTR by α- secretase which is followed by the processing by γ -secretase and the release of the intracellular domain of p75NTR (p75NTRICD). Once cleaved, p75NTRICD recruits two intracellular interactors, NRIF and TRAF6, which allows NRIF phosphorylation by JNK. The phosphorylated form of NRIF then translocates to the nucleus and induces the expression of pro-apoptotic proteins. In this chapter we will summarize the mechanisms by which ROS- induce protein modifications, which proteins are susceptible to be modified, how these modifications affect function and signaling and, finally, how they can be related to neurodegenerative diseases.

  2. Chronic traumatic encephalopathy pathology in a neurodegenerative disorders brain bank.

    Science.gov (United States)

    Bieniek, Kevin F; Ross, Owen A; Cormier, Kerry A; Walton, Ronald L; Soto-Ortolaza, Alexandra; Johnston, Amelia E; DeSaro, Pamela; Boylan, Kevin B; Graff-Radford, Neill R; Wszolek, Zbigniew K; Rademakers, Rosa; Boeve, Bradley F; McKee, Ann C; Dickson, Dennis W

    2015-12-01

    Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive traumatic brain injury (TBI) and characterized by deposition of hyperphosphorylated tau at the depths of sulci. We sought to determine the presence of CTE pathology in a brain bank for neurodegenerative disorders for individuals with and without a history of contact sports participation. Available medical records of 1721 men were reviewed for evidence of past history of injury or participation in contact sports. Subsequently, cerebral cortical samples were processed for tau immunohistochemistry in cases with a documented history of sports exposure as well as age- and disease-matched men and women without such exposure. For cases with available frozen tissue, genetic analysis was performed for variants in APOE, MAPT, and TMEM106B. Immunohistochemistry revealed 21 of 66 former athletes had cortical tau pathology consistent with CTE. CTE pathology was not detected in 198 individuals without exposure to contact sports, including 33 individuals with documented single-incident TBI sustained from falls, motor vehicle accidents, domestic violence, or assaults. Among those exposed to contact sports, those with CTE pathology did not differ from those without CTE pathology with respect to noted clinicopathologic features. There were no significant differences in genetic variants for those with CTE pathology, but we observed a slight increase in MAPT H1 haplotype, and there tended to be fewer homozygous carriers of the protective TMEM106B rs3173615 minor allele in those with sports exposure and CTE pathology compared to those without CTE pathology. In conclusion, this study has identified a small, yet significant, subset of individuals with neurodegenerative disorders and concomitant CTE pathology. CTE pathology was only detected in individuals with documented participation in contact sports. Exposure to contact sports was the greatest risk factor for CTE pathology. Future

  3. Environmental Pollutants as Risk Factors for Neurodegenerative Disorders

    Directory of Open Access Journals (Sweden)

    Miguel eChin-Chan

    2015-04-01

    Full Text Available Neurodegenerative diseases including Alzheimer (AD and Parkinson (PD have attracted attention in last decades due to their high incidence worldwide. The etiology of these diseases is still unclear; however the role of the environment, from diet to the new nanomaterials as putative risk factors has gained importance. More worryingly is the evidence that pre- and post-natal exposures to environmental factors predispose to the onset of neurodegenerative diseases in later life. Neurotoxic metals such as lead, mercury, aluminum, cadmium and arsenic, as well as some pesticides and metal-based nanoparticles have been involved in AD due to their ability to increase beta-amyloid (Aβ peptide and the phosphorylation of Tau protein (P-Tau, causing senile/amyloid plaques and neurofibrillary tangles characteristic of AD. The exposure to lead, manganese, solvents and some pesticides has been related to hallmarks of PD such as mitochondrial dysfunction, alterations in metal homeostasis and aggregation of proteins such as α-synuclein (α-syn, which is a key constituent of Lewy bodies, a crucial factor in PD pathogenesis. Common mechanisms of environmental pollutants to increase Aβ, P-Tau, α-syn and neuronal death have been reported, including the oxidative stress mainly involved in the increase of Aβ and α-syn, and the reduced activity/protein levels of Aβ degrading enzymes such as neprilysin or insulin degrading enzyme. In addition, epigenetic mechanisms by maternal nutrient supplementation and exposure to heavy metals and pesticides have been proposed to lead phenotypic diversity and susceptibility to neurodegenerative diseases. This review discusses data from epidemiological and experimental studies about the role of environmental factors in the development of idiopathic AD and PD, and their mechanisms of action.

  4. Evidence-based therapy for sleep disorders in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    LIU Ling

    2013-08-01

    Full Text Available Objective To evaluate the effectiveness of the treatments for sleep disorders in neurodegenerative diseases so as to provide the best therapeutic regimens for the evidence-based treatment. Methods Search PubMed, MEDLINE, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure (CNKI databases with "sleep disorder or sleep disturbance", "neurodegenerative diseases", "Parkinson's disease or PD", "Alzheimer's disease or AD", "multiple system atrophy or MSA" as retrieval words. The quality of the articles were evaluated with Jadad Scale. Results A total of 35 articles, including 2 systematic reviews, 5 randomized controlled trials, 13 clinical controlled trials, 13 case series and 2 epidemiological investigation studies were included for evaluation, 13 of which were high grade and 22 were low grade articles. Clinical evidences showed that: 1 advice on sleep hygiene, careful use of dopaminergic drugs and hypnotic sedative agents should be considered for PD. Bright light therapy (BLT may improve circadian rhythm sleep disorders and clonazepam may be effective for rapid eye movement sleep behavior disorder (RBD. However, to date, very few controlled studies are available to make a recommendation for the management of sleep disorders in PD; 2 treatments for sleep disorders in AD include drug therapy (e.g. melatonin, acetylcholinesterase inhibitors, antipsychotic drugs, antidepressants and non-drug therapy (e.g. BLT, behavior therapy, but very limited evidence shows the effectiveness of these treatments; 3 the first line treatment for sleep-related breathing disorder in MSA is nasal continuous positive airway pressure (nCPAP, and clonazepam is effective for RBD in MSA; 4 there is rare evidence related to the treatment of sleep disorders in dementia with Lewy body (DLB and amyotrophic lateral sclerosis (ALS. Conclusion Evidence-based medicine can provide the best clinical evidence on sleep disorders' treatment in neurodegenerative

  5. Triptolide induces lysosomal-mediated programmed cell death in MCF-7 breast cancer cells

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    Owa C

    2013-09-01

    Full Text Available Chie Owa, Michael E Messina Jr, Reginald HalabyDepartment of Biology, Montclair State University, Montclair, NJ, USABackground: Breast cancer is a major cause of death; in fact, it is the most common type, in order of the number of global deaths, of cancer in women worldwide. This research seeks to investigate how triptolide, an extract from the Chinese herb Tripterygium wilfordii Hook F, induces apoptosis in MCF-7 human breast cancer cells. Accumulating evidence suggests a role for lysosomal proteases in the activation of apoptosis. However, there is also some controversy regarding the direct participation of lysosomal proteases in activation of key apoptosis-related caspases and release of mitochondrial cytochrome c. In the present study, we demonstrate that triptolide induces an atypical, lysosomal-mediated apoptotic cell death in MCF-7 cells because they lack caspase-3.Methods: MCF-7 cell death was characterized via cellular morphology, chromatin condensation, 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide colorimetric cell growth inhibition assay and the expression levels of proapoptotic proteins. Acridine orange and LysoTracker® staining were performed to visualize lysosomes. Lysosomal enzymatic activity was monitored using an acid phosphatase assay and western blotting of cathepsin B protein levels in the cytosolic fraction, which showed increased enzymatic activity in drug-treated cells.Results: These experiments suggest that triptolide-treated MCF-7 cells undergo atypical apoptosis and that, during the early stages, lysosomal enzymes leak into the cytosol, indicating lysosomal membrane permeability.Conclusion: Our results suggest that further studies are warranted to investigate triptolide's potential as an anticancer therapeutic agent.Keywords: triptolide, MCF-7 breast cancer cells, apoptosis, lysosomes, lysosomal membrane permeabilization (LMP

  6. Coronavirus cell entry occurs through the endo-/lysosomal pathway in a proteolysis-dependent manner.

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    Christine Burkard

    2014-11-01

    Full Text Available Enveloped viruses need to fuse with a host cell membrane in order to deliver their genome into the host cell. While some viruses fuse with the plasma membrane, many viruses are endocytosed prior to fusion. Specific cues in the endosomal microenvironment induce conformational changes in the viral fusion proteins leading to viral and host membrane fusion. In the present study we investigated the entry of coronaviruses (CoVs. Using siRNA gene silencing, we found that proteins known to be important for late endosomal maturation and endosome-lysosome fusion profoundly promote infection of cells with mouse hepatitis coronavirus (MHV. Using recombinant MHVs expressing reporter genes as well as a novel, replication-independent fusion assay we confirmed the importance of clathrin-mediated endocytosis and demonstrated that trafficking of MHV to lysosomes is required for fusion and productive entry to occur. Nevertheless, MHV was shown to be less sensitive to perturbation of endosomal pH than vesicular stomatitis virus and influenza A virus, which fuse in early and late endosomes, respectively. Our results indicate that entry of MHV depends on proteolytic processing of its fusion protein S by lysosomal proteases. Fusion of MHV was severely inhibited by a pan-lysosomal protease inhibitor, while trafficking of MHV to lysosomes and processing by lysosomal proteases was no longer required when a furin cleavage site was introduced in the S protein immediately upstream of the fusion peptide. Also entry of feline CoV was shown to depend on trafficking to lysosomes and processing by lysosomal proteases. In contrast, MERS-CoV, which contains a minimal furin cleavage site just upstream of the fusion peptide, was negatively affected by inhibition of furin, but not of lysosomal proteases. We conclude that a proteolytic cleavage site in the CoV S protein directly upstream of the fusion peptide is an essential determinant of the intracellular site of fusion.

  7. The role of mitochondrial DNA mutation on neurodegenerative diseases.

    Science.gov (United States)

    Cha, Moon-Yong; Kim, Dong Kyu; Mook-Jung, Inhee

    2015-03-13

    Many researchers have reported that oxidative damage to mitochondrial DNA (mtDNA) is increased in several age-related disorders. Damage to mitochondrial constituents and mtDNA can generate additional mitochondrial dysfunction that may result in greater reactive oxygen species production, triggering a circular chain of events. However, the mechanisms underlying this vicious cycle have yet to be fully investigated. In this review, we summarize the relationship of oxidative stress-induced mitochondrial dysfunction with mtDNA mutation in neurodegenerative disorders.

  8. REM behaviour disorder detection associated with neurodegenerative diseases

    DEFF Research Database (Denmark)

    Kempfner, Jacob; Sorensen, Gertrud; Zoetmulder, Marielle

    2010-01-01

    Abnormal skeleton muscle activity during REM sleep is characterized as REM Behaviour Disorder (RBD), and may be an early marker for different neurodegenerative diseases. Early detection of RBD is therefore highly important, and in this ongoing study a semi-automatic method for RBD detection......, a computerized algorithm has been attempted implemented. By analysing the REM and non-REM EMG activity, using advanced signal processing tools combined with a statistical classifier, it is possible to discriminate normal and abnormal EMG activity. Due to the small number of patients, the overall performance...

  9. Stem cell treatment for age-related neurodegenerative diseases

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    Nurković J.

    2015-01-01

    Full Text Available The belief in the inability of neurogenesis, that is the inability to create new neurons after embryonic and early postnatal development of the central nervous system, was rejected in the mid-nineties, when the existence of neurogenesis in restricted areas of CNS adult mammals, including humans, was discovered.Transplantation of stem cells or their derivatives into respective tissues or organs is considered as one of the most promising remedies for many incurable diseases.In this review, we summarized current knowledge and present and future perspectives andchallenges regarding stem cells treatment for Parkinson's and Alzheimer's disease, as the most common age-related neurodegenerative diseases.

  10. Inducerede pluripotente stamceller revolutionerer forskningen i neurodegenerative sygdomme

    DEFF Research Database (Denmark)

    Schmidt, Sissel Ida; Jul Knudsen, Matias; Bogetofte Thomasen, Helle

    2016-01-01

    Research into the causes of neurodegenerative diseases like Parkinson's- and Alzheimer's disease has long been hampered by the lack of access to live disease-afflicted neurons for in vitro studies. The introduction of induced pluripotent stem (iPS) cells has made such studies possible. iPS cells...... can be reprogrammed from somatic patient-derived cells (e.g. skin cells) and differentiated into any cell type of the body. This allows for the production of neurons, which have the genetic background of the patients and show disease-relevant phenotypes....

  11. Combined effects of thermal stress and Cd on lysosomal biomarkers and transcription of genes encoding lysosomal enzymes and HSP70 in mussels, Mytilus galloprovincialis

    Energy Technology Data Exchange (ETDEWEB)

    Izagirre, Urtzi; Errasti, Aitzpea; Bilbao, Eider; Múgica, María; Marigómez, Ionan, E-mail: ionan.marigomez@ehu.es

    2014-04-01

    Highlights: • Thermal stress and Cd caused lysosomal enlargement and membrane destabilisation. • hex, gusb and ctsl but not hsp70 were up-regulated at elevated temperature but down-regulated by Cd. • Thermal stress influenced lysosomal responses to Cd exposure. • The presence of Cd jeopardised responsiveness against thermal stress. - Abstract: In estuaries and coastal areas, intertidal organisms may be subject to thermal stress resulting from global warming, together with pollution. In the present study, the combined effects of thermal stress and exposure to Cd were investigated in the endo-lysosomal system of digestive cells in mussels, Mytilus galloprovincialis. Mussels were maintained for 24 h at 18 °C and 26 °C seawater temperature in absence and presence of 50 μg Cd/L seawater. Cadmium accumulation in digestive gland tissue, lysosomal structural changes and membrane stability were determined. Semi-quantitative PCR was applied to reveal the changes elicited by the different experimental conditions in hexosaminidase (hex), β-glucuronidase (gusb), cathepsin L (ctsl) and heat shock protein 70 (hsp70) gene transcription levels. Thermal stress provoked lysosomal enlargement whilst Cd-exposure led to fusion of lysosomes. Both thermal stress and Cd-exposure caused lysosomal membrane destabilisation. hex, gusb and ctsl genes but not hsp70 gene were transcriptionally up-regulated as a result of thermal stress. In contrast, all the studied genes were transcriptionally down-regulated in response to Cd-exposure. Cd bioaccumulation was comparable at 18 °C and 26 °C seawater temperatures but interactions between thermal stress and Cd-exposure were remarkable both in lysosomal biomarkers and in gene transcription. hex, gusb and ctsl genes, reacted to elevated temperature in absence of Cd but not in Cd-exposed mussels. Therefore, thermal stress resulting from global warming might influence the use and interpretation of lysosomal biomarkers in marine pollution

  12. A Two-Photon Fluorescent Probe for Lysosomal Thiols in Live Cells and Tissues

    Science.gov (United States)

    Fan, Jiangli; Han, Zhichao; Kang, Yao; Peng, Xiaojun

    2016-01-01

    Lysosome-specific fluorescent probes are exclusive to elucidate the functions of lysosomal thiols. Moreover, two-photon microscopy offers advantages of less phototoxicity, better three dimensional spatial localization, deeper penetration depth and lower self-absorption. However, such fluorescent probes for thiols are still rare. In this work, an efficient two-photon fluorophore 1,8-naphthalimide-based probe conjugating a 2,4-dinitrobenzenesulfonyl chloride and morpholine was designed and synthesized, which exhibited high selectivity and sensitivity towards lysosomal thiols by turn-on fluorescence method quantitatively and was successfully applied to the imaging of thiols in live cells and tissues by two-photon microscopy.

  13. Energy storage

    CERN Document Server

    Brunet, Yves

    2013-01-01

    Energy storage examines different applications such as electric power generation, transmission and distribution systems, pulsed systems, transportation, buildings and mobile applications. For each of these applications, proper energy storage technologies are foreseen, with their advantages, disadvantages and limits. As electricity cannot be stored cheaply in large quantities, energy has to be stored in another form (chemical, thermal, electromagnetic, mechanical) and then converted back into electric power and/or energy using conversion systems. Most of the storage technologies are examined: b

  14. Effect of milk extract of Semecarpus anacardium nuts on glycohydrolases and lysosomal stability in adjuvant arthritis in rats.

    Science.gov (United States)

    Vijayalakshmi, T; Muthulakshmi, V; Sachdanandam, P

    1997-09-01

    Lysosomal acid hydrolases are thought to play an important role in inflammation associated with rheumatoid arthritis. A Siddha preparation of Semecarpus anacardium nut extract called Serankottai Nei was tested for its capacity to stabilize lysosomes obtained from liver and kidney of adjuvant-induced arthritic animals. Lysosomal membrane stability was measured by determining the release of acid hydrolases from the lysosomes. The drug was administered at a dose level of 150 mg/kg body weight for 14 days to arthritic animals after the adjuvant injection. The total and free activity of lysosomal enzymes were significantly increased in arthritic rats with concomitant increase in plasma levels of protein-bound carbohydrates. Significantly increased lysosomal membrane fragility as observed in arthritic condition was reduced in drug-treated animals. Antiarthritic activity of the drug through its stabilizing action on lysosomal membranes could be inferred from this study.

  15. Ghrelin: a link between ageing, metabolism and neurodegenerative disorders.

    Science.gov (United States)

    Stoyanova, I I

    2014-12-01

    Along with the increase in life expectancy over the last century comes the increased risk for development of age-related disorders, including metabolic and neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases. These chronic disorders share two main characteristics: 1) neuronal loss in motor, sensory or cognitive systems, leading to cognitive and motor decline; and 2) a strong correlation between metabolic changes and neurodegeneration. In order to treat them, a better understanding of their complexity is required: it is necessary to interpret the neuronal damage in light of the metabolic changes, and to find the disrupted link between the peripheral organs governing energy metabolism and the CNS. This review is an attempt to present ghrelin as part of molecular regulatory interface between energy metabolism, neuroendocrine and neurodegenerative processes. Ghrelin takes part in lipid and glucose metabolism, in higher brain functions such as sleep-wake state, learning and memory consolidation; it influences mitochondrial respiration and shows neuroprotective effect. All these make ghrelin an attractive target for development of biomarkers or therapeutics for prevention or treatment of disorders, in which cell protection and recruitment of new neurons or synapses are needed. Copyright © 2014. Published by Elsevier Inc.

  16. Multifaceted effects of aluminium in neurodegenerative diseases: A review.

    Science.gov (United States)

    Maya, S; Prakash, T; Madhu, Krishna Das; Goli, Divakar

    2016-10-01

    Aluminium (Al) is the most common metal and widely distributed in our environment. Al was first isolated as an element in 1827, and its use began only after 1886. Al is widely used for industrial applications and consumer products. Apart from these it is also used in cooking utensils and in pharmacological agents, including antacids and antiperspirants from which the element usually enters into the human body. Evidence for the neurotoxicity of Al is described in various studies, but still the exact mechanism of Al toxicity is not known. However, the evidence suggests that the Al can potentiate oxidative stress and inflammatory events and finally leads to cell death. Al is considered as a well-established neurotoxin and have a link between the exposure and development of neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), dementia, Gulf war syndrome and Parkinsonism. Here, we review the detailed possible pathogenesis of Al neurotoxicity. This review summarizes Al induced events likewise oxidative stress, cell mediated toxicity, apoptosis, inflammatory events in the brain, glutamate toxicity, effects on calcium homeostasis, gene expression and Al induced Neurofibrillary tangle (NFT) formation. Apart from these we also discussed animal models that are commonly used for Al induced neurotoxicity and neurodegeneration studies. These models help to find out a better way to treat and prevent the progression in Al induced neurodegenerative diseases. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Lee J. Martin

    2010-03-01

    Full Text Available Alzheimer’s disease (AD, Parkinson’s disease (PD and amyotrophic lateral sclerosis (ALS are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal cell death are unresolved. Morphological, biochemical, genetic, as well as cell and animal model studies reveal that mitochondria could have roles in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations, triggering neurodegeneration according to a cell death matrix theory. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Aβ and amyloid precursor protein have been reported. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review summarizes how mitochondrial pathobiology might contribute to neuronal death in AD, PD, and ALS and could serve as a target for drug therapy.

  18. Cerebellum and neurodegenerative diseases: Beyond conventional magnetic resonance imaging

    Science.gov (United States)

    Mormina, Enricomaria; Petracca, Maria; Bommarito, Giulia; Piaggio, Niccolò; Cocozza, Sirio; Inglese, Matilde

    2017-01-01

    The cerebellum plays a key role in movement control and in cognition and cerebellar involvement is described in several neurodegenerative diseases. While conventional magnetic resonance imaging (MRI) is widely used for brain and cerebellar morphologic evaluation, advanced MRI techniques allow the investigation of cerebellar microstructural and functional characteristics. Volumetry, voxel-based morphometry, diffusion MRI based fiber tractography, resting state and task related functional MRI, perfusion, and proton MR spectroscopy are among the most common techniques applied to the study of cerebellum. In the present review, after providing a brief description of each technique’s advantages and limitations, we focus on their application to the study of cerebellar injury in major neurodegenerative diseases, such as multiple sclerosis, Parkinson’s and Alzheimer’s disease and hereditary ataxia. A brief introduction to the pathological substrate of cerebellar involvement is provided for each disease, followed by the review of MRI studies exploring structural and functional cerebellar abnormalities and by a discussion of the clinical relevance of MRI measures of cerebellar damage in terms of both clinical status and cognitive performance. PMID:29104740

  19. Perspective Insights of Exosomes in Neurodegenerative Diseases: A Critical Appraisal

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    Arif Tasleem Jan

    2017-09-01

    Full Text Available Exosomes are small membranous entities of endocytic origin. Their production by a wide variety of cells in eukaryotes implicates their roles in the execution of essential processes, especially cellular communication. Exosomes are secreted under both physiological and pathophysiological conditions, and their actions on neighboring and distant cells lead to the modulations of cellular behaviors. They also assist in the delivery of disease causing entities, such as prions, α-syn, and tau, and thus, facilitate spread to non-effected regions and accelerate the progressions of neurodegenerative diseases. The characterization of exosomes, provides information on aberrant processes, and thus, exosome analysis has many clinical applications. Because they are associated with the transport of different cellular entities across the blood-brain barrier (BBB, exosomes might be useful for delivering drugs and other therapeutic molecules to brain. Herein, we review roles played by exosomes in different neurodegenerative diseases, and the possibilities of using them as diagnostic biomarkers of disease progression, drug delivery vehicles and in gene therapy.

  20. Perspective Insights of Exosomes in Neurodegenerative Diseases: A Critical Appraisal

    Science.gov (United States)

    Jan, Arif Tasleem; Malik, Mudasir A.; Rahman, Safikur; Yeo, Hye R.; Lee, Eun J.; Abdullah, Tasduq S.; Choi, Inho

    2017-01-01

    Exosomes are small membranous entities of endocytic origin. Their production by a wide variety of cells in eukaryotes implicates their roles in the execution of essential processes, especially cellular communication. Exosomes are secreted under both physiological and pathophysiological conditions, and their actions on neighboring and distant cells lead to the modulations of cellular behaviors. They also assist in the delivery of disease causing entities, such as prions, α-syn, and tau, and thus, facilitate spread to non-effected regions and accelerate the progressions of neurodegenerative diseases. The characterization of exosomes, provides information on aberrant processes, and thus, exosome analysis has many clinical applications. Because they are associated with the transport of different cellular entities across the blood-brain barrier (BBB), exosomes might be useful for delivering drugs and other therapeutic molecules to brain. Herein, we review roles played by exosomes in different neurodegenerative diseases, and the possibilities of using them as diagnostic biomarkers of disease progression, drug delivery vehicles and in gene therapy. PMID:29033828

  1. Microbiota-Brain-Gut Axis and Neurodegenerative Diseases.

    Science.gov (United States)

    Quigley, Eamonn M M

    2017-10-17

    The purposes of this review were as follows: first, to provide an overview of the gut microbiota and its interactions with the gut and the central nervous system (the microbiota-gut-brain axis) in health, second, to review the relevance of this axis to the pathogenesis of neurodegenerative diseases, such as Parkinson's disease, and, finally, to assess the potential for microbiota-targeted therapies. Work on animal models has established the microbiota-gut-brain axis as a real phenomenon; to date, the evidence for its operation in man has been limited and has been confronted by considerable logistical challenges. Animal and translational models have incriminated a disturbed gut microbiota in a number of CNS disorders, including Parkinson's disease; data from human studies is scanty. While a theoretical basis can be developed for the use of microbiota-directed therapies in neurodegenerative disorders, support is yet to come from high-quality clinical trials. In theory, a role for the microbiota-gut-brain axis is highly plausible; clinical confirmation is awaited.

  2. Hormone Replacement Therapy and Risk for Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Richelin V. Dye

    2012-01-01

    Full Text Available Over the past two decades, there has been a significant amount of research investigating the risks and benefits of hormone replacement therapy (HRT with regards to neurodegenerative disease. Here, we review basic science studies, randomized clinical trials, and epidemiological studies, and discuss the putative neuroprotective effects of HRT in the context of Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia, and HIV-associated neurocognitive disorder. Findings to date suggest a reduced risk of Alzheimer’s disease and improved cognitive functioning of postmenopausal women who use 17β-estradiol. With regards to Parkinson’s disease, there is consistent evidence from basic science studies for a neuroprotective effect of 17β-estradiol; however, results of clinical and epidemiological studies are inconclusive at this time, and there is a paucity of research examining the association between HRT and Parkinson’s-related neurocognitive impairment. Even less understood are the effects of HRT on risk for frontotemporal dementia and HIV-associated neurocognitive disorder. Limits to the existing research are discussed, along with proposed future directions for the investigation of HRT and neurodegenerative diseases.

  3. Magnesium Modulates Doxorubicin Activity through Drug Lysosomal Sequestration and Trafficking.

    Science.gov (United States)

    Trapani, Valentina; Luongo, Francesca; Arduini, Daniela; Wolf, Federica I

    2016-03-21

    Magnesium is directly involved in the control of cell growth and survival, but its role in cancer biology and therapy is multifaceted; in particular, it is highly controversial whether magnesium levels can affect therapy outcomes. Here we investigated whether magnesium availability can modulate cellular responses to the widely used chemotherapeutic doxorubicin. We used an in vitro model consisting of mammary epithelial HC11 cells and found that high magnesium availability was correlated with diminished sensitivity both in cells chronically adapted to high magnesium concentrations and in acutely magnesium-supplemented cells. This decrease in sensitivity resulted from reduced intracellular doxorubicin accumulation in the face of a similar drug uptake rate. We observed that high-magnesium conditions caused a decrease in intracellular drug retention by altering drug lysosomal sequestration and trafficking. In our model, magnesium supplementation correspondingly modulated expression of the TRPM7 channel, which is known to control cytoskeletal organization and dynamics and may be involved in the proposed mechanism. Our findings suggest that magnesium supplementation in hypomagnesemic cancer patients may hinder response to therapy.

  4. Atomic storage

    CERN Multimedia

    Ricadela, A

    2003-01-01

    IBM is supplying CERN, the European Organization for Nuclear Research, with its Storage Tank file system virtualization software, 20 terabytes of storage capacity, and services under a three-year deal to build computer systems that will support the Large Hadron Collider accelerator (1 paragraph).

  5. Lysosome biogenesis mediated by vps-18 affects apoptotic cell degradation in Caenorhabditis elegans.

    Science.gov (United States)

    Xiao, Hui; Chen, Didi; Fang, Zhou; Xu, Jing; Sun, Xiaojuan; Song, Song; Liu, Jiajia; Yang, Chonglin

    2009-01-01

    Appropriate clearance of apoptotic cells (cell corpses) is an important step of programmed cell death. Although genetic and biochemical studies have identified several genes that regulate the engulfment of cell corpses, how these are degraded after being internalized in engulfing cell remains elusive. Here, we show that VPS-18, the Caenorhabditis elegans homologue of yeast Vps18p, is critical to cell corpse degradation. VPS-18 is expressed and functions in engulfing cells. Deletion of vps-18 leads to significant accumulation of cell corpses that are not degraded properly. Furthermore, vps-18 mutation causes strong defects in the biogenesis of endosomes and lysosomes, thus affecting endosomal/lysosomal protein degradation. Importantly, we demonstrate that phagosomes containing internalized cell corpses are unable to fuse with lysosomes in vps-18 mutants. Our findings thus provide direct evidence for the important role of endosomal/lysosomal degradation in proper clearance of apoptotic cells during programmed cell death.

  6. A TRP Channel Senses Lysosome Neutralization by Pathogens to Trigger Their Expulsion

    Science.gov (United States)

    Miao, Yuxuan; Li, Guojie; Zhang, Xiaoli; Xu, Haoxing; Abraham, Soman N.

    2015-01-01

    SUMMARY Vertebrate cells have evolved elaborate cell-autonomous defense programs to monitor subcellular compartments for infection and to evoke counter-responses. These programs are activated by pathogen-associated pattern molecules and by various strategies intracellular pathogens employ to alter cellular microenvironments. Here, we show that when uropathogenic E. coli (UPEC) infect bladder epithelial cells (BECs), they are targeted by autophagy but avoid degradation because of their capacity to neutralize lysosomal pH. This change is detected by mucolipin TRP channel 3 (TRPML3), a transient receptor potential cation channel localized to lysosomes. TRPML3 activation then spontaneously initiates lysosome exocytosis, resulting in expulsion of exosome-encased bacteria. These studies reveal a cellular default system for lysosome homeostasis that has been co-opted by the autonomous defense program to clear recalcitrant pathogens. PMID:26027738

  7. Lysosome-Targeting Amplifiers of Reactive Oxygen Species as Anticancer Prodrugs

    Czech Academy of Sciences Publication Activity Database

    Daum, S.; Reshetnikov, M.S.V.; Šíša, Miroslav; Dumych, T.; Lootsik, M. D.; Bilyy, R.; Bila, E.; Janko, C.; Alexiou, C.; Herrmann, M.; Sellner, L.; Mokhir, A.

    2017-01-01

    Roč. 56, č. 49 (2017), s. 15545-15549 ISSN 1433-7851 Institutional support: RVO:61389030 Keywords : aminoferrocene * cancer * lysosomes * prodrugs * reactive oxygen species Subject RIV: ED - Physiology Impact factor: 11.994, year: 2016

  8. Lysosome associated membrane proteins maintain pancreatic acinar cell homeostasis : LAMP-2 deficient mice develop pancreatitis

    NARCIS (Netherlands)

    Mareninova, Olga A; Sendler, Matthias; Malla, Sudarshan Ravi; Yakubov, Iskandar; French, Samuel W; Tokhtaeva, Elmira; Vagin, Olga; Oorschot, Viola; Lüllmann-Rauch, Renate; Blanz, Judith; Dawson, David; Klumperman, Judith; Lerch, Markus M; Mayerle, Julia; Gukovsky, Ilya; Gukovskaya, Anna S

    2015-01-01

    BACKGROUND & AIMS: The pathogenic mechanism of pancreatitis is poorly understood. Recent evidence implicates defective autophagy in pancreatitis responses; however, the pathways mediating impaired autophagy in pancreas remain largely unknown. Here, we investigate the role of lysosome associated

  9. Neuronal-Targeted TFEB Accelerates Lysosomal Degradation of APP, Reducing Aβ Generation and Amyloid Plaque Pathogenesis.

    Science.gov (United States)

    Xiao, Qingli; Yan, Ping; Ma, Xiucui; Liu, Haiyan; Perez, Ronaldo; Zhu, Alec; Gonzales, Ernesto; Tripoli, Danielle L; Czerniewski, Leah; Ballabio, Andrea; Cirrito, John R; Diwan, Abhinav; Lee, Jin-Moo

    2015-09-02

    In AD, an imbalance between Aβ production and removal drives elevated brain Aβ levels and eventual amyloid plaque deposition. APP undergoes nonamyloidogenic processing via α-cleavage at the plasma membrane, amyloidogenic β- and γ-cleavage within endosomes to generate Aβ, or lysosomal degradation in neurons. Considering multiple reports implicating impaired lysosome function as a driver of increased amyloidogenic processing of APP, we explored the efficacy of targeting transcription factor EB (TFEB), a master regulator of lysosomal pathways, to reduce Aβ levels. CMV promoter-driven TFEB, transduced via stereotactic hippocampal injections of adeno-associated virus particles in APP/PS1 mice, localized primarily to neuronal nuclei and upregulated lysosome biogenesis. This resulted in reduction of APP protein, the α and β C-terminal APP fragments (CTFs), and in the steady-state Aβ levels in the brain interstitial fluid. In aged mice, total Aβ levels and amyloid plaque load were selectively reduced in the TFEB-transduced hippocampi. TFEB transfection in N2a cells stably expressing APP695, stimulated lysosome biogenesis, reduced steady-state levels of APP and α- and β-CTFs, and attenuated Aβ generation by accelerating flux through the endosome-lysosome pathway. Cycloheximide chase assays revealed a shortening of APP half-life with exogenous TFEB expression, which was prevented by concomitant inhibition of lysosomal acidification. These data indicate that TFEB enhances flux through lysosomal degradative pathways to induce APP degradation and reduce Aβ generation. Activation of TFEB in neurons is an effective strategy to attenuate Aβ generation and attenuate amyloid plaque deposition in AD. A key driver for AD pathogenesis is the net balance between production and clearance of Aβ, the major component of amyloid plaques. Here we demonstrate that lysosomal degradation of holo-APP influences Aβ production by limiting the availability of APP for amyloidogenic

  10. Lysosomal exocytosis in response to subtle membrane damage following nanosecond pulse exposure

    Science.gov (United States)

    Dalzell, Danielle R.; Roth, Caleb C.; Bernhard, Joshua A.; Payne, Jason A.; Wilmink, Gerald J.; Ibey, Bennett L.

    2011-03-01

    The cellular response to subtle membrane damage following exposure to nanosecond electric pulses (nsEP) is not well understood. Recent work has shown that when cells are exposed to nsEP, ion permeable nanopores ( 2nm) created by longer micro and millisecond duration pulses. Macroscopic damage to a plasma membrane by a micropipette has been shown to cause internal vesicles (lysosomes) to undergo exocytosis to repair membrane damage, a calcium mediated process called lysosomal exocytosis. Formation of large pores in the plasma membrane by electrical pulses has been shown to elicit lysosomal exocytosis in a variety of cell types. Our research objective is to determine whether lysosomal exocytosis will occur in response to nanopores formed by exposure to nsEP. In this paper we used propidium iodide (PI) and Calcium Green-1 AM ester (CaGr) to differentiate between large and small pores formed in CHO-K1 cells following exposure to either 1 or 20, 600-ns duration electrical pulses at 16.2 kV/cm. This information was compared to changes in membrane organization observed by increases in FM1-43 fluorescence, both in the presence and absence of calcium ions in the outside buffer. In addition, we monitored the real time migration of lysosomes within the cell using Cellular Lights assay to tag LAMP-1, a lysosomal membrane protein. Both 1 and 20 pulses elicited a large influx of extracellular calcium, while little PI uptake was observed following a single pulse exposure. Statistically significant increases in FM1-43 fluorescence were seen in samples containing calcium suggesting that calcium-triggered membrane repair may be occurring. Lastly, density of lysosomes within cells, specifically around the nucleus, appeared to change rapidly upon nsEP stimulation suggesting lysosomal migration.

  11. Analysis of lysosomal membrane proteins exposed to melanin in HeLa cells

    OpenAIRE

    Bang, Seung Hyuck; Park, Dong Jun; Kim, Yang-Hoon; Min, Jiho

    2016-01-01

    Objectives There have been developed to use targeting ability for antimicrobial, anticancerous, gene therapy and cosmetics through analysis of various membrane proteins isolated from cell organelles. Methods It was examined about the lysosomal membrane protein extracted from lysosome isolated from HeLa cell treated by 100 ppm melanin for 24 hours in order to find associated with targeting ability to melanin using by 2-dimensional electrophoresis. Results The result showed 14 up-regulated (1.5...

  12. Dual-stimuli responsive i-motif/nanoflares for sensing ATP in lysosomes.

    Science.gov (United States)

    Jin, Fen; Zheng, Jing; Liu, Changhui; Yang, Sheng; Li, Yinhui; Li, Jishan; Lian, Yan; Yang, Ronghua

    2014-08-07

    A dual-stimuli responsive i-motif/nanoflare for molecule detection in lysosomes was designed. By combining the structure-switchable i-motif sequence and high recognition ability of an adenosine triphosphate (ATP) aptamer, subcellular sensing and visualization sensing of ATP in lysosomes at the subcellular level can be achieved. This general sensing technique can be applied for a broad range of cellular communication studies to improve our understanding of subcellular signaling and function.

  13. Eps8 is recruited to lysosomes and subjected to chaperone-mediated autophagy in cancer cells.

    Science.gov (United States)

    Welsch, Thilo; Younsi, Alexander; Disanza, Andrea; Rodriguez, Jose Antonio; Cuervo, Ana Maria; Scita, Giorgio; Schmidt, Jan

    2010-07-15

    Eps8 controls actin dynamics directly through its barbed end capping and actin-bundling activity, and indirectly by regulating Rac-activation when engaged into a trimeric complex with Eps8-Abi1-Sos1. Recently, Eps8 has been associated with promotion of various solid malignancies, but neither its mechanisms of action nor its regulation in cancer cells have been elucidated. Here, we report a novel association of Eps8 with the late endosomal/lysosomal compartment, which is independent from actin polymerization and specifically occurs in cancer cells. Endogenous Eps8 localized to large vesicular lysosomal structures in metastatic pancreatic cancer cell lines, such as AsPC-1 and Capan-1 that display high Eps8 levels. Additionally, ectopic expression of Eps8 increased the size of lysosomes. Structure-function analysis revealed that the region encompassing the amino acids 184-535 of Eps8 was sufficient to mediate lysosomal recruitment. Notably, this fragment harbors two KFERQ-like motifs required for chaperone-mediated autophagy (CMA). Furthermore, Eps8 co-immunoprecipitated with Hsc70 and LAMP-2, which are key elements for the CMA degradative pathway. Consistently, in vitro, a significant fraction of Eps8 bound to (11.9+/-5.1%) and was incorporated into (5.3+/-6.5%) lysosomes. Additionally, Eps8 binding to lysosomes was competed by other known CMA-substrates. Fluorescence recovery after photobleaching revealed that Eps8 recruitment to the lysosomal membrane was highly dynamic. Collectively, these results indicate that Eps8 in certain human cancer cells specifically localizes to lysosomes, and is directed to CMA. These results open a new field for the investigation of how Eps8 is regulated and contributes to tumor promotion in human cancers.

  14. Uptake and degradation of cytoplasmic RNA by lysosomes in the perfused rat liver

    Energy Technology Data Exchange (ETDEWEB)

    Heydrick, S.J.; Lardeux, B.; Mortimore, G.E.

    1987-05-01

    The release of (/sup 14/C)cytidine has been shown previously to be a valid marker for RNA degradation in rat hepatocytes. The breakdown of RNA measured with this marker in perfused livers prelabeled in vivo with (6-/sup 14/C)orotic acid was found to be regulated acutely by perfusate amino acids over a wide range, from 0.29 to 3.48%/h. This regulation paralleled that of lysosomal proteolysis. Chloroquine inhibited RNA degradation 60-70%. In subsequent cell fractionation studies labelled cytidine was released; the distribution of this release paralleled that of a lysosomal marker enzyme. The release plateaued after two hours, defining a distinct lysosomal pool of RNA. The lysosomal location of the RNA pool was confirmed in experiments where a 22% increase in the apparent pool size was obtained by lowering the homogenate pH from 7.0 to 5.5. The pool size correlated linearly with the rate of RNA degradation measured during perfusion, giving a turnover constant in reasonable agreement with values reported for autophagy. These results indicate that cytoplasmic RNA degradation occurs primarily in the lysosome and is regulated under these conditions by the amino acid control of lysosomal sequestration of cytoplasm.

  15. An efficient ratiometric fluorescent probe for tracking dynamic changes in lysosomal pH.

    Science.gov (United States)

    Wang, Qianqian; Zhou, Liyi; Qiu, Liping; Lu, Danqing; Wu, Yongxiang; Zhang, Xiao-Bing

    2015-08-21

    Lysosomes are acidic organelles (approximately pH 4.5-5.5) and tracking the changes in lysosomal pH is of great biological importance. To address this issue, quite a few of fluorescent probes have been developed. However, few of these probes can realize the tracking of dynamic changes in lysosomal pH. Herein, we report a new lysosome-targeted ratiometric fluorescent probe (FR-Lys) by hybridizing morpholine with a xanthane derivative and an o-hydroxy benzoxazole group. In this probe, the morpholine group serves as a targeting unit for lysosome, the xanthane derivative exhibits a pH-modulated open/close reaction of the spirocycle, while the o-hydroxy benzoxazole moiety shows a pH modulated excited-state intramolecular proton transfer (ESIPT) process. Such a design affords the probe a ratiometric fluorescence response towards pH with pH values ranging from 4.0 to 6.3. The response of the probe to pH was fast and reversible with high selectivity. Moreover, this probe possesses further advantages such as easy synthesis, high photostability and low cytotoxicity. These features are favorable for tracking dynamic pH changes in biosystems. It was then applied for dynamic imaging pH changes in lysosomes with satisfactory results.

  16. Wilson disease protein ATP7B utilizes lysosomal exocytosis to maintain copper homeostasis.

    Science.gov (United States)

    Polishchuk, Elena V; Concilli, Mafalda; Iacobacci, Simona; Chesi, Giancarlo; Pastore, Nunzia; Piccolo, Pasquale; Paladino, Simona; Baldantoni, Daniela; van IJzendoorn, Sven C D; Chan, Jefferson; Chang, Christopher J; Amoresano, Angela; Pane, Francesca; Pucci, Piero; Tarallo, Antonietta; Parenti, Giancarlo; Brunetti-Pierri, Nicola; Settembre, Carmine; Ballabio, Andrea; Polishchuk, Roman S

    2014-06-23

    Copper is an essential yet toxic metal and its overload causes Wilson disease, a disorder due to mutations in copper transporter ATP7B. To remove excess copper into the bile, ATP7B traffics toward canalicular area of hepatocytes. However, the trafficking mechanisms of ATP7B remain elusive. Here, we show that, in response to elevated copper, ATP7B moves from the Golgi to lysosomes and imports metal into their lumen. ATP7B enables lysosomes to undergo exocytosis through the interaction with p62 subunit of dynactin that allows lysosome translocation toward the canalicular pole of hepatocytes. Activation of lysosomal exocytosis stimulates copper clearance from the hepatocytes and rescues the most frequent Wilson-disease-causing ATP7B mutant to the appropriate functional site. Our findings indicate that lysosomes serve as an important intermediate in ATP7B trafficking, whereas lysosomal exocytosis operates as an integral process in copper excretion and hence can be targeted for therapeutic approaches to combat Wilson disease. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  17. [Changes in active cysteine cathepsins in lysosomes from tissues thyroid papillary carcinomas with various biological characteristics].

    Science.gov (United States)

    Kalinichenko, O V; Myshunina, T M; Tron'ko, M D

    2013-01-01

    To clarify possible role of cysteine cathepsin H, B and L in the proteolytic processes that contribute to the progression of tumor growth in the thyroid, we studied their activity in lysosomes isolated from the tissue of papillary carcinomas. It was shown that for these enzymes there is a dependence of the changes in their activity on a number of biological characteristics of the tumors. Thus, the sharp increase in the activity ofcathepsin H observed in lysosomes of tissue carcinomas category T2 and T3, with intra-and ekstrathyroid and lymphatic invasion of tumor cells. An increase in the activity of cathepsin B is set in the lysosomes of tissue heterogeneous follicular structure, especially in the presence of solid areas, in comparison with typical papillary tumors and in the lysosomes of tissue carcinomas in intrathyroid and cathepsin L-at extrathyroid invasion. A common feature of the enzymes is to increase the activity of cathepsins in lysosomes of tissue nonencapsulated papillary carcinomas. These enzymes probably do not take part in the invasion of tumor cells into blood vessels and in the mechanisms of tumor metastasis to regional lymph nodes. The latter shows no changes in the activity of cathepsins in lysosomes of tissue carcinomas category N1. The results indicate the different role of cathepsin H, B and L in thyroid carcinogenesis, where each enzyme has its specific function.

  18. Tay-Sachs Disease: MedlinePlus Health Topic

    Science.gov (United States)

    ... and Tutorials What Is Tay-Sachs Disease? (Dolan DNA Learning ... Articles References and abstracts from MEDLINE/PubMed (National Library of Medicine) Article: Mutation Frequency of Three Neurodegenerative Lysosomal Storage Diseases: From ...

  19. Computed tomography of neurodegenerative disease in childhood. Serial CT findings and their diagnostic values

    Energy Technology Data Exchange (ETDEWEB)

    Kataoka, Kenkichi; Nakagawa, Yoshihiro; Hojo, Hiroatsu

    1984-12-01

    Serial computed tomographic scans were performed on seven children with neurodegenerative disorders. In two cases of white-matter diseases (Krabbe's disease and metachromatic leukodystrophy), diffuse, low-density lesions of white matter were visible in the early stage of the diseases. In one case of adrenoleukodystrophy, regional low-density lesions of the white matter around the posterior horns and peculiar high-density strip lesions were visible in the early stage. In two cases of storage-type gray-matter diseases (Tay-Sachs' and infantile Gaucher's disease), there were no abnormalities in the early stage, but diffuse cortical atrophies in the late stage. In one case of Leigh's disease, there were small, low-density lesions of the basal ganglia and multiple low-density lesions of the gray matter in the early stage. In one case of subacute sclerosing panencephalitis, there were no abnormalities in the early stage, but small, low-density lesions of the basal ganglia and diffuse cerebral atrophies in the late stage. Diagnostic values were recognized dominantly in two cases of adrenoleukodystrophy and Leigh's disease. In the other cases, however, serial CT scans were useful in the diagnostic process. (author).

  20. Resting state brain networks and their implications in neurodegenerative disease

    Science.gov (United States)

    Sohn, William S.; Yoo, Kwangsun; Kim, Jinho; Jeong, Yong

    2012-10-01

    Neurons are the basic units of the brain, and form network by connecting via synapses. So far, there have been limited ways to measure the brain networks. Recently, various imaging modalities are widely used for this purpose. In this paper, brain network mapping using resting state fMRI will be introduced with several applications including neurodegenerative disease such as Alzheimer's disease, frontotemporal lobar degeneration and Parkinson's disease. The resting functional connectivity using intrinsic functional connectivity in mouse is useful since we can take advantage of perturbation or stimulation of certain nodes of the network. The study of brain connectivity will open a new era in understanding of brain and diseases thus will be an essential foundation for future research.

  1. Modelling Neurodegenerative Diseases Using Human Pluripotent Stem Cells

    DEFF Research Database (Denmark)

    Hall, Vanessa Jane

    2016-01-01

    Neurodegenerative diseases are being modelled in-vitro using human patient-specific, induced pluripotent stem cells and transgenic embryonic stem cells to determine more about disease mechanisms, as well as to discover new treatments for patients. Current research in modelling Alzheimer’s disease......, frontotemporal dementia and Parkinson’s disease using pluripotent stem cells is described, along with the advent of gene-editing, which has been the complimentary tool for the field. Current methods used to model these diseases are predominantly dependent on 2D cell culture methods. Outcomes reveal that only...... some of the phenotype can be observed in-vitro, but these phenotypes, when compared to the patient, correlate extremely well. Many studies have found novel molecular mechanisms involved in the disease and therefore elucidate new potential targets for reversing the phenotype. Future research...

  2. Memory in neurodegenerative disease: biological, cognitive, and clinical perspectives

    National Research Council Canada - National Science Library

    Tröster, Alexander I

    1998-01-01

    ...  . ,  . , - ,  .    .  36 4 Neurochemical aspects of memory dysfunction in neurodegenerative disease     .  87 5 Structural neuroimaging correlates...

  3. Adeno-associated viral gene delivery in neurodegenerative disease.

    Science.gov (United States)

    Morgenstern, Peter F; Marongiu, Roberta; Musatov, Sergei A; Kaplitt, Michael G

    2011-01-01

    The advent of viral gene therapy technology has contributed greatly to the study of a variety of medical conditions, and there is increasing promise for clinical translation of gene therapy into human treatments. Adeno-associated viral (AAV) vectors provide one of the more promising approaches to gene delivery, and have been used extensively over the last 20 years. Derived from nonpathogenic parvoviruses, these vectors allow for stable and robust expression of desired transgenes in vitro and in vivo. AAV vectors efficiently and stably transduce neurons, with some strains targeting neurons exclusively in the brain. Thus, AAV vectors are particularly useful for neurodegenerative diseases, which have led to numerous preclinical studies and several human trials of gene therapy in patients with Parkinson's disease, Alzheimer's disease, and pediatric neurogenetic disorders. Here, we describe an efficient and reliable method for the production and purification of AAV serotype 2 vectors for both in vitro and in vivo applications.

  4. Support system and method for detecting neurodegenerative disorder

    DEFF Research Database (Denmark)

    2013-01-01

    The present invention relates to a system and a method for detection of abnormal motor activity during REM sleep, and further to systems and method for assisting in detecting neurodegenerative disorders such as Parkinson's. One embodiment relates to a method for detection of abnormal motor activity...... during REM sleep comprising the steps of: performing polysomnographic recordings of a sleeping subject, thereby obtaining one or more electromyography (EMG) derivations, preferably surface EMG recordings, and one or more EEG derivations, and/or one or more electrooculargraphy (EOG) derivations, detecting...... one or more REM sleep stages, preferably based on the one or more EEG and/or EOG derivations, determining the level of muscle activity during the one or more REM sleep stages based on the one or more EMG derivations, wherein a subject having an increased level of muscle activity during REM sleep...

  5. Genetic manipulation for inherited neurodegenerative diseases: myth or reality?

    Science.gov (United States)

    Yu-Wai-Man, Patrick

    2016-10-01

    Rare genetic diseases affect about 7% of the general population and over 7000 distinct clinical syndromes have been described with the majority being due to single gene defects. This review will provide a critical overview of genetic strategies that are being pioneered to halt or reverse disease progression in inherited neurodegenerative diseases. This field of research covers a vast area and only the most promising treatment paradigms will be discussed with a particular focus on inherited eye diseases, which have paved the way for innovative gene therapy paradigms, and mitochondrial diseases, which are currently generating a lot of debate centred on the bioethics of germline manipulation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  6. Nanoparticles and Colloids as Contributing Factors in Neurodegenerative Disease

    Science.gov (United States)

    Bondy, Stephen C.

    2011-01-01

    This review explores the processes underlying the deleterious effects of the presence of insoluble or colloidal depositions within the central nervous system. These materials are chemically unreactive and can have a prolonged residence in the brain. They can be composed of mineral or proteinaceous materials of intrinsic or exogenous origin. Such nanoparticulates and colloids are associated with a range of slow-progressing neurodegenerative states. The potential common basis of toxicity of these materials is discussed. A shared feature of these disorders involves the appearance of deleterious inflammatory changes in the CNS. This may be due to extended and ineffective immune responses. Another aspect is the presence of excess levels of reactive oxygen species within the brain. In addition with their induction by inflammatory events, these may be further heightened by the presence of redox active transition metals to the large surface area afforded by nanoparticles and amphipathic micelles. PMID:21776226

  7. Targeting New Candidate Genes by Small Molecules Approaching Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Hueng-Chuen Fan

    2015-12-01

    Full Text Available Neurodegenerative diseases (NDs are among the most feared of the disorders that afflict humankind for the lack of specific diagnostic tests and effective treatments. Understanding the molecular, cellular, biochemical changes of NDs may hold therapeutic promise against debilitating central nerve system (CNS disorders. In the present review, we summarized the clinical presentations and biology backgrounds of NDs, including Parkinson’s disease (PD, Huntington’s disease (HD, and Alzheimer’s disease (AD and explored the role of molecular mechanisms, including dys-regulation of epigenetic control mechanisms, Ataxia-telangiectasia-mutated protein kinase (ATM, and neuroinflammation in the pathogenesis of NDs. Targeting these mechanisms may hold therapeutic promise against these devastating diseases.

  8. Codon usage biases in Alzheimer's disease and other neurodegenerative diseases.

    Science.gov (United States)

    Yang, Jie; Zhu, Tong-Yang; Jiang, Zheng-Xin; Chen, Cheng; Wang, Yue-Lan; Zhang, Song; Jiang, Xiong-Fei; Wang, Ting-Ting; Wang, Lin; Xia, Wen-Hao; Li, Lei; Chen, Ji-Jun; Wang, Jia-Yue; Wang, Wei-Wei; Zheng, Wei-Juan

    2010-05-01

    Establishing codon usage biases are crucial for understanding the etiology of central nervous system neurodegenerative diseases (CNSNDD) especially Alzheimer's disease (AD) as well as genetic factors. G and C ending codons are strongly biased in the coding sequences of these proteins as a result of genomic GC composition constraints. On the other hand, codons that identified as translationally optimal in the major trend all end in C or G, suggesting translational selection should also be taken into consideration additional to compositional constraints. Furthermore, this investigation reveals that three common codons, CGC (Arg), AGC (Ser), and GGC (Gly), are also critical in affecting codon usage bias. They not only can offer an insight into the codon usage bias of AD and its mechanism, but also may help in the possible cures for these diseases.

  9. Extracellular Vesicles in Brain Tumors and Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Federica Ciregia

    2017-08-01

    Full Text Available Extracellular vesicles (EVs can be classified into apoptotic bodies, microvesicles (MVs, and exosomes, based on their origin or size. Exosomes are the smallest and best characterized vesicles which derived from the endosomal system. These vesicles are released from many different cell types including neuronal cells and their functions in the nervous system are investigated. They have been proposed as novel means for intercellular communication, which takes part not only to the normal neuronal physiology but also to the transmission of pathogenic proteins. Indeed, exosomes are fundamental to assemble and transport proteins during development, but they can also transfer neurotoxic misfolded proteins in pathogenesis. The present review will focus on their roles in neurological diseases, specifically brain tumors, such as glioblastoma (GBM, neuroblastoma (NB, medulloblastoma (MB, and metastatic brain tumors and chronic neurodegenerative diseases, such as Alzheimer, Parkinson, multiple sclerosis (MS, amyotrophic lateral sclerosis (ALS, Huntington, and Prion diseseases highlighting their involvement in spreading neurotoxicity, in therapeutics, and in pathogenesis.

  10. Extracellular Vesicles in Brain Tumors and Neurodegenerative Diseases

    Science.gov (United States)

    Ciregia, Federica; Urbani, Andrea; Palmisano, Giuseppe

    2017-01-01

    Extracellular vesicles (EVs) can be classified into apoptotic bodies, microvesicles (MVs), and exosomes, based on their origin or size. Exosomes are the smallest and best characterized vesicles which derived from the endosomal system. These vesicles are released from many different cell types including neuronal cells and their functions in the nervous system are investigated. They have been proposed as novel means for intercellular communication, which takes part not only to the normal neuronal physiology but also to the transmission of pathogenic proteins. Indeed, exosomes are fundamental to assemble and transport proteins during development, but they can also transfer neurotoxic misfolded proteins in pathogenesis. The present review will focus on their roles in neurological diseases, specifically brain tumors, such as glioblastoma (GBM), neuroblastoma (NB), medulloblastoma (MB), and metastatic brain tumors and chronic neurodegenerative diseases, such as Alzheimer, Parkinson, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Huntington, and Prion diseseases highlighting their involvement in spreading neurotoxicity, in therapeutics, and in pathogenesis. PMID:28912682

  11. TFEB activation promotes the recruitment of lysosomal glycohydrolases β-hexosaminidase and β-galactosidase to the plasma membrane

    Energy Technology Data Exchange (ETDEWEB)

    Magini, Alessandro [Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia (Italy); Department of Medical and Biological Sciences (DSMB), University of Udine, Udine (Italy); Polchi, Alice; Urbanelli, Lorena [Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia (Italy); Cesselli, Daniela; Beltrami, Antonio [Department of Medical and Biological Sciences (DSMB), University of Udine, Udine (Italy); Tancini, Brunella [Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia (Italy); Emiliani, Carla, E-mail: carla.emiliani@unipg.it [Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia (Italy)

    2013-10-18

    Highlights: •TFEB activation promotes the increase of Hex and Gal activities. •The increase of Hex and Gal activities is related to transcriptional regulation. •TFEB promotes the recruitment of mature Hex and Gal on cell surface. -- Abstract: Lysosomes are membrane-enclosed organelles containing acid hydrolases. They mediate a variety of physiological processes, such as cellular clearance, lipid homeostasis, energy metabolism and pathogen defence. Lysosomes can secrete their content through a process called lysosome exocytosis in which lysosomes fuse with the plasma membrane realising their content into the extracellular milieu. Lysosomal exocytosis is not only responsible for the secretion of lysosomal enzymes, but it also has a crucial role in the plasma membrane repair. Recently, it has been demonstrated that lysosome response to the physiologic signals is regulated by the transcription factor EB (TFEB). In particular, lysosomal secretion is transcriptionally regulated by TFEB which induces both the docking and fusion of lysosomes with the plasma membrane. In this work we demonstrated that TFEB nuclear translocation is accompanied by an increase of mature glycohydrolases β-hexosaminidase and β-galactosidase on cell surface. This evidence contributes to elucidate an unknown TFEB biological function leading the lysosomal glycohydrolases on plasma membrane.

  12. The LAMP-like protein p67 plays an essential role in the lysosome of African trypanosomes.

    Science.gov (United States)

    Peck, Ronald F; Shiflett, April M; Schwartz, Kevin J; McCann, Amanda; Hajduk, Stephen L; Bangs, James D

    2008-05-01

    RNAi knockdown was employed to study the function of p67, a lysosome-associated membrane protein (LAMP)-like type I transmembrane lysosomal glycoprotein in African trypanosomes. Conditional induction of p67 dsRNA resulted in specific approximately 90% reductions in de novo p67 synthesis in both mammalian bloodstream and procyclic insect-stage parasites. Bloodstream cell growth was severely retarded with extensive death after > 24 h of induction. Biosynthetic trafficking of residual p67, and of the soluble lysosomal protease trypanopain, were unimpaired. Endocytosis of tomato lectin, a surrogate receptor-mediated cargo, was only mildly impaired (approximately 20%), but proper lysosomal targeting was unaffected. p67 ablation had dramatic effects on lysosomal morphology with gross enlargement (four- to fivefold) and internal membrane profiles reminiscent of autophagic vacuoles. Ablation of p67 expression rendered bloodstream trypanosomes refractory to lysis by human trypanolytic factor (TLF), a lysosomally activated host innate immune mediator. Similar effects on lysosomal morphology and TLF sensitivity were also obtained by two pharmacological agents that neutralize lysosomal pH--chloroquine and bafilomycin A1. Surprisingly, however, lysosomal pH was not affected in ablated cells suggesting that other physiological alterations must account for increased resistance to TLF. These results indicate p67 plays an essential role in maintenance of normal lysosomal structure and physiology in bloodstream-stage African trypanosomes.

  13. Impact of Plant-Derived Flavonoids on Neurodegenerative Diseases.

    Science.gov (United States)

    Costa, Silvia Lima; Silva, Victor Diogenes Amaral; Dos Santos Souza, Cleide; Santos, Cleonice Creusa; Paris, Irmgard; Muñoz, Patricia; Segura-Aguilar, Juan

    2016-07-01

    Neurodegenerative disorders have a common characteristic that is the involvement of different cell types, typically the reactivity of astrocytes and microglia, characterizing gliosis, which in turn contributes to the neuronal dysfunction and or death. Flavonoids are secondary metabolites of plant origin widely investigated at present and represent one of the most important and diversified among natural products phenolic groups. Several biological activities are attributed to this class of polyphenols, such as antitumor activity, antioxidant, antiviral, and anti-inflammatory, among others, which give significant pharmacological importance. Our group have observed that flavonoids derived from Brazilian plants Dimorphandra mollis Bent., Croton betulaster Müll. Arg., e Poincianella pyramidalis Tul., botanical synonymous Caesalpinia pyramidalis Tul. also elicit a broad spectrum of responses in astrocytes and neurons in culture as activation of astrocytes and microglia, astrocyte associated protection of neuronal progenitor cells, neuronal differentiation and neuritogenesis. It was observed the flavonoids also induced neuronal differentiation of mouse embryonic stem cells and human pluripotent stem cells. Moreover, with the objective of seeking preclinical pharmacological evidence of these molecules, in order to assess its future use in the treatment of neurodegenerative disorders, we have evaluated the effects of flavonoids in preclinical in vitro models of neuroinflammation associated with Parkinson's disease and glutamate toxicity associated with ischemia. In particular, our efforts have been directed to identify mechanisms involved in the changes in viability, morphology, and glial cell function induced by flavonoids in cultures of glial cells and neuronal cells alone or in interactions and clarify the relation with their neuroprotective and morphogetic effects.

  14. Adult Neurogenesis and Neurodegenerative Diseases: A Systems Biology Perspective

    Science.gov (United States)

    Horgusluoglu, Emrin; Nudelman, Kelly; Nho, Kwangsik; Saykin, Andrew J.

    2016-01-01

    New neurons are generated throughout adulthood in two regions of the brain, the olfactory bulb and dentate gyrus of the hippocampus, and are incorporated into the hippocampal network circuitry; disruption of this process has been postulated to contribute to neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. Known modulators of adult neurogenesis include signal transduction pathways, the vascular and immune systems, metabolic factors, and epigenetic regulation. Multiple intrinsic and extrinsic factors such as neurotrophic factors, transcription factors, and cell cycle regulators control neural stem cell proliferation, maintenance in the adult neurogenic niche, and differentiation into mature neurons; these factors act in networks of signaling molecules that influence each other during construction and maintenance of neural circuits, and in turn contribute to learning and memory. The immune system and vascular system are necessary for neuronal formation and neural stem cell fate determination. Inflammatory cytokines regulate adult neurogenesis in response to immune system activation, whereas the vasculature regulates the neural stem cell niche. Vasculature, immune/support cell populations (microglia/astrocytes), adhesion molecules, growth factors, and the extracellular matrix also provide a homing environment for neural stem cells. Epigenetic changes during hippocampal neurogenesis also impact memory and learning. Some genetic variations in neurogenesis related genes may play important roles in the alteration of neural stem cells differentiation into new born neurons during adult neurogenesis, with important therapeutic implications. In this review, we discuss mechanisms of and interactions between these modulators of adult neurogenesis, as well as implications for neurodegenerative disease and current therapeutic research. PMID:26879907

  15. Melatonin in Alzheimer's disease and other neurodegenerative disorders

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    Poeggeler B

    2006-05-01

    Full Text Available Abstract Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer's disease (AD, Parkinson's disease (PD and Huntington's disease (HD. As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-β toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning. Taken together, these findings suggest that melatonin

  16. Few patients with neurodegenerative disorders require spinal surgery

    Science.gov (United States)

    Epstein, Nancy E.; Gottesman, Malcolm

    2014-01-01

    Background: Few patients with neurodegenerative disorders (ND) (e.g., Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), and Postpolio Syndrome (PPS)) require spinal surgery. Typically, their neurological symptoms and signs reflect their underlying neurologic disorders rather than structural spinal pathology reported on magnetic resonance images (MR) or computed tomographic scans (CT). Methods: The first author, a neurosurgeon, reviewed 437 spinal consultations performed over a 20-month period. Of 254 patients seen in first opinion (e.g., had not been seen by a spinal surgeon), 9 had MS, while 2 had ALS. Of 183 patients seen in second opinion (e.g., prior spinal surgeons recommended surgery), 4 had MS, 2 had ALS, and 1 had PPS. We performed this study to establish how often patients with ND, seen in first or second opinion, require spinal surgery. We focused on whether second opinions from spinal surgeons would limit the number of operations offered to these patients. Results: Two of 11 patients with ND seen in first opinion required surgery. The first patient required a C5-7 laminectomy/C2-T2 fusion, followed by a L2-S1 laminectomy/L5S1 fusion. The second patient required a L2-L3 laminectomy/diskectomy/fusion. However, none of the seven patients seen in second opinion, who were previously told by outside surgeons they needed spinal surgery, required operations. Conclusions: Few patients with neurodegenerative syndromes (MS, ALS, PPS) and reported “significant” spondyloitic spinal disease interpreted on MR/CT studies required surgery. Great caution should be exercised in offering patients with ND spinal surgery, and second opinions should be encouraged to limit “unnecessary” procedures. PMID:24843817

  17. Adult neurogenesis and neurodegenerative diseases: A systems biology perspective.

    Science.gov (United States)

    Horgusluoglu, Emrin; Nudelman, Kelly; Nho, Kwangsik; Saykin, Andrew J

    2017-01-01

    New neurons are generated throughout adulthood in two regions of the brain, the olfactory bulb and dentate gyrus of the hippocampus, and are incorporated into the hippocampal network circuitry; disruption of this process has been postulated to contribute to neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Known modulators of adult neurogenesis include signal transduction pathways, the vascular and immune systems, metabolic factors, and epigenetic regulation. Multiple intrinsic and extrinsic factors such as neurotrophic factors, transcription factors, and cell cycle regulators control neural stem cell proliferation, maintenance in the adult neurogenic niche, and differentiation into mature neurons; these factors act in networks of signaling molecules that influence each other during construction and maintenance of neural circuits, and in turn contribute to learning and memory. The immune system and vascular system are necessary for neuronal formation and neural stem cell fate determination. Inflammatory cytokines regulate adult neurogenesis in response to immune system activation, whereas the vasculature regulates the neural stem cell niche. Vasculature, immune/support cell populations (microglia/astrocytes), adhesion molecules, growth factors, and the extracellular matrix also provide a homing environment for neural stem cells. Epigenetic changes during hippocampal neurogenesis also impact memory and learning. Some genetic variations in neurogenesis related genes may play important roles in the alteration of neural stem cells differentiation into new born neurons during adult neurogenesis, with important therapeutic implications. In this review, we discuss mechanisms of and interactions between these modulators of adult neurogenesis, as well as implications for neurodegenerative disease and current therapeutic research. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. Early Diagnosis and Monitoring of Neurodegenerative Langerhans Cell Histiocytosis.

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    Elena Sieni

    Full Text Available Neurodegenerative Langerhans Cell Histiocytosis (ND-LCH is a rare, unpredictable consequence that may devastate the quality of life of patients cured from LCH. We prospectively applied a multidisciplinary diagnostic work-up to early identify and follow-up patients with ND-LCH, with the ultimate goal of better determining the appropriate time for starting therapy.We studied 27 children and young adults with either ND-LCH verified by structural magnetic resonance imaging (MRI (group 1 or specific risk factors for (diabetes insipidus, craniofacial bone lesions, but no evidence of, neurodegenerative MRI changes (group 2. All patients underwent clinical, neurophysiological and MRI studies.Seventeen patients had MRI alterations typical for ND-LCH. Nine showed neurological impairment but only three were symptomatic; 11 had abnormal somatosensory evoked potentials (SEPs, and five had abnormal brainstem auditory evoked potentials (BAEPs. MR spectroscopy (MRS showed reduced cerebellar NAA/Cr ratio in nine patients. SEPs showed sensitivity, specificity, positive predictive value (PPV and negative predictive value (NPV for predicting ND-LCH of 70.6% (95%CI, 44.0%-89.7%, 100% (69.2%-100%, 100% (73.5%-100%, and 66.7% (38.4%-88.2%, respectively. Repeated investigations in group 1 revealed increasingly abnormal EP parameters, or neurological examination, or both, in nine of fifteen patients while MRI remained unchanged in all but one patient.A targeted MRI study should be performed in all patients with risk factors for ND-LCH for early identification of demyelination. The combined use of SEPs and careful neurological evaluation may represent a valuable, low-cost, well-tolerated and easily available methodology to monitor patients from pre-symptomatic to symptomatic stages. We suggest a multidisciplinary protocol including clinical, MRS, and neurophysiological investigations to identify a population target for future therapeutic trials.

  19. Does neuroinflammation fan the flame in neurodegenerative diseases?

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    McAlpine Fiona E

    2009-11-01

    Full Text Available Abstract While peripheral immune access to the central nervous system (CNS is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults. Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS. This acute neuroinflammatory response includes activation of the resident immune cells (microglia resulting in a phagocytic phenotype and the release of inflammatory mediators such as cytokines and chemokines. While an acute insult may trigger oxidative and nitrosative stress, it is typically short-lived and unlikely to be detrimental to long-term neuronal survival. In contrast, chronic neuroinflammation is a long-standing and often self-perpetuating neuroinflammatory response that persists long after an initial injury or insult. Chronic neuroinflammation includes not only long-standing activation of microglia and subsequent sustained release of inflammatory mediators, but also the resulting increased oxidative and nitrosative stress. The sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors. Neurodegenerative CNS disorders, including multiple sclerosis (MS, Alzheimer's disease (AD, Parkinson's disease (PD, Huntington's disease (HD, amyotrophic lateral sclerosis (ALS, tauopathies, and age-related macular degeneration (ARMD, are associated with chronic neuroinflammation and elevated levels of several cytokines. Here we review the hallmarks of acute and chronic inflammatory responses in the CNS, the reasons why microglial activation represents a convergence point for diverse stimuli that may promote or compromise neuronal survival, and the epidemiologic, pharmacologic and genetic evidence implicating neuroinflammation in the

  20. A neurodegenerative vascular burden index and the impact on cognition

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    Sebastian eHeinzel

    2014-07-01

    Full Text Available A wide range of vascular burden factors have been identified to impact vascular function and structure as indicated by carotid intima-media thickness (IMT. On the basis of their impact on IMT, vascular factors may be selected and clustered in a vascular burden index (VBI. Since many vascular factors increase the risk of Alzheimer's disease (AD, a multifactorial neurodegenerative VBI may be related to early pathological processes in AD and cognitive decline in its preclinical stages.We investigated an elderly cohort at risk for neurodegeneration (TREND study, n = 1102 for the multifactorial influence of vascular burden factors on IMT measured by ultrasound. To create a VBI for this cohort, vascular factors and their definitions (considering medical history, medication and/or blood marker data were selected based on their statistical effects on IMT in multiple regressions including age and sex. The impact of the VBI on cognitive performance was assessed using the Trail-Making Test (TMT and the CERAD neuropsychological battery.IMT was significantly predicted by age (standardized β = .26, sex (.09; males > females and the factors included in the VBI: obesity (.18, hypertension (.14, smoking (.08, diabetes (.07, and atherosclerosis (.05, whereas other cardiovascular diseases or hypercholesterolemia were not significant. Individuals with 2 or more VBI factors compared to individuals without had an odds ratio of 3.17 regarding overly increased IMT (≥1.0 mm. The VBI showed an impact on executive control (log(TMT B-A, p = .047 and a trend towards decreased global cognitive function (CERAD total score, p = .057 independent of age, sex and education.A VBI established on the basis of IMT may help to identify individuals with overly increased vascular burden linked to decreased cognitive function indicating neurodegenerative processes. The longitudinal study of this risk cohort will reveal the value of the VBI as prodromal marker for cognitive decline and

  1. Membrane cholesterol regulates lysosome-plasma membrane fusion events and modulates Trypanosoma cruzi invasion of host cells.

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    Bárbara Hissa

    Full Text Available BACKGROUND: Trypomastigotes of Trypanosoma cruzi are able to invade several types of non-phagocytic cells through a lysosomal dependent mechanism. It has been shown that, during invasion, parasites trigger host cell lysosome exocytosis, which initially occurs at the parasite-host contact site. Acid sphingomyelinase released from lysosomes then induces endocytosis and parasite internalization. Lysosomes continue to fuse with the newly formed parasitophorous vacuole until the parasite is completely enclosed by lysosomal membrane, a process indispensable for a stable infection. Previous work has shown that host membrane cholesterol is also important for the T. cruzi invasion process in both professional (macrophages and non-professional (epithelial phagocytic cells. However, the mechanism by which cholesterol-enriched microdomains participate in this process has remained unclear. METHODOLOGY/PRINCIPAL FINDING: In the present work we show that cardiomyocytes treated with MβCD, a drug able to sequester cholesterol from cell membranes, leads to a 50% reduction in invasion by T. cruzi trypomastigotes, as well as a decrease in the number of recently internalized parasites co-localizing with lysosomal markers. Cholesterol depletion from host membranes was accompanied by a decrease in the labeling of host membrane lipid rafts, as well as excessive lysosome exocytic events during the earlier stages of treatment. Precocious lysosomal exocytosis in MβCD treated cells led to a change in lysosomal distribution, with a reduction in the number of these organelles at the cell periphery, and probably compromises the intracellular pool of lysosomes necessary for T. cruzi invasion. CONCLUSION/SIGNIFICANCE: Based on these results, we propose that cholesterol depletion leads to unregulated exocytic events, reducing lysosome availability at the cell cortex and consequently compromise T. cruzi entry into host cells. The results also suggest that two different pools of

  2. Oxidant-induced autophagy and ferritin degradation contribute to epithelial–mesenchymal transition through lysosomal iron

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    Sioutas A

    2017-03-01

    Full Text Available Apostolos Sioutas,1 Linda K Vainikka,2 Magnus Kentson,3 Sören Dam-Larsen,4 Urban Wennerström,5 Petra Jacobson,1 Hans Lennart Persson1 1Division of Respiratory Medicine, Department of Medical and Health Sciences, 2Division of Experimental Pathology, Department of Clinical and Experimental Medicine, Linköping University, Linköping,3Division of Medicine, Ryhov Hospital, Jönköping, 4Division of Medicine, Hospital of Eksjö, Eksjö, 5Division of Medicine, Hospital of Västervik, Västervik, Sweden Purpose: Transforming growth factor (TGF-β1 triggers epithelial–mesenchymal transition (EMT through autophagy, which is partly driven by reactive oxygen species (ROS. The aim of this study was to determine whether leaking lysosomes and enhanced degradation of H-ferritin could be involved in EMT and whether it could be possible to prevent EMT by iron chelation targeting of the lysosome. Materials and methods: EMT, H-ferritin, and autophagy were evaluated in TGF-β1-stimulated A549 human lung epithelial cells cultured in vitro using Western blotting, with the additional morphological assessment of EMT. By using immunofluorescence and flow cytometry, lysosomes and ROS were assessed by acridine orange and 6-carboxy-2’,7’-dichlorodihydrofluorescein acetate assays, respectively. Results: TGF-β1-stimulated cells demonstrated a loss of H-ferritin, which was prevented by the antioxidant N-acetyl-L-cysteine (NAC and inhibitors of lysosomal degradation. TGF-β1 stimulation generated ROS and autophagosome formation and led to EMT, which was further promoted by the additional ROS-generating cytokine, tumor necrosis factor-α. Lysosomes of TGF-β1-stimulated cells were sensitized to oxidants but also completely protected by lysosomal loading with dextran-bound deferoxamine (DFO. Autophagy and EMT were prevented by NAC, DFO, and inhibitors of autophagy and lysosomal degradation. Conclusion: The findings of this study support the role of enhanced autophagic

  3. Impairment of lysosomal integrity by B10, a glycosylated derivative of betulinic acid, leads to lysosomal cell death and converts autophagy into a detrimental process.

    Science.gov (United States)

    Gonzalez, P; Mader, I; Tchoghandjian, A; Enzenmüller, S; Cristofanon, S; Basit, F; Debatin, K-M; Fulda, S

    2012-08-01

    In this study, we report a novel mechanism of action for a cytotoxic derivative of betulinic acid (BA). B10 is a semi-synthetic glycosylated derivative of BA selected for its enhanced cytotoxic activity. Interestingly, although B10 induces apoptosis, caspase-3 downregulation incompletely prevents B10-induced cell death, Bcl-2 overexpression fails to protect cells and DNA fragmentation rates do not reflect cell death rates in contrast to cytoplasmic membrane permeabilization. These results implicate that apoptotic and non-apoptotic cell death coexist upon B10 treatment. Unexpectedly, we found that B10 induces autophagy and also abrogates the autophagic flux. B10 destabilizes lysosomes as shown by Lysotracker Red staining and by cathepsin Z and B release from lysosomes into the cytoplasm. Consistently, the cathepsin inhibitor Ca074Me significantly decreases B10-induced cell death, further supporting the fact that the release of lysosomal enzymes contributes to B10-triggered cell death. Downregulation of ATG7, ATG5 or BECN1 by RNAi significantly decreases caspase-3 activation, lysosomal permeabilization and cell death. Thus, by concomitant induction of autophagy and inhibition of the autophagic flux, B10 turns autophagy into a cell death mechanism. These findings have important implications for the therapeutic exploitation of BA derivatives, particularly in apoptosis-resistant cancers.

  4. Genetic and Transcriptomic Profiles of Inflammation in Neurodegenerative Diseases: Alzheimer, Parkinson, Creutzfeldt-Jakob and Tauopathies

    National Research Council Canada - National Science Library

    López González, Irene; Garcia-Esparcia, Paula; Llorens, Franc; Ferrer, Isidre

    2016-01-01

    Polymorphisms in certain inflammatory-related genes have been identified as putative differential risk factors of neurodegenerative diseases with abnormal protein aggregates, such as sporadic Alzheimer's disease (AD...

  5. Lipid droplets as ubiquitous fat storage organelles in C. elegans

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    Guo Fengli

    2010-12-01

    Full Text Available Abstract Background Lipid droplets are a class of eukaryotic cell organelles for storage of neutral fat such as triacylglycerol (TAG and cholesterol ester (CE. We and others have recently reported that lysosome-related organelles (LROs are not fat storage structures in the nematode C. elegans. We also reported the formation of enlarged lipid droplets in a class of peroxisomal fatty acid β-oxidation mutants. In the present study, we seek to provide further evidence on the organelle nature and biophysical properties of fat storage structures in wild-type and mutant C. elegans. Results In this study, we provide biochemical, histological and ultrastructural evidence of lipid droplets in wild-type and mutant C. elegans that lack lysosome related organelles (LROs. The formation of lipid droplets and the targeting of BODIPY fatty acid analogs to lipid droplets in live animals are not dependent on lysosomal trafficking or peroxisome dysfunction. However, the targeting of Nile Red to lipid droplets in live animals occurs only in mutants with defective peroxisomes. Nile Red labelled-lipid droplets are characterized by a fluorescence emission spectrum distinct from that of Nile Red labelled-LROs. Moreover, we show that the recently developed post-fix Nile Red staining method labels lipid droplets exclusively. Conclusions Our results demonstrate lipid droplets as ubiquitous fat storage organelles and provide a unified explanation for previous studies on fat labelling methods in C. elegans. These results have important applications to the studies of fat storage and lipid droplet regulation in the powerful genetic system, C. elegans.

  6. Quantitation of the rates of hepatic and intestinal cholesterol synthesis in lysosomal acid lipase-deficient mice before and during treatment with ezetimibe.

    Science.gov (United States)

    Chuang, Jen-Chieh; Lopez, Adam M; Turley, Stephen D

    2017-07-01

    Esterified cholesterol (EC) and triglycerides, contained within lipoproteins taken up by cells, are hydrolysed by lysosomal acid lipase (LAL) in the late endosomal/lysosomal (E/L) compartment. The resulting unesterified cholesterol (UC) is transported via Niemann-Pick type C2 and C1 into the cytosolic compartment where it enters a putative pool of metabolically active cholesterol that is utilized in accordance with cellular needs. Loss-of-function mutations in LIPA, the gene encoding LAL, result in dramatic increases in tissue concentrations of EC, a hallmark feature of Wolman disease and cholesteryl ester storage disease (CESD). The lysosomal sequestration of EC causes cells to respond to a perceived deficit of sterol by increasing their rate of cholesterol synthesis, particularly in the liver. A similar compensatory response occurs with treatments that disrupt the enterohepatic movement of cholesterol or bile acids. Here we measured rates of cholesterol synthesis in vivo in the liver and small intestine of a mouse model for CESD given the cholesterol absorption inhibitor ezetimibe from weaning until early adulthood. Consistent with previous findings, this treatment significantly reduced the amount of EC sequestered in the liver (from 132.43±7.35 to 70.07±6.04mg/organ) and small intestine (from 2.78±0.21 to 1.34±0.09mg/organ) in the LAL-deficient mice even though their rates of hepatic and intestinal cholesterol synthesis were either comparable to, or exceeded those in matching untreated Lal -/- mice. These data reveal the role of intestinal cholesterol absorption in driving the expansion of tissue EC content and disease progression in LAL deficiency. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Imaging plus X: multimodal models of neurodegenerative disease.

    Science.gov (United States)

    Oxtoby, Neil P; Alexander, Daniel C

    2017-08-01

    This article argues that the time is approaching for data-driven disease modelling to take centre stage in the study and management of neurodegenerative disease. The snowstorm of data now available to the clinician defies qualitative evaluation; the heterogeneity of data types complicates integration through traditional statistical methods; and the large datasets becoming available remain far from the big-data sizes necessary for fully data-driven machine-learning approaches. The recent emergence of data-driven disease progression models provides a balance between imposed knowledge of disease features and patterns learned from data. The resulting models are both predictive of disease progression in individual patients and informative in terms of revealing underlying biological patterns. Largely inspired by observational models, data-driven disease progression models have emerged in the last few years as a feasible means for understanding the development of neurodegenerative diseases. These models have revealed insights into frontotemporal dementia, Huntington's disease, multiple sclerosis, Parkinson's disease and other conditions. For example, event-based models have revealed finer graded understanding of progression patterns; self-modelling regression and differential equation models have provided data-driven biomarker trajectories; spatiotemporal models have shown that brain shape changes, for example of the hippocampus, can occur before detectable neurodegeneration; and network models have provided some support for prion-like mechanistic hypotheses of disease propagation. The most mature results are in sporadic Alzheimer's disease, in large part because of the availability of the Alzheimer's disease neuroimaging initiative dataset. Results generally support the prevailing amyloid-led hypothetical model of Alzheimer's disease, while revealing finer detail and insight into disease progression. The emerging field of disease progression modelling provides a natural

  8. Characterizing a neurodegenerative syndrome: primary progressive apraxia of speech.

    Science.gov (United States)

    Josephs, Keith A; Duffy, Joseph R; Strand, Edythe A; Machulda, Mary M; Senjem, Matthew L; Master, Ankit V; Lowe, Val J; Jack, Clifford R; Whitwell, Jennifer L

    2012-05-01

    Apraxia of speech is a disorder of speech motor planning and/or programming that is distinguishable from aphasia and dysarthria. It most commonly results from vascular insults but can occur in degenerative diseases where it has typically been subsumed under aphasia, or it occurs in the context of more widespread neurodegeneration. The aim of this study was to determine whether apraxia of speech can present as an isolated sign of neurodegenerative disease. Between July 2010 and July 2011, 37 subjects with a neurodegenerative speech and language disorder were prospectively recruited and underwent detailed speech and language, neurological, neuropsychological and neuroimaging testing. The neuroimaging battery included 3.0 tesla volumetric head magnetic resonance imaging, [(18)F]-fluorodeoxyglucose and [(11)C] Pittsburg compound B positron emission tomography scanning. Twelve subjects were identified as having apraxia of speech without any signs of aphasia based on a comprehensive battery of language tests; hence, none met criteria for primary progressive aphasia. These subjects with primary progressive apraxia of speech included eight females and four males, with a mean age of onset of 73 years (range: 49-82). There were no specific additional shared patterns of neurological or neuropsychological impairment in the subjects with primary progressive apraxia of speech, but there was individual variability. Some subjects, for example, had mild features of behavioural change, executive dysfunction, limb apraxia or Parkinsonism. Voxel-based morphometry of grey matter revealed focal atrophy of superior lateral premotor cortex and supplementary motor area. Voxel-based morphometry of white matter showed volume loss in these same regions but with extension of loss involving the inferior premotor cortex and body of the corpus callosum. These same areas of white matter loss were observed with diffusion tensor imaging analysis, which also demonstrated reduced fractional anisotropy

  9. Exploring mitochondrial system properties of neurodegenerative diseases through interactome mapping.

    Science.gov (United States)

    Vlasblom, James; Jin, Ke; Kassir, Sandy; Babu, Mohan

    2014-04-04

    Mitochondria are double membraned, dynamic organelles that are required for a large number of cellular processes, and defects in their function have emerged as causative factors for a growing number of human disorders and are highly associated with cancer, metabolic, and neurodegenerative (ND) diseases. Biochemical and genetic investigations have uncovered small numbers of candidate mitochondrial proteins (MPs) involved in ND disease, but given the diversity of processes affected by MP function and the difficulty of detecting interactions involving these proteins, many more likely remain unknown. However, high-throughput proteomic and genomic approaches developed in genetically tractable model prokaryotes and lower eukaryotes have proven to be effective tools for querying the physical (protein-protein) and functional (gene-gene) relationships between diverse types of proteins, including cytosolic and membrane proteins. In this review, we highlight how experimental and computational approaches developed recently by our group and others can be effectively used towards elucidating the mitochondrial interactome in an unbiased and systematic manner to uncover network-based connections. We discuss how the knowledge from the resulting interaction networks can effectively contribute towards the identification of new mitochondrial disease gene candidates, and thus further clarify the role of mitochondrial biology and the complex etiologies of ND disease. Biochemical and genetic investigations have uncovered small numbers of candidate mitochondrial proteins (MPs) involved in neurodegenerative (ND) diseases, but given the diversity of processes affected by MP function and the difficulty of detecting interactions involving these proteins, many more likely remain unknown. Large-scale proteomic and genomic approaches developed in model prokaryotes and lower eukaryotes have proven to be effective tools for querying the physical (protein-protein) and functional (gene

  10. The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases

    Science.gov (United States)

    Lackie, Rachel E.; Maciejewski, Andrzej; Ostapchenko, Valeriy G.; Marques-Lopes, Jose; Choy, Wing-Yiu; Duennwald, Martin L.; Prado, Vania F.; Prado, Marco A. M.

    2017-01-01

    The accumulation of misfolded proteins in the human brain is one of the critical features of many neurodegenerative diseases, including Alzheimer's disease (AD). Assembles of beta-amyloid (Aβ) peptide—either soluble (oligomers) or insoluble (plaques) and of tau protein, which form neurofibrillary tangles, are the major hallmarks of AD. Chaperones and co-chaperones regulate protein folding and client maturation, but they also target misfolded or aggregated proteins for refolding or for degradation, mostly by the proteasome. They form an important line of defense against misfolded proteins and are part of the cellular quality control system. The heat shock protein (Hsp) family, particularly Hsp70 and Hsp90, plays a major part in this process and it is well-known to regulate protein misfolding in a variety of diseases, including tau levels and toxicity in AD. However, the role of Hsp90 in regulating protein misfolding is not yet fully understood. For example, knockdown of Hsp90 and its co-chaperones in a Caenorhabditis elegans model of Aβ misfolding leads to increased toxicity. On the other hand, the use of Hsp90 inhibitors in AD mouse models reduces Aβ toxicity, and normalizes synaptic function. Stress-inducible phosphoprotein 1 (STI1), an intracellular co-chaperone, mediates the transfer of clients from Hsp70 to Hsp90. Importantly, STI1 has been shown to regulate aggregation of amyloid-like proteins in yeast. In addition to its intracellular function, STI1 can be secreted by diverse cell types, including astrocytes and microglia and function as a neurotrophic ligand by triggering signaling via the cellular prion protein (PrPC). Extracellular STI1 can prevent Aβ toxic signaling by (i) interfering with Aβ binding to PrPC and (ii) triggering pro-survival signaling cascades. Interestingly, decreased levels of STI1 in C. elegans can also increase toxicity in an amyloid model. In this review, we will discuss the role of intracellular and extracellular STI1 and the

  11. The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Rachel E. Lackie

    2017-05-01

    Full Text Available The accumulation of misfolded proteins in the human brain is one of the critical features of many neurodegenerative diseases, including Alzheimer's disease (AD. Assembles of beta-amyloid (Aβ peptide—either soluble (oligomers or insoluble (plaques and of tau protein, which form neurofibrillary tangles, are the major hallmarks of AD. Chaperones and co-chaperones regulate protein folding and client maturation, but they also target misfolded or aggregated proteins for refolding or for degradation, mostly by the proteasome. They form an important line of defense against misfolded proteins and are part of the cellular quality control system. The heat shock protein (Hsp family, particularly Hsp70 and Hsp90, plays a major part in this process and it is well-known to regulate protein misfolding in a variety of diseases, including tau levels and toxicity in AD. However, the role of Hsp90 in regulating protein misfolding is not yet fully understood. For example, knockdown of Hsp90 and its co-chaperones in a Caenorhabditis elegans model of Aβ misfolding leads to increased toxicity. On the other hand, the use of Hsp90 inhibitors in AD mouse models reduces Aβ toxicity, and normalizes synaptic function. Stress-inducible phosphoprotein 1 (STI1, an intracellular co-chaperone, mediates the transfer of clients from Hsp70 to Hsp90. Importantly, STI1 has been shown to regulate aggregation of amyloid-like proteins in yeast. In addition to its intracellular function, STI1 can be secreted by diverse cell types, including astrocytes and microglia and function as a neurotrophic ligand by triggering signaling via the cellular prion protein (PrPC. Extracellular STI1 can prevent Aβ toxic signaling by (i interfering with Aβ binding to PrPC and (ii triggering pro-survival signaling cascades. Interestingly, decreased levels of STI1 in C. elegans can also increase toxicity in an amyloid model. In this review, we will discuss the role of intracellular and extracellular

  12. Glycation, Glycolysis, and Neurodegenerative Diseases: Is There Any Connection?

    Science.gov (United States)

    Muronetz, V I; Melnikova, A K; Seferbekova, Z N; Barinova, K V; Schmalhausen, E V

    2017-08-01

    This review considers the interrelation between different types of protein glycation, glycolysis, and the development of amyloid neurodegenerative diseases. The primary focus is on the role of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase in changing the concentration of carbonyl compounds - first and foremost, glyceraldehyde-3-phosphate and methylglyoxal. It has been suggested that various modifications of the enzyme - from the oxidation of the sulfhydryl groups of the active site to glycation with sugars - can lead to its inactivation, which causes a direct increase in glyceraldehyde-3-phosphate concentration and an indirect increase in the content of other aldehydes. This "primary inactivation" of glyceraldehyde-3-phosphate dehydrogenase promotes its glycation with aldehydes, including its own substrate, and a further irreversible decrease in its activity. Such a cycle can lead to numerous consequences - from the induction of apoptosis, which is activated by modified forms of the enzyme, to glycation of amyloidogenic proteins by glycolytic aldehydes. Of particular importance during the inhibition of glyceraldehyde-3-phosphate dehydrogenase is an increase in the content of the glycating compound methylglyoxal, which is much more active than reducing sugars (glucose, fructose, and others). In addition, methylglyoxal is formed by two pathways - in the cascade of reactions during glycation and from glycolytic aldehydes. The ability of methylglyoxal to glycate proteins makes it the main participant in this protein modification. We consider the effect of glycation on the pathological transformation of amyloidogenic proteins and peptides - β-amyloid peptide, α-synuclein, and prions. Our primary focus is on the glycation of monomeric forms of these proteins with methylglyoxal, although most works are dedicated to the analysis of the presence of "advanced glycation end products" in the already formed aggregates and fibrils of amyloid proteins. In our

  13. Energy storage cells

    Energy Technology Data Exchange (ETDEWEB)

    Gulia, N.V.

    1980-01-01

    The book deals with the characteristics and potentialities of energy storage cells of various types. Attention is given to electrical energy storage cells (electrochemical, electrostatic, and electrodynamic cells), mechanical energy storage cells (mechanical flywheel storage cells), and hybrid storage systems.

  14. Evidence for lysosomal exocytosis and release of aggrecan-degrading hydrolases from hypertrophic chondrocytes, in vitro and in vivo

    Directory of Open Access Journals (Sweden)

    Edward R. Bastow

    2012-02-01

    The abundant proteoglycan, aggrecan, is resorbed from growth plate cartilage during endochondral bone ossification, yet mice with genetically-ablated aggrecan-degrading activity have no defects in bone formation. To account for this apparent anomaly, we propose that lysosomal hydrolases degrade extracellular, hyaluronan-bound aggrecan aggregates in growth plate cartilage, and that lysosomal hydrolases are released from hypertrophic chondrocytes into growth plate cartilage via Ca2+-dependent lysosomal exocytosis. In this study we confirm that hypertrophic chondrocytes release hydrolases via lysosomal exocytosis in vitro and we show in vivo evidence for lysosomal exocytosis in hypertrophic chondrocytes during skeletal development. We show that lysosome-associated membrane protein 1 (LAMP1 is detected at the cell surface following in vitro treatment of epiphyseal chondrocytes with the calcium ionophore, ionomycin. Furthermore, we show that in addition to the lysosomal exocytosis markers, cathepsin D and β-hexosaminidase, ionomycin induces release of aggrecan- and hyaluronan-degrading activity from cultured epiphyseal chondrocytes. We identify VAMP-8 and VAMP7 as v-SNARE proteins with potential roles in lysosomal exocytosis in hypertrophic chondrocytes, based on their colocalisation with LAMP1 at the cell surface in secondary ossification centers in mouse tibiae. We propose that resorbing growth plate cartilage involves release of destructive hydrolases from hypertrophic chondrocytes, via lysosomal exocytosis.

  15. Depletion of kinesin 5B affects lysosomal distribution and stability and induces peri-nuclear accumulation of autophagosomes in cancer cells

    DEFF Research Database (Denmark)

    Cardoso, Carla M P; Groth-Pedersen, Line; Høyer-Hansen, Maria

    2009-01-01

    in HeLa cervix carcinoma cells as analyzed by subcellular fractionation. The depletion of KIF5B triggered peripheral aggregations of lysosomes followed by lysosomal destabilization, and cell death in HeLa cells. Lysosomal exocytosis in response to plasma membrane damage as well as fluid phase......BACKGROUND: Enhanced lysosomal trafficking is associated with metastatic cancer. In an attempt to discover cancer relevant lysosomal motor proteins, we compared the lysosomal proteomes from parental MCF-7 breast cancer cells with those from highly invasive MCF-7 cells that express an active form...... of the ErbB2 (DeltaN-ErbB2). METHODOLOGY/PRINCIPAL FINDINGS: Mass spectrometry analysis identified kinesin heavy chain protein KIF5B as the only microtubule motor associated with the lysosomes in MCF-7 cells, and ectopic DeltaN-ErbB2 enhanced its lysosomal association. KIF5B associated with lysosomes also...

  16. Disruption of lysosome function promotes tumor growth and metastasis in Drosophila.

    Science.gov (United States)

    Chi, Congwu; Zhu, Huanhu; Han, Min; Zhuang, Yuan; Wu, Xiaohui; Xu, Tian

    2010-07-09

    Lysosome function is essential to many physiological processes. It has been suggested that deregulation of lysosome function could contribute to cancer. Through a genetic screen in Drosophila, we have discovered that mutations disrupting lysosomal degradation pathway components contribute to tumor development and progression. Loss-of-function mutations in the Class C vacuolar protein sorting (VPS) gene, deep orange (dor), dramatically promote tumor overgrowth and invasion of the Ras(V12) cells. Knocking down either of the two other components of the Class C VPS complex, carnation (car) and vps16A, also renders Ras(V12) cells capable for uncontrolled growth and metastatic behavior. Finally, chemical disruption of the lysosomal function by feeding animals with antimalarial drugs, chloroquine or monensin, leads to malignant tumor growth of the Ras(V12) cells. Taken together, our data provide evidence for a causative role of lysosome dysfunction in tumor growth and invasion and indicate that members of the Class C VPS complex behave as tumor suppressors.

  17. Defects in ER–endosome contacts impact lysosome function in hereditary spastic paraplegia

    Science.gov (United States)

    Newton, Timothy; Connell, James W.; Winner, Beate

    2017-01-01

    Contacts between endosomes and the endoplasmic reticulum (ER) promote endosomal tubule fission, but the mechanisms involved and consequences of tubule fission failure are incompletely understood. We found that interaction between the microtubule-severing enzyme spastin and the ESCRT protein IST1 at ER–endosome contacts drives endosomal tubule fission. Failure of fission caused defective sorting of mannose 6-phosphate receptor, with consequently disrupted lysosomal enzyme trafficking and abnormal lysosomal morphology, including in mouse primary neurons and human stem cell–derived neurons. Consistent with a role for ER-mediated endosomal tubule fission in lysosome function, similar lysosomal abnormalities were seen in cellular models lacking the WASH complex component strumpellin or the ER morphogen REEP1. Mutations in spastin, strumpellin, or REEP1 cause hereditary spastic paraplegia (HSP), a disease characterized by axonal degeneration. Our results implicate failure of the ER–endosome contact process in axonopathy and suggest that coupling of ER-mediated endosomal tubule fission to lysosome function links different classes of HSP proteins, previously considered functionally distinct, into a unifying pathway for axonal degeneration. PMID:28389476

  18. Defects in ER-endosome contacts impact lysosome function in hereditary spastic paraplegia.

    Science.gov (United States)

    Allison, Rachel; Edgar, James R; Pearson, Guy; Rizo, Tania; Newton, Timothy; Günther, Sven; Berner, Fiamma; Hague, Jennifer; Connell, James W; Winkler, Jürgen; Lippincott-Schwartz, Jennifer; Beetz, Christian; Winner, Beate; Reid, Evan

    2017-05-01

    Contacts between endosomes and the endoplasmic reticulum (ER) promote endosomal tubule fission, but the mechanisms involved and consequences of tubule fission failure are incompletely understood. We found that interaction between the microtubule-severing enzyme spastin and the ESCRT protein IST1 at ER-endosome contacts drives endosomal tubule fission. Failure of fission caused defective sorting of mannose 6-phosphate receptor, with consequently disrupted lysosomal enzyme trafficking and abnormal lysosomal morphology, including in mouse primary neurons and human stem cell-derived neurons. Consistent with a role for ER-mediated endosomal tubule fission in lysosome function, similar lysosomal abnormalities were seen in cellular models lacking the WASH complex component strumpellin or the ER morphogen REEP1. Mutations in spastin, strumpellin, or REEP1 cause hereditary spastic paraplegia (HSP), a disease characterized by axonal degeneration. Our results implicate failure of the ER-endosome contact process in axonopathy and suggest that coupling of ER-mediated endosomal tubule fission to lysosome function links different classes of HSP proteins, previously considered functionally distinct, into a unifying pathway for axonal degeneration. © 2017 Allison et al.

  19. Iron-induced myocardial and hepatic lysosomal abnormalities in the guinea pig.

    Science.gov (United States)

    Adams, E T; Schwartz, K A

    1993-01-01

    The guinea pig model of iron overload, described in the preceding article, was used to investigate the mechanism of excess iron toxicity in hepatic and cardiac tissues. Effects of iron overload on both lysosomal membrane fragility and membrane peroxidation were studied. The free activity of selected myocardial and hepatic lysosomal enzymes, in addition to serum activity, was measured in guinea pigs treated with iron dextran (0.25, 0.5, 1.0, and 2.0 g Fe/kg body weight); controls received dextran. Levels of malondialdehyde were also determined in whole homogenates of heart and liver in animals loaded with 0.5 and 1.5 g Fe/kg of iron dextran. Results indicated that the free activity of hepatic glucosaminidase (p iron loading; hepatic acid phosphatase was increased at all but the lowest iron dose. Similarly, increased serum glucosaminidase activity was observed (p iron dose (p iron dose (1.5 g Fe/kg) in whole homogenates of both heart and liver (p iron loading in this model profoundly alters the stability of hepatic and myocardial lysosomal membranes; furthermore, changes in serum glucosaminidase activity may be reflective of modified tissue lysosomal properties. Elevated levels of malondialdehyde in whole homogenates suggest that iron-mediated lipid peroxidation may be responsible in part for enhanced lysosomal membrane fragility.

  20. Burn-induced stimulation of lysosomal enzyme synthesis in skeletal muscle

    Energy Technology Data Exchange (ETDEWEB)

    Odessey, R.

    1986-05-01

    A localized burn injury to a rat hindlimb results in atrophy of soleus muscle (in the absence of cellular damage) which is attributable to an increase in muscle protein breakdown. Previous work has shown that lysosomal enzyme activities (cathepsins B, H, L, and D) are elevated in muscle from the burned leg by 50% to 100%. There is no change in endogenous neutral protease activity (+/- Ca/sup + +/). The increase in protease activity can not be attributed to changes in endogenous protease inhibitors. The latency ((Triton X100 treated - control)/triton treated) of lysosomal enzymes is approximately 50% and is not altered by burn injury. The rate of sucrose uptake is also not altered by burn. These experiments suggest that the rate of substrate supply to the lysosomal apparatus via endocytosis or autophagocytosis is not altered by burn. When muscles are preincubated with /sup 3/H-phenylalanine or /sup 3/H-mannose burn increased incorporation into protein of the fraction containing lysosomes by 100%. Preincubation in the presence of tunicamycin (an inhibitor of glycoprotein synthesis) inhibited incorporation of both labels into a microsomal fraction of the muscle from the burned leg, but has little effect on incorporation in the control muscle. These findings are consistent with the hypothesis that the burn-induced increase in protein breakdown is caused by an increase in lysosomal protease synthesis.

  1. Not nanocarbon but dispersant induced abnormality in lysosome in macrophages in vivo

    Science.gov (United States)

    Yudasaka, Masako; Zhang, Minfang; Matsumura, Sachiko; Yuge, Ryota; Ichihashi, Toshinari; Irie, Hiroshi; Shiba, Kiyotaka; Iijima, Sumio

    2015-05-01

    The properties of nanocarbons change from hydrophobic to hydrophilic as a result of coating them with dispersants, typically phospholipid polyethylene glycols, for biological studies. It has been shown that the dispersants remain attached to the nanocarbons when they are injected in mice and influence the nanocarbons’ biodistribution in vivo. We show in this report that the effects of dispersants also appear at the subcellular level in vivo. Carbon nanohorns (CNHs), a type of nanocarbon, were dispersed with ceramide polyethylene glycol (CPEG) and intravenously injected in mice. Histological observations and electron microscopy with energy dispersive x-ray analysis revealed that, in liver and spleen, the lysosome membranes were damaged, and the nanohorns formed a complex with hemosiderin in the lysosomes of the macrophages. It is inferred that the lysosomal membrane was damaged by sphigosine generated as a result of CPEG decomposition, which changed the intra lysosomal conditions, inducing the formation of the CPEG-CNH and hemosiderin complex. For comparison, when glucose was used instead of CPEG, neither the nanohorn-hemosiderin complex nor lysosomal membrane damage was found. Our results suggest that surface functionalization can control the behavior of nancarbons in cells in vivo and thereby improve their suitability for medical applications.

  2. LAMP-2 is required for incorporating syntaxin-17 into autophagosomes and for their fusion with lysosomes

    Directory of Open Access Journals (Sweden)

    Virginie Hubert

    2016-10-01

    Full Text Available Autophagy is an evolutionarily conserved process used for removing surplus and damaged proteins and organelles from the cytoplasm. The unwanted material is incorporated into autophagosomes that eventually fuse with lysosomes, leading to the degradation of their cargo. The fusion event is mediated by the interaction between the Qa-SNARE syntaxin-17 (STX17 on autophagosomes and the R-SNARE VAMP8 on lysosomes. Cells deficient in lysosome membrane-associated protein-2 (LAMP-2 have increased numbers of autophagosomes but the underlying mechanism is poorly understood. By transfecting LAMP-2-deficient and LAMP-1/2­-double-deficient mouse embryonic fibroblasts (MEFs with a tandem fluorescent-tagged LC3 we observed a failure of fusion between the autophagosomes and the lysosomes that could be rescued by complementation with LAMP-2A. Although we observed no change in expression and localization of VAMP8, its interacting partner STX17 was absent from autophagosomes of LAMP-2-deficient cells. Thus, LAMP-2 is essential for STX17 expression by the autophagosomes and this absence is sufficient to explain their failure to fuse with lysosomes. The results have clear implications for situations associated with a reduction of LAMP-2 expression.

  3. Does Vitamin C Influence Neurodegenerative Diseases and Psychiatric Disorders?

    Science.gov (United States)

    Kocot, Joanna; Luchowska-Kocot, Dorota; Kiełczykowska, Małgorzata; Musik, Irena; Kurzepa, Jacek

    2017-06-27

    Vitamin C (Vit C) is considered to be a vital antioxidant molecule in the brain. Intracellular Vit C helps maintain integrity and function of several processes in the central nervous system (CNS), including neuronal maturation and differentiation, myelin formation, synthesis of catecholamine, modulation of neurotransmission and antioxidant protection. The importance of Vit C for CNS function has been proven by the fact that targeted deletion of the sodium-vitamin C co-transporter in mice results in widespread cerebral hemorrhage and death on post-natal day one. Since neurological diseases are characterized by increased free radical generation and the highest concentrations of Vit C in the body are found in the brain and neuroendocrine tissues, it is suggested that Vit C may change the course of neurological diseases and display potential therapeutic roles. The aim of this review is to update the current state of knowledge of the role of vitamin C on neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis and amyotrophic sclerosis, as well as psychiatric disorders including depression, anxiety and schizophrenia. The particular attention is attributed to understanding of the mechanisms underlying possible therapeutic properties of ascorbic acid in the presented disorders.

  4. Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Lila Carniglia

    2017-01-01

    Full Text Available Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.

  5. Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases.

    Science.gov (United States)

    Irwin, Michael H; Moos, Walter H; Faller, Douglas V; Steliou, Kosta; Pinkert, Carl A

    2016-05-01

    Preclinical Research In this review, we discuss epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function. Energy metabolism and mitochondrial dysfunction are viewed as determinants in the aging process that may afford therapeutic targets for a host of disease conditions, the brain being primary in such thinking. Mitochondrial dysfunction is a core feature in the pathophysiology of both Alzheimer and Parkinson diseases and rare mitochondrial diseases. The potential of new therapies in this area extends to glaucoma and other ophthalmic disorders, migraine, Creutzfeldt-Jakob disease, post-traumatic stress disorder, systemic exertion intolerance disease, and chemotherapy-induced cognitive impairment. An emerging and hopefully more promising approach to addressing these hard-to-treat diseases leverages their sensitivity to activation of master regulators of antioxidant and cytoprotective genes, antioxidant response elements, and mitophagy. Drug Dev Res 77 : 109-123, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  6. The emerging role of 5-hydroxymethylcytosine in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Sahar eAl-Mahdawi

    2014-12-01

    Full Text Available DNA methylation primarily occurs within human cells as a 5-methylcytosine (5mC modification of the cytosine bases in CpG dinucleotides. 5mC has proven to be an important epigenetic mark that is involved in the control of gene transcription for processes such as development and differentiation. However, recent studies have identified an alternative modification, 5-hydroxymethylcytosine (5hmC, which is formed by oxidation of 5mC by ten-eleven translocation (TET enzymes. The overall levels of 5hmC in the mammalian genome are approximately 10% of 5mC levels, although higher levels have been detected in tissues of the central nervous system (CNS. The functions of 5hmC are not yet fully known, but evidence suggests that 5hmC may be both an intermediate product during the removal of 5mC by passive or active demethylation processes and also an epigenetic modification in its own right, regulating chromatin or transcriptional factors involved in processes such as neurodevelopment or environmental stress response. This review highlights our current understanding of the role that 5hmC plays in neurodegenerative diseases, including Alzheimer’s disease (AD, amyotrophic lateral sclerosis (ALS, fragile X-associated tremor/ataxia syndrome (FXTAS, Friedreich ataxia (FRDA, Huntington’s disease (HD, and Parkinson’s disease (PD.

  7. Molecular Pathological Classification of Neurodegenerative Diseases: Turning towards Precision Medicine

    Directory of Open Access Journals (Sweden)

    Gabor G. Kovacs

    2016-02-01

    Full Text Available Neurodegenerative diseases (NDDs are characterized by selective dysfunction and loss of neurons associated with pathologically altered proteins that deposit in the human brain but also in peripheral organs. These proteins and their biochemical modifications can be potentially targeted for therapy or used as biomarkers. Despite a plethora of modifications demonstrated for different neurodegeneration-related proteins, such as amyloid-β, prion protein, tau, α-synuclein, TAR DNA-binding protein 43 (TDP-43, or fused in sarcoma protein (FUS, molecular classification of NDDs relies on detailed morphological evaluation of protein deposits, their distribution in the brain, and their correlation to clinical symptoms together with specific genetic alterations. A further facet of the neuropathology-based classification is the fact that many protein deposits show a hierarchical involvement of brain regions. This has been shown for Alzheimer and Parkinson disease and some forms of tauopathies and TDP-43 proteinopathies. The present paper aims to summarize current molecular classification of NDDs, focusing on the most relevant biochemical and morphological aspects. Since the combination of proteinopathies is frequent, definition of novel clusters of patients with NDDs needs to be considered in the era of precision medicine. Optimally, neuropathological categorizing of NDDs should be translated into in vivo detectable biomarkers to support better prediction of prognosis and stratification of patients for therapy trials.

  8. Oxidative Stress in Neurodegenerative Diseases: Mechanisms and Therapeutic Perspectives

    Directory of Open Access Journals (Sweden)

    Ailton Melo

    2011-01-01

    Full Text Available The incidence and prevalence of neurodegenerative diseases (ND increase with life expectancy. This paper reviews the role of oxidative stress (OS in ND and pharmacological attempts to fight against reactive oxygen species (ROS-induced neurodegeneration. Several mechanisms involved in ROS generation in neurodegeneration have been proposed. Recent articles about molecular pathways involved in ROS generation were reviewed. The progress in the development of neuroprotective therapies has been hampered because it is difficult to define targets for treatment and determine what should be considered as neuroprotective. Therefore, the attention was focused on researches about pharmacological targets that could protect neurons against OS. Since it is necessary to look for genes as the ultimate controllers of all biological processes, this paper also tried to identify gerontogenes involved in OS and neurodegeneration. Since neurons depend on glial cells to survive, recent articles about the functioning of these cells in aging and ND were also reviewed. Finally, clinical trials testing potential neuroprotective agents were critically reviewed. Although several potential drugs have been screened in in vitro and in vivo models of ND, these results were not translated in benefit of patients, and disappointing results were obtained in the majority of clinical trials.

  9. Infectious Agents and Neurodegenerative Diseases: Exploring the Links.

    Science.gov (United States)

    Alam, Mohammad Zubair; Alam, Qamre; Kamal, Mohammad Amjad; Jiman-Fatani, Asif Ahmad; Azhar, Esam I; Khan, Mohammad Azhar; Haque, Absarul

    2017-01-01

    Recent studies have shown that bacterial and viral infections are risk factors for various neurodegenerative diseases such as Amyotrophic lateral sclerosis (ALS), Multiple Sclerosis (MS), Alzheimer's disease (AD), and Lyme disease (LD). However, it is still controversial how the infections play a role in neurological diseases progression. Infections in central nervous system may lead multiple damages in infected and neighboring cells. The infection leads to the activation of inflammatory processes and host immune responses, which acts as defense mechanism and also causes damage to the host neuronal functions and viability. Several bacterial and viral pathogens have been reported for neurodegeneration, such as the production and deposit of misfolded protein aggregates, oxidative stress, deficient autophagic processes, synaptopathies and neuronal death. These effects may act in combination with other factors, like aging, metabolic diseases and the genetic makeup of the host. We will focus in this review on the possible link between neurodegeneration and infections particularly Chlamydophila pneumoniae, Borrelia burgdorferi, Mycoplasma etc. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. Therapeutic potential of cannabinoids in neurodegenerative disorders: a selective review.

    Science.gov (United States)

    Velayudhan, Latha; Van Diepen, Erik; Marudkar, Mangesh; Hands, Oliver; Suribhatla, Srinivas; Prettyman, Richard; Murray, Jonathan; Baillon, Sarah; Bhattacharyya, Sagnik

    2014-01-01

    The endocannabinoid system (ECS) is now recognised as an important modulator of various central nervous system processes. More recently, an increasing body of evidence has accumulated to suggest antioxidant, anti-inflammatory and neuroprotective roles of ECS. In this review we discuss the role and therapeutic potential of ECS in neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease, multiple sclerosis, Huntington's disease, Tourette's syndrome, brain ischemia and amyotrophic lateral sclerosis (ALS). Elements of the ECS, such as fatty acid amide hydrolase or the cannabinoid receptors are now considered as promising pharmacological targets for some diseases. Although still preliminary, recent reports suggest that modulation of the ECS may constitute a novel approach for the treatment of AD. There are windows of opportunity in conditions caused by acute events such as trauma and ischemia as well in conditions that may involve altered functionality of the target receptors of the ECS, such as in AD. The ECS changes in Parkinson's disease could be compensatory as well as pathogenic of the illness process and needs further understanding and clinical studies are still in the preliminary stage. There is not enough evidence to support use of cannabinoids in treating Huntington's disease, tics and obsessive compulsive behaviour in Tourette's syndrome. Evidence on therapeutic use of cannabinoids in multiple sclerosis and ALS is currently limited. A major challenge for future research is the development of novel compounds with more selectivity for various components of the ECS which could target different neurotoxic pathways and be used in combination therapy.

  11. Molecular origin of polyglutamine aggregation in neurodegenerative diseases.

    Directory of Open Access Journals (Sweden)

    2005-08-01

    Full Text Available Expansion of polyglutamine (polyQ tracts in proteins results in protein aggregation and is associated with cell death in at least nine neurodegenerative diseases. Disease age of onset is correlated with the polyQ insert length above a critical value of 35-40 glutamines. The aggregation kinetics of isolated polyQ peptides in vitro also shows a similar critical-length dependence. While recent experimental work has provided considerable insights into polyQ aggregation, the molecular mechanism of aggregation is not well understood. Here, using computer simulations of isolated polyQ peptides, we show that a mechanism of aggregation is the conformational transition in a single polyQ peptide chain from random coil to a parallel beta-helix. This transition occurs selectively in peptides longer than 37 glutamines. In the beta-helices observed in simulations, all residues adopt beta-strand backbone dihedral angles, and the polypeptide chain coils around a central helical axis with 18.5 +/- 2 residues per turn. We also find that mutant polyQ peptides with proline-glycine inserts show formation of antiparallel beta-hairpins in their ground state, in agreement with experiments. The lower stability of mutant beta-helices explains their lower aggregation rates compared to wild type. Our results provide a molecular mechanism for polyQ-mediated aggregation.

  12. PENN neurodegenerative disease research - in the spirit of Benjamin Franklin.

    Science.gov (United States)

    Trojanowski, John Q

    2008-01-01

    Benjamin Franklin (1706-1790) was entrepreneur, statesman, supporter of the public good as well as inventor, and his most significant invention was the University of Pennsylvania (PENN). Franklin outlined his plans for a college providing practical and classical instruction to prepare youth for real-world pursuits in his 'Proposals Relating to the Education of Youth in Pensilvania' (1749), and Franklin's spirit of learning to serve society guides PENN to the present day. This is evidenced by the series of articles in this special issue of Neurosignals, describing research conducted by seasoned and newly recruited PENN faculty, addressing consequences of the longevity revolution which defines our epoch at the dawn of this millennium. While aging affects all organ systems, the nervous system is most critical to successful aging. Thus, the articles in this special issue of Neurosignals focus on research at PENN that is designed to prevent or ameliorate aging-related neurodegenerative disorders such as Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. This research could enhance our chances of aging successfully in the continuing longevity revolution, and the essay here provides context and background on this research.

  13. The involvement of microRNAs in neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Simona eMaciotta Rolandin

    2013-12-01

    Full Text Available Neurodegenerative diseases (NDDs originate from loss of neurons in the central nervous system and are severely debilitating. They are worldwide spread and their incidence increases with age so that they are supposed to become more common due to extended life expectancy. Since no cure is available they have become a major challenge to neurobiology. The increasing relevance of microRNAs (miRNAs in biology has prompt the scientific society to investigate on their possible involvement in neurodegeneration with the aim to find new therapeutic targets. Indeed the idea of using miRNAs as therapeutic targets is nowadays not far from realization but important issues need to be addressed before moving towards the clinics. With the present review we aim to resume what have been so far disclose on the