Peña-Oliver, Y; Buchman, V L; Dalley, J W; Robbins, T.W; Schumann, G; Ripley, T. L.; King, S L; Stephens, D. N.
The presynaptic protein alpha-synuclein, associated with Parkinson's Disease (PD), plays a role in dopaminergic neurotransmission and is implicated in impulse control disorders (ICDs) such as drug addiction. In this study we investigated a potential causal relationship between alpha-synuclein and impulsivity, by evaluating differences in motor impulsivity in the 5-choice serial reaction time task (5-CSRTT) in strains of mice that differ in the expression of the alpha-synuclein gene. C57BL/6JO...
Raghavan, Ravi; Kruijff, Loes de; Sterrenburg, Monique D; Rogers, Beverly B; Hladik, Christa L; White, Charles L
Alpha (alpha)-synuclein is a presynaptic protein, abnormal expression of which has been associated with neurodegenerative and neoplastic diseases. It is abundant in the developing vertebrate central nervous system (CNS), but less is known about its developmental expression in the human CNS. Immunohistochemical expression of alpha-synuclein was studied in 39 fetal, perinatal, pediatric, and adolescent brains. Perikaryal expression of alpha-synuclein is observed as early as 11-wk gestation in the cortical plate. Several discrete neuronal groups in the hippocampus, basal ganglia, and brain stem express perikaryal alpha-synuclein by 20-wk gestation, persisting through the first few years of life. In the cerebellum, alpha-synuclein is present by 21-wk gestation and persists into adult life as a coarse granular neuropil reaction product in the internal granular layer, and as a diffuse neuropil "blush" in the molecular layer. The germinal matrix, glia, endothelial cells, external granular layer, Pukinje cells, and dentate neurons are consistently negative for alpha-synuclein. We conclude that alpha-synuclein is expressed very early in human gestation, and that its distribution and temporal sequence of expression varies in discrete neuronal groups. Perikaryal alpha-synuclein starts disappearing from the neuronal cytosol in early childhood, and only the neuropil retains immunoreactivity into adulthood. The reappearance of alpha-synuclein in the adult neuronal cytosol in certain disease processes may represent reemergence of cues from an earlier developmental stage as part of a stress response. PMID:15547775
Niklas K U Koehler
Full Text Available There is unequivocal evidence that alpha-synuclein plays a pivotal pathophysiological role in neurodegenerative diseases, and in particular in synucleinopathies. These disorders present with a variable extent of cognitive impairment and alpha-synuclein is being explored as a biomarker in CSF, blood serum and plasma. Considering key events of aging that include proteostasis, alpha-synuclein may not only be useful as a marker for differential diagnosis but also for aging per se. To explore this hypothesis, we developed a highly specific ELISA to measure alpha-synuclein. In healthy males plasma alpha-synuclein levels correlated strongly with age, revealing much lower concentrations in older (avg. 58.1 years compared to younger (avg. 27.6 years individuals. This difference between the age groups was enhanced after acidification of the plasmas (p<0.0001, possibly reflecting a decrease of alpha-synuclein-antibody complexes or chaperone activity in older individuals. Our results support the concept that alpha-synuclein homeostasis may be impaired early on, possibly due to disturbance of the proteostasis network, a key component of healthy aging. Thus, alpha-synuclein may be a novel biomarker of aging, a factor that should be considered when analyzing its presence in biological specimens.
Seidel, Kay; Schöls, Ludger; Nuber, Silke; Petrasch-Parwez, Elisabeth; Gierga, Kristin; Wszolek, Zbigniew; Dickson, Dennis; Gai, Wei P; Bornemann, Antje; Riess, Olaf; Rami, Abdelhaq; Den Dunnen, Wilfried F A; Deller, Thomas; Rüb, Udo; Krüger, Rejko
Familial Parkinson disease (PD) due to the A30P mutation in the SNCA gene encoding alpha-synuclein is clinically associated with PD symptoms. In this first pathoanatomical study of the brain of an A30P mutation carrier, we observed neuronal loss in the substantia nigra, locus coeruleus, and dorsal motor vagal nucleus, as well as widespread occurrence of alpha-synuclein immunopositive Lewy bodies, Lewy neurites, and glial aggregates. Alpha-synuclein aggregates ultrastructurally resembled Lewy bodies, and biochemical analyses disclosed a significant load of insoluble alpha-synuclein, indicating neuropathological similarities between A30P disease patients and idiopathic PD, with a more severe neuropathology in A30P carriers. PMID:20437567
Brudek, Tomasz; Winge, Kristian; Bredo Rasmussen, Nadja;
-1 isoforms. In MSA brains, alpha-synuclein140 and alpha-synuclein112 isoform levels were significantly increased,whereas levels of the alpha-synuclein126 isoform were decreased in the substantia nigra, striatum, cerebellar cortex, and nucleus dentatus vs. CONTROLS: Moreover, in MSA cases, we showed...... increased levels of parkin isoforms lacking the N-terminal ubiquitin-like domain and an aggregation-prone synphiln-1A isoform that causes neuronal toxicity in MSA. In PD brains, Parkin transcript variant 3, 7 and 11 were significantly and specifically overexpressed in the striatum and cerebellar cortex......, together with synphilin-1A and 1C. The changes of isoform expression profiles in neurodegenerative diseases suggest alterations in the regulation of transcription and/or splicing events, leading to regional/cellular events that may be important for the highly increased aggregation of alpha-synuclein in the...
Necula, Mihaela; Chirita, Carmen N; Kuret, Jeff
Parkinson's disease is characterized by the aggregation of alpha-synuclein into filamentous forms within affected neurons of the basal ganglia. Fibrillization of purified recombinant alpha-synuclein is inefficient in vitro but can be enhanced by the addition of various agents including glycosaminoglycans and polycations. Here we report that fatty acids and structurally related anionic detergents greatly accelerate fibrillization of recombinant alpha-synuclein at low micromolar concentrations with lag times as short as 11 min and apparent first order growth rate constants as fast as 10.4 h-1. All detergents and fatty acids were micellar at active concentrations because of an alpha-synuclein-dependent depression of their critical micelle concentrations. Other anionic surfaces, such as those supplied by anionic phospholipid vesicles, also induced alpha-synuclein fibrillization, with resultant filaments originating from their surface. These data suggest that anionic surfaces presented as micelles or vesicles can serve to nucleate alpha-synuclein fibrillization, that this mechanism underlies the inducer activity of anionic surfactants, and that anionic membranes may serve this function in vivo. PMID:14506232
Tjakko J van Ham
Full Text Available Inclusions in the brain containing alpha-synuclein are the pathological hallmark of Parkinson's disease, but how these inclusions are formed and how this links to disease is poorly understood. We have developed a C. elegans model that makes it possible to monitor, in living animals, the formation of alpha-synuclein inclusions. In worms of old age, inclusions contain aggregated alpha- synuclein, resembling a critical pathological feature. We used genome-wide RNA interference to identify processes involved in inclusion formation, and identified 80 genes that, when knocked down, resulted in a premature increase in the number of inclusions. Quality control and vesicle-trafficking genes expressed in the ER/Golgi complex and vesicular compartments were overrepresented, indicating a specific role for these processes in alpha-synuclein inclusion formation. Suppressors include aging-associated genes, such as sir-2.1/SIRT1 and lagr-1/LASS2. Altogether, our data suggest a link between alpha-synuclein inclusion formation and cellular aging, likely through an endomembrane-related mechanism. The processes and genes identified here present a framework for further study of the disease mechanism and provide candidate susceptibility genes and drug targets for Parkinson's disease and other alpha-synuclein related disorders.
Golovko, Mikhail Y; Færgeman, Nils J.; Cole, Nelson B;
Alpha-synuclein is an abundant protein in the central nervous system that is associated with a number of neurodegenerative disorders, including Parkinson's disease. Its physiological function is poorly understood, although recently it was proposed to function as a fatty acid binding protein. To b....... Thus, alpha-synuclein has effects on 16:0 uptake and metabolism similar to those of an FABP, but unlike FABP, it does not directly bind 16:0; hence, the mechanism underlying these effects is different from that of a classical FABP....
Full Text Available Cardiovascular autonomic dysfunction, such as orthostatic hypotension consequent to baroreflex failure and cardiac sympathetic denervation, is frequently observed in the synucleinopathy Parkinson’s disease (PD. In the present study, the baroreceptor reflex was assessed in mice overexpressing human wildtype alpha-synuclein (Thy1-aSyn, a genetic mouse model of synucleinopathy. The beat-to-beat change in heart rate, computed from R-R interval, in relation to blood pressure was measured in anesthetized and conscious mice equipped with arterial blood pressure telemetry transducers during transient bouts of hypertension and hypotension. Compared to wildtype, tachycardia following nitroprusside-induced hypotension was significantly reduced in Thy1-aSyn mice. Thy1-aSyn mice also showed an abnormal cardiovascular response (i.e., diminished tachycardia to muscarinic blockade with atropine. We conclude that Thy1-aSyn mice have impaired basal and dynamic range of sympathetic and parasympathetic-mediated changes in heart rate and will be a useful model for long-term study of cardiovascular autonomic dysfunction associated with PD.
Welinder, Charlotte; Jönsson, Göran B.; Ingvar, Christian; Lundgren, Lotta; Baldetorp, Bo; Olsson, Håkan; Breslin, Thomas; Rezeli, Melinda; Jansson, Bo; Fehniger, Thomas E.; Laurell, Thomas; Wieslander, Elisabet; Pawlowski, Krzysztof; Marko-Varga, György
Globally, malignant melanoma shows a steady increase in the incidence among cancer diseases. Malignant melanoma represents a cancer type where currently no biomarker or diagnostics is available to identify disease stage, progression of disease or personalized medicine treatment. The aim of this study was to assess the tissue expression of alpha-synuclein, a protein implicated in several disease processes, in metastatic tissues from malignant melanoma patients. A targeted Selected Reaction Monitoring (SRM) assay was developed and utilized together with stable isotope labeling for the relative quantification of two target peptides of alpha-synuclein. Analysis of alpha-synuclein protein was then performed in ten metastatic tissue samples from the Lund Melanoma Biobank. The calibration curve using peak area ratio (heavy/light) versus concentration ratios showed linear regression over three orders of magnitude, for both of the selected target peptide sequences. In support of the measurements of specific protein expression levels, we also observed significant correlation between the protein and mRNA levels of alpha-synuclein in these tissues. Investigating levels of tissue alpha-synuclein may add novel aspect to biomarker development in melanoma, help to understand disease mechanisms and ultimately contribute to discriminate melanoma patients with different prognosis. PMID:25333933
Welinder, Charlotte; Jönsson, Göran B; Ingvar, Christian; Lundgren, Lotta; Baldetorp, Bo; Olsson, Håkan; Breslin, Thomas; Rezeli, Melinda; Jansson, Bo; Fehniger, Thomas E; Laurell, Thomas; Wieslander, Elisabet; Pawlowski, Krzysztof; Marko-Varga, György
Globally, malignant melanoma shows a steady increase in the incidence among cancer diseases. Malignant melanoma represents a cancer type where currently no biomarker or diagnostics is available to identify disease stage, progression of disease or personalized medicine treatment. The aim of this study was to assess the tissue expression of alpha-synuclein, a protein implicated in several disease processes, in metastatic tissues from malignant melanoma patients. A targeted Selected Reaction Monitoring (SRM) assay was developed and utilized together with stable isotope labeling for the relative quantification of two target peptides of alpha-synuclein. Analysis of alpha-synuclein protein was then performed in ten metastatic tissue samples from the Lund Melanoma Biobank. The calibration curve using peak area ratio (heavy/light) versus concentration ratios showed linear regression over three orders of magnitude, for both of the selected target peptide sequences. In support of the measurements of specific protein expression levels, we also observed significant correlation between the protein and mRNA levels of alpha-synuclein in these tissues. Investigating levels of tissue alpha-synuclein may add novel aspect to biomarker development in melanoma, help to understand disease mechanisms and ultimately contribute to discriminate melanoma patients with different prognosis. PMID:25333933
Full Text Available Globally, malignant melanoma shows a steady increase in the incidence among cancer diseases. Malignant melanoma represents a cancer type where currently no biomarker or diagnostics is available to identify disease stage, progression of disease or personalized medicine treatment. The aim of this study was to assess the tissue expression of alpha-synuclein, a protein implicated in several disease processes, in metastatic tissues from malignant melanoma patients. A targeted Selected Reaction Monitoring (SRM assay was developed and utilized together with stable isotope labeling for the relative quantification of two target peptides of alpha-synuclein. Analysis of alpha-synuclein protein was then performed in ten metastatic tissue samples from the Lund Melanoma Biobank. The calibration curve using peak area ratio (heavy/light versus concentration ratios showed linear regression over three orders of magnitude, for both of the selected target peptide sequences. In support of the measurements of specific protein expression levels, we also observed significant correlation between the protein and mRNA levels of alpha-synuclein in these tissues. Investigating levels of tissue alpha-synuclein may add novel aspect to biomarker development in melanoma, help to understand disease mechanisms and ultimately contribute to discriminate melanoma patients with different prognosis.
Full Text Available Dysfunctions of chaperone-mediated autophagy (CMA, the main catabolic pathway for alpha-synuclein, have been linked to the pathogenesis of Parkinson’s disease (PD. Since till now there is limited information on how PD-related toxins may affect CMA, in this study we explored the effect of mitochondrial complex I inhibitor rotenone on CMA substrates, alpha-synuclein and MEF2D, and effectors, lamp2A and hsc70, in a human dopaminergic neuroblastoma SH-SY5Y cell line. Rotenone induced an upregulation of alpha-synuclein and MEF2D protein levels through the stimulation of their de novo synthesis rather than through a reduction of their CMA-mediated degradation. Moreover, increased MEF2D transcription resulted in higher nuclear protein levels that exert a protective role against mitochondrial dysfunction and oxidative stress. These results were compared with those obtained after lysosome inhibition with ammonium chloride. As expected, this toxin induced the cytosolic accumulation of both alpha-synuclein and MEF2D proteins, as the result of the inhibition of their lysosome-mediated degradation, while, differently from rotenone, ammonium chloride decreased MEF2D nuclear levels through the downregulation of its transcription, thus reducing its protective function. These results highlight that rotenone affects alpha-synuclein and MEF2D protein levels through a mechanism independent from lysosomal degradation inhibition.
Oaks, Adam W; Maya Frankfurt; Finkelstein, David I.; Anita Sidhu
Expression of A53T mutant human alpha-synuclein under the mouse prion promoter is among the most successful transgenic models of Parkinson's disease. Accumulation of A53T alpha-synuclein causes adult mice to develop severe motor impairment resulting in early death at 8-12 months of age. In younger, pre-symptomatic animals, altered motor activity and anxiety-like behaviors have also been reported. These behavioral changes, which precede severe neuropathology, may stem from non-pathological fun...
Paleček, Emil; Ostatná, Veronika; Masařík, Michal; Bertoncini, C.W.; Jovin, T.
Roč. 133, - (2008), s. 76-84. ISSN 0003-2654 R&D Projects: GA AV ČR(CZ) KAN400310651; GA MŠk(CZ) LC06035 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : alpha-synuclein * Parkinson's disease Subject RIV: BO - Biophysics Impact factor: 3.761, year: 2008
Masařík, Michal; Stobiecka, A.; Kizek, René; Jelen, František; Pechan, Zdeněk; Hoyer, W.; Jovin, T.; Subramaniam, V.; Paleček, Emil
Roč. 16, 13-14 (2004), s. 1172-1181. ISSN 1040-0397 R&D Projects: GA ČR GA204/03/0566 Institutional research plan: CEZ:AV0Z5004920 Keywords : electrochemistry of proteins * alpha-synuclein aggregation * adsorptive transfer stripping Subject RIV: BO - Biophysics Impact factor: 2.038, year: 2004
Seidel, Kay; Schoels, Ludger; Nuber, Silke; Petrasch-Parwez, Elisabeth; Gierga, Kristin; Wszolek, Zbigniew; Dickson, Dennis; Gai, Wei P.; Bornemann, Antje; Riess, Olaf; Rami, Abdelhaq; den Dunnen, Wilfried F. A.; Deller, Thomas; Rueb, Udo; Krueger, Rejko
Familial Parkinson disease (PD) due to the A30P mutation in the SNCA gene encoding alpha-synuclein is clinically associated with PD symptoms. In this first pathoanatomical study of the brain of an A30P mutation carrier, we observed neuronal loss in the substantia nigra, locus coeruleus, and dorsal m
Robotta, M.; Gerding, H.R.; Vogel, A.; Hauser, K.; Schildknecht, S.; Karreman, C.; Leist, M.; Subramaniam, V.; Drescher, M.
The human alpha-Synuclein (alphaS) protein is of significant interest because of its association with Parkinson's disease and related neurodegenerative disorders. The intrinsically disordered protein (140 amino acids) is characterized by the absence of a well-defined structure in solution. It displa
Marxreiter, Franz; Nuber, Silke; Kandasamy, Mahesh; Klucken, Jochen; Aigner, Robert; Burgmayer, Ralf; Couillard-Despres, Sebastien; Riess, Olaf; Winkler, Jürgen; Winner, Beate
In familial and sporadic forms of Parkinson's disease (PD), alpha-synuclein pathology is present in the brain stem nuclei and olfactory bulb (OB) long before Lewy bodies are detected in the substantia nigra. The OB is an active region of adult neurogenesis, where newly generated neurons physiologically integrate. While accumulation of wild-type alpha-synuclein is one of the pathogenic hallmarks of non-genetic forms of PD, the A30P alpha-synuclein mutation results in an earlier disease onset and a severe clinical phenotype. Here, we study the regulation of adult neurogenesis in the subventricular zone (SVZ)/OB system in a tetracycline-suppressive (tet-off) transgenic model of synucleinopathies, expressing human mutant A30P alpha-synuclein under the control of the calcium/calmodulin-dependent protein kinase II alpha (CaMK) promoter. In A30P transgenic mice alpha-synuclein was abundant at the site of integration in the glomerular cell layer of the OB. Without changes in proliferation in the SVZ, significantly fewer newly generated neurons were observed in the OB granule cell and glomerular layers of A30P transgenic mice than in controls, most probably due to increased cell death. By tetracycline-dependent abrogation of A30P alpha-synuclein expression, OB neurogenesis and programmed cell death was restored to control levels. Our results indicate that, using A30P conditional (tet-off) mice, A30P alpha-synuclein has a negative impact on olfactory neurogenesis and suppression of A30P alpha-synuclein enhances survival of newly generated neurons. This finding suggests that interfering with alpha-synuclein pathology can rescue newly generated neurons, possibly leading to new targets for therapeutic interventions in synucleinopathies. PMID:19291219
Pearce Ronald KB
Full Text Available Abstract Background The role of both microglial activation and alpha-synuclein deposition in Parkinson's disease remain unclear. We have tested the hypothesis that if microglia play a primary role in Parkinson's disease pathogenesis, the microglial "activated" phenotype should be associated with histopathological and/or clinical features of the disease. Methods We have examined microglial MHC class II expression, a widely used marker of microglial activation, the occurrence of CD68-positive phagocytes and alpha-synuclein immunoreactivity in post-mortem human substantia nigra affected by idiopathic Parkinson's disease (PD. Using semi-quantitative severity ratings, we have examined the relationship between microglial activation, alpha-synuclein deposition, classical neuropathological criteria for PD, subtype of the disease and clinical course. Results While we did not observe an association between microglial MHC class II expression and clinical parameters, we did find a correlation between disease duration and the macrophage marker CD68 which is expressed by phagocytic microglia. In addition, we observed a significant correlation between the degree of MHC class II expression and alpha-synuclein deposition in the substantia nigra in PD. Conclusion While microglia appeared to respond to alpha-synuclein deposition, MHC class II antigen expression by microglia in the substantia nigra cannot be used as an indicator of clinical PD severity or disease progression. In addition, a contributory or even causative role for microglia in the neuronal loss associated with PD as suggested by some authors seems unlikely. Our data further suggest that an assessment of microglial activation in the aged brain on the basis of immunohistochemistry for MHC class II antigens alone should be done with caution.
Malkiewicz, Katarzyna; Mohammed, Roma; Folkesson, Ronnie;
Polychlorinated Biphenyls (PCBs)-induced changes in synaptic transmission are one of the effects of their neurotoxicity but the mechanism remains unknown. We assessed the in vivo effects of the PCBs mixture, Aroclor 1254 on the expression of neuronal proteins that are involved in the synaptic...... function and/or are associated with neurodegeneration. Wistar rats were treated orally with repeated doses of Aroclor 1254 and the levels of soluble alpha-synuclein, parkin, synaptophysin and amyloid precursor protein (APP) in the brain were determined by Western blotting. The results showed that Aroclor...... did not cause changes in the expression and processing of APP but at a dose 100 microg/g/day repeated for 6 days caused a decrease in the expression of alpha-synuclein in the cerebellum, cortex, hippocampus and hypothalamus of the animals sacrificed 2 days after treatment. The decrease in alpha...
Colby, R; Hulleman, J; Padalkar, S; Rochet, J C; Stanciu, L A
Biomolecular templates provide an excellent potential tool for bottom-up device fabrication. Self-assembling alpha-synuclein protein fibrils, the formation of which has been linked to Parkinson's disease, have yet to be explored for potential device fabrication. In this paper, alpha-synuclein fibrils were used as a template for palladium (Pd), gold (Au) and copper (Cu) nanoparticle chains synthesis. Deposition over a range of conditions resulted in metal-coated fibers with reproducible average diameters between 50 and 200 nm. Active elemental palladium deposited on the protein fibrils is used as a catalyst for the electroless deposition of Au and Cu. Nanoparticle chains were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray energy dispersive spectrometry (XEDS), and electron energy loss spectrometry (EELS). PMID:18464436
Ostatná, Veronika; Paleček, Emil
Seville, 2008. s. 1. [The 59th Annual Meeting of the International Society of Electrochemistry. 07.09.2008-12.09.2008, Seville] R&D Projects: GA ČR(CZ) GA301/07/0490; GA ČR(CZ) GP202/07/P497; GA MŠk(CZ) LC06035 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : aggregation * alpha-synuclein * electrochemical analysis Subject RIV: BO - Biophysics
Masařík, Michal; Stobiecka, A.; Kizek, René; Jelen, František; Hoyer, W.; Jovin, T.; Paleček, Emil
Brno: Masarykova univerzita v Brně, 2004 - (Wimmerová, M.; Beneš, P.). s. 32 ISBN 80-210-3321-5. [Pracovní setkání biochemiků a molekulárních biologů /8./. 03.02.2004-04.02.2004, Brno] R&D Projects: GA ČR GA204/03/0566 Keywords : alpha-synuclein * electrochemical detection Subject RIV: BO - Biophysics
Sebastian R Schreglmann
Full Text Available Adult neurogenesis mirrors the brain´s endogenous capacity to generate new neurons throughout life. In the subventricular zone/ olfactory bulb system adult neurogenesis is linked to physiological olfactory function and has been shown to be impaired in murine models of neuronal alpha-Synuclein overexpression. We analyzed the degree and temporo-spatial dynamics of adult olfactory bulb neurogenesis in transgenic mice expressing human wild-type alpha-Synuclein (WTS under the murine Thy1 (mThy1 promoter, a model known to have a particularly high tg expression associated with impaired olfaction.Survival of newly generated neurons (NeuN-positive in the olfactory bulb was unchanged in mThy1 transgenic animals. Due to decreased dopaminergic differentiation a reduction in new dopaminergic neurons within the olfactory bulb glomerular layer was present. This is in contrast to our previously published data on transgenic animals that express WTS under the control of the human platelet-derived growth factor β (PDGF promoter, that display a widespread decrease in survival of newly generated neurons in regions of adult neurogenesis, resulting in a much more pronounced neurogenesis deficit. Temporal and quantitative expression analysis using immunofluorescence co-localization analysis and Western blots revealed that in comparison to PDGF transgenic animals, in mThy1 transgenic animals WTS is expressed from later stages of neuronal maturation only but at significantly higher levels both in the olfactory bulb and cortex.The dissociation between higher absolute expression levels of alpha-Synuclein but less severe impact on adult olfactory neurogenesis in mThy1 transgenic mice highlights the importance of temporal expression characteristics of alpha-Synuclein on the maturation of newborn neurons.
Full Text Available Levels of glutathione are lower in the substantia nigra (SN early in Parkinson's disease (PD and this may contribute to mitochondrial dysfunction and oxidative stress. Oxidative stress may increase the accumulation of toxic forms of alpha-synuclein (SNCA. We hypothesized that supplementation with n-acetylcysteine (NAC, a source of cysteine--the limiting amino acid in glutathione synthesis, would protect against alpha-synuclein toxicity. Transgenic mice overexpressing wild-type human alpha-synuclein drank water supplemented with NAC or control water supplemented with alanine from ages 6 weeks to 1 year. NAC increased SN levels of glutathione within 5-7 weeks of treatment; however, this increase was not sustained at 1 year. Despite the transient nature of the impact of NAC on brain glutathione, the loss of dopaminergic terminals at 1 year associated with SNCA overexpression was significantly attenuated by NAC supplementation, as measured by immunoreactivity for tyrosine hydroxylase in the striatum (p = 0.007; unpaired, two-tailed t-test, with a similar but nonsignificant trend for dopamine transporter (DAT immunoreactivity. NAC significantly decreased the levels of human SNCA in the brains of PDGFb-SNCA transgenic mice compared to alanine treated transgenics. This was associated with a decrease in nuclear NFkappaB localization and an increase in cytoplasmic localization of NFkappaB in the NAC-treated transgenics. Overall, these results indicate that oral NAC supplementation decreases SNCA levels in brain and partially protects against loss of dopaminergic terminals associated with overexpression of alpha-synuclein in this model.
Adam W Oaks
Full Text Available Expression of A53T mutant human alpha-synuclein under the mouse prion promoter is among the most successful transgenic models of Parkinson's disease. Accumulation of A53T alpha-synuclein causes adult mice to develop severe motor impairment resulting in early death at 8-12 months of age. In younger, pre-symptomatic animals, altered motor activity and anxiety-like behaviors have also been reported. These behavioral changes, which precede severe neuropathology, may stem from non-pathological functions of alpha-synuclein, including modulation of monoamine neurotransmission. Our analysis over the adult life-span of motor activity, anxiety-like, and depressive-like behaviors identifies perturbations both before and after the onset of disease. Young A53T mice had increased distribution of the dopamine transporter (DAT to the membrane that was associated with increased striatal re-uptake function. DAT function decreased with aging, and was associated with neurochemical alterations that included increased expression of beta-synuclein and gamma synuclein. Prior to normalization of dopamine uptake, transient activation of Tau kinases and hyperphosphorylation of Tau in the striatum were also observed. Aged A53T mice had reduced neuron counts in the substantia nigra pars compacta, yet striatal medium spiny neuron dendritic spine density was largely maintained. These findings highlight the involvement of the synuclein family of proteins and phosphorylation of Tau in the response to dopaminergic dysfunction of the nigrostriatal pathway.
Unal-Cevik, Isin; Gursoy-Ozdemir, Yasemin; Yemisci, Muge; Lule, Sevda; Gurer, Gunfer; Can, Alp; Müller, Veronica; Kahle, Philip J; Dalkara, Turgay
Alpha-synuclein oligomerization and aggregation are considered to have a role in the pathogenesis of neurodegenerative diseases. However, despite numerous in vitro studies, the impact of aggregates in the intact brain is unclear. In vitro, oxidative/nitrative stress and acidity induce α-synuclein oligomerization. These conditions favoring α-synuclein fibrillization are present in the ischemic brain, which may serve as an in vivo model to study α-synuclein aggregation. In this study, we show that 30-minute proximal middle cerebral artery (MCA) occlusion and 72 hours reperfusion induce oligomerization of wild-type α-synuclein in the ischemic mouse brain. The nonamyloidogenic isoform β-synuclein did not form oligomers. Alpha-synuclein aggregates were confined to neurons and colocalized with ubiquitin immunoreactivity. We also found that 30 minutes proximal MCA occlusion and 24 hours reperfusion induced larger infarcts in C57BL/6(Thy1)-h[A30P]alphaSYN transgenic mice, which have an increased tendency to form synuclein fibrils. Trangenics also developed more selective neuronal necrosis when subjected to 20 minutes distal MCA occlusion and 72 hours reperfusion. Enhanced 3-nitrotyrosine immunoreactivity in transgenic mice suggests that oxidative/nitrative stress may be one of the mechanisms mediating aggregate toxicity. Thus, the increased vulnerability of transgenic mice to ischemia suggests that α-synuclein aggregates not only form during ischemia but also negatively impact neuronal survival, supporting the idea that α-synuclein misfolding may be neurotoxic. PMID:20877387
Nuber, Silke; Tadros, Daniel; Fields, Jerel; Overk, Cassia Rose; Ettle, Benjamin; Kosberg, Kori; Mante, Michael; Rockenstein, Edward; Trejo, Margarita; Masliah, Eliezer
The olfactory bulb (OB) is one of the first brain regions in Parkinson's disease (PD) to contain alpha-synuclein (α-syn) inclusions, possibly associated with nonmotor symptoms. Mechanisms underlying olfactory synucleinopathy, its contribution to progressive aggregation pathology and nigrostriatal dopaminergic loss observed at later stages, remain unclear. A second hit, such as environmental toxins, is suggestive for α-syn aggregation in olfactory neurons, potentially triggering disease progression. To address the possible pathogenic role of olfactory α-syn accumulation in early PD, we exposed mice with site-specific and inducible overexpression of familial PD-linked mutant α-syn in OB neurons to a low dose of the herbicide paraquat. Here, we found that olfactory α-syn per se elicited structural and behavioral abnormalities, characteristic of an early time point in models with widespread α-syn expression, including hyperactivity and increased striatal dopaminergic marker. Suppression of α-syn reversed the dopaminergic phenotype. In contrast, paraquat treatment synergistically induced degeneration of olfactory dopaminergic cells and opposed the higher reactive phenotype. Neither neurodegeneration nor behavioral abnormalities were detected in paraquat-treated mice with suppressed α-syn expression. By increasing calpain activity, paraquat induced a pathological cascade leading to inhibition of autophagy clearance and accumulation of calpain-cleaved truncated and insoluble α-syn, recapitulating biochemical and structural changes in human PD. Thus our results underscore the primary role of proteolytic failure in aggregation pathology. In addition, we provide novel evidence that olfactory dopaminergic neurons display an increased vulnerability toward neurotoxins in dependence to presence of human α-syn, possibly mediating an olfactory-striatal dopaminergic network dysfunction in mouse models and early PD. PMID:24509835
Golovko, Mikhail Y; Rosenberger, Thad A; Feddersen, Søren;
incorporation rate and turnover in ethanolamine glycerophospholipid, phosphatidylserine, and phosphatidylinositol pools. Increased 22:6n-3-CoA mass was not the result of altered Acsl activity, which was unaffected by the absence of Snca. While Snca bound 22:6n-3, Kd = 1.0 +/- 0.5 micromol/L, it did not bind 22......Previously, we demonstrated that ablation of alpha-synuclein (Snca) reduces arachidonate (20:4n-6) turnover in brain phospholipids through modulation of an endoplasmic reticulum-localized acyl-CoA synthetase (Acsl). The effect of Snca ablation on docosahexaenoic acid (22:6n-3) metabolism is unknown...
Ostatná, Veronika; Masařík, Michal; Bertoncini, C.W.; Jovin, T.; Paleček, Emil
Brno, 2008. s. 39. [Satellite Symposium to ESEAC 2008. Electrochemistry of Nucleic Acids and Proteins. New Tools for Biotechnologies. 19.06.2008-22.06.2008, Brno] R&D Projects: GA ČR(CZ) GP202/07/P497; GA ČR(CZ) GA301/07/0490; GA MŠk(CZ) LC06035 Institutional research plan: CEZ:AV0Z50040507; CEZ:AV0Z50040702 Keywords : aggregation * alpha-synuclein * electrochemical analysis Subject RIV: AQ - Safety, Health Protection, Human - Machine
Demetrius M. Maraganore
Full Text Available The purpose of this paper is to provide the rationale for therapeutic silencing of the alpha-synuclein gene (SNCA in Parkinson’s disease (PD. The paper reviews the public health significance of PD; the causal links between rare SNCA variants and familial PD; the association of common SNCA variants and PD susceptibility; the association of SNCA variants also with age at onset and motor and cognitive outcomes in PD; therapeutic strategies targeting SNCA in PD; and preliminary findings and considerations on small interfering RNA-based therapies and PD.
Kumar, Ashutosh; Leinisch, Fabian; Kadiiska, Maria B; Corbett, Jean; Mason, Ronald P
Parkinson's disease (PD) is a debilitating, progressive, neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and motor deficits. Alpha-synuclein-containing aggregates represent a feature of a variety of neurodegenerative disorders, including PD; however, the mechanism that initiates and promotes intraneuronal alpha-synuclein aggregation remains unknown. We hypothesized protein radical formation as an initiating mechanism for alpha-synuclein aggregation. Therefore, we used the highly sensitive immuno-spin trapping technique to investigate protein radical formation as a possible mechanism of alpha-synuclein aggregation as well as to investigate the source of protein radical formation in the midbrains of Maneb- and paraquat-coexposed mice. Coexposure to Maneb and paraquat for 6 weeks resulted in active microgliosis, NADPH oxidase activation, and inducible nitric oxide synthase (iNOS) induction, which culminated in protein radical formation in the midbrains of mice. Results obtained with immuno-spin trapping and immunoprecipitation experiments confirmed formation of alpha-synuclein radicals in dopaminergic neurons of exposed mice. Free radical formation requires NADPH oxidase and iNOS, as indicated by decreased protein radical formation in knockout mice (P47phox(-/-) and iNOS(-/-)) and in mice treated with inhibitors such as FeTPPS (a peroxynitrite decomposition catalyst), 1400 W (an iNOS inhibitor), or apocynin (a NADPH oxidase inhibitor). Concurrence of protein radical formation with dopaminergic neuronal death indicated a link between protein radicals and disease progression. Taken together, these results show for the first time the formation and detection of the alpha-synuclein radical and suggest that NADPH oxidase and iNOS play roles in peroxynitrite-mediated protein radical formation and subsequent neuronal death in the midbrains of Maneb- and paraquat-coexposed mice. PMID:25952542
Beach, Thomas G; Adler, Charles H; Sue, Lucia I; Vedders, Linda; Lue, Lihfen; White Iii, Charles L; Akiyama, Haru; Caviness, John N; Shill, Holly A; Sabbagh, Marwan N; Walker, Douglas G
A sensitive immunohistochemical method for phosphorylated alpha-synuclein was used to stain sets of sections of spinal cord and tissue from 41 different sites in the bodies of 92 subjects, including 23 normal elderly, 7 with incidental Lewy body disease (ILBD), 17 with Parkinson's disease (PD), 9 with dementia with Lewy bodies (DLB), 19 with Alzheimer's disease with Lewy bodies (ADLB) and 17 with Alzheimer's disease with no Lewy bodies (ADNLB). The relative densities and frequencies of occurrence of phosphorylated alpha-synuclein histopathology (PASH) were tabulated and correlated with diagnostic category. The greatest densities and frequencies of PASH occurred in the spinal cord, followed by the paraspinal sympathetic ganglia, the vagus nerve, the gastrointestinal tract and endocrine organs. The frequency of PASH within other organs and tissue types was much lower. Spinal cord and peripheral PASH was most common in subjects with PD and DLB, where it appears likely that it is universally widespread. Subjects with ILBD had lesser densities of PASH within all regions, but had frequent involvement of the spinal cord and paraspinal sympathetic ganglia, with less-frequent involvement of end-organs. Subjects with ADLB had infrequent involvement of the spinal cord and paraspinal sympathetic ganglia with rare involvement of end-organs. Within the gastrointestinal tract, there was a rostrocaudal gradient of decreasing PASH frequency and density, with the lower esophagus and submandibular gland having the greatest involvement and the colon and rectum the lowest. PMID:20306269
Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons.
Richter, Franziska; Gao, Fuying; Medvedeva, Vera; Lee, Patrick; Bove, Nicholas; Fleming, Sheila M; Michaud, Magali; Lemesre, Vincent; Patassini, Stefano; De La Rosa, Krystal; Mulligan, Caitlin K; Sioshansi, Pedrom C; Zhu, Chunni; Coppola, Giovanni; Bordet, Thierry; Pruss, Rebecca M; Chesselet, Marie-Françoise
Cholesterol-oximes TRO19622 and TRO40303 target outer mitochondrial membrane proteins and have beneficial effects in preclinical models of neurodegenerative diseases leading to their advancement to clinical trials. Dopaminergic neurons degenerate in Parkinson's disease (PD) and are prone to oxidative stress and mitochondrial dysfunction. In order to provide insights into the neuroprotective potential of TRO19622 and TRO40303 for dopaminergic neurons in vivo, we assessed their effects on gene expression in laser captured nigrostriatal dopaminergic neurons of wildtype mice and of mice that over-express alpha-synuclein, a protein involved in both familial and sporadic forms of PD (Thy1-aSyn mice). Young mice were fed the drugs in food pellets or a control diet from 1 to 4months of age, approximately 10months before the appearance of striatal dopamine loss in this model. Unbiased weighted gene co-expression network analysis (WGCNA) of transcriptional changes revealed effects of cholesterol oximes on transcripts related to mitochondria, cytoprotection and anti-oxidant response in wild-type and transgenic mice, including increased transcription of stress defense (e.g. Prdx1, Prdx2, Glrx2, Hspa9, Pink1, Drp1, Trak1) and dopamine-related (Th, Ddc, Gch1, Dat, Vmat2, Drd2, Chnr6a) genes. Even at this young age transgenic mice showed alterations in transcripts implicated in mitochondrial function and oxidative stress (e.g. Bcl-2, Bax, Casp3, Nos2), and both drugs normalized about 20% of these alterations. Young Thy1-aSyn mice exhibit motor deficits that differ from parkinsonism and are established before the onset of treatment; these deficits were not improved by cholesterol oximes. However, high doses of TRO40303 improved olfaction and produced the same effects as dopamine agonists on a challenging beam test, specifically an increase in footslips, an observation congruent with its effects on transcripts involved in dopamine synthesis. High doses of TRO19622 increased alpha-synuclein
Puschmann, Andreas; Ross, Owen A; Vilariño-Güell, Carles;
A de novo alpha-synuclein A53T (p.Ala53 Th; c.209G > A) mutation has been identified in a Swedish family with autosomal dominant Parkinson's disease (PD). Two affected individuals had early-onset (before 31 and 40 years), severe levodopa-responsive PD with prominent dysphasia, dysarthria, and...
Tosatto, Laura; Horrocks, Mathew H.; Dear, Alexander J.; Knowles, Tuomas P. J.; Dalla Serra, Mauro; Cremades, Nunilo; Dobson, Christopher M.; Klenerman, David
Oligomers of alpha-synuclein are toxic to cells and have been proposed to play a key role in the etiopathogenesis of Parkinson’s disease. As certain missense mutations in the gene encoding for alpha-synuclein induce early-onset forms of the disease, it has been suggested that these variants might have an inherent tendency to produce high concentrations of oligomers during aggregation, although a direct experimental evidence for this is still missing. We used single-molecule Förster Resonance Energy Transfer to visualize directly the protein self-assembly process by wild-type alpha-synuclein and A53T, A30P and E46K mutants and to compare the structural properties of the ensemble of oligomers generated. We found that the kinetics of oligomer formation correlates with the natural tendency of each variant to acquire beta-sheet structure. Moreover, A53T and A30P showed significant differences in the averaged FRET efficiency of one of the two types of oligomers formed compared to the wild-type oligomers, indicating possible structural variety among the ensemble of species generated. Importantly, we found similar concentrations of oligomers during the lag-phase of the aggregation of wild-type and mutated alpha-synuclein, suggesting that the properties of the ensemble of oligomers generated during self-assembly might be more relevant than their absolute concentration for triggering neurodegeneration.
Sandal, Massimo; Tessari, Isabella; Mammi, Stefano; Bergantino, Elisabetta; Musiani, Francesco; Brucale, Marco; Bubacco, Luigi; Samori', Bruno
Natively unstructured proteins defy the classical "one sequence-one structure" paradigm of protein science. Monomers of these proteins in pathological conditions can aggregate in the cell, a process that underlies socially relevant neurodegenerative diseases such as Alzheimer and Parkinson. A full comprehension of the formation and structure of the so-called misfolded intermediates from which the aggregated states ensue is still lacking. We characterized the folding and the conformational diversity of alpha-synuclein (aSyn), a natively unstructured protein involved in Parkinson disease, by mechanically stretching single molecules of this protein and recording their mechanical properties. These experiments permitted us to directly observe directly and quantify three main classes of conformations that, under in vitro physiological conditions, exist simultaneously in the aSyn sample, including disordered and "beta-like" structures. We found that this class of "beta-like" structures is directly related to aSyn ag...
Tarasova, T V; Lytkina, O A; Roman, A Yu; Bachurin, S O; Ustyugov, A A
Alpha-synuclein is a presynaptic protein of vertebrates that belongs to the family of synucleins. Normal functions of synucleins remain unknown. Alpha-synuclein is one of the causative factors of the familial and idiopathic forms of Parkinson's disease (PD). The progressive loss of dopaminergic (DA) neurons is characteristic of PD and the most severe damage occurs in the substantia nigra (SN). This leads to an erraticism of the synthesis and synaptic secretion of the neurotransmitters, subsequently resulting in the loss of the connections between brain areas. This work shows that alpha-synuclein is directly involved in the formation of the mature DA neurons of the midbrain at different stages of the ontogenesis and these findings are consistent with data obtained in other studies. Thus, alpha-synuclein may have a varying modulating effect on the growth dynamics and the fate of populations of DA neurons. PMID:27021360
Kim, Yong-Hwan; Rane, Anand; Lussier, Stephanie; Julie K. Andersen
Lithium has recently been suggested to have neuroprotective properties in relation to several neurodegenerative diseases. In this study, we examined the potential cytoprotective effect of lithium in preventing oxidative stress-induced protein accumulation and neuronal cell death in the presence of increased alpha-synuclein levels in vitro and in vivo. Specifically, lithium administration was found to protect against cell death in a hydrogen peroxide treated, stable alpha-synuclein-EGFP over-e...
Yu, Wai Haung; Matsuoka, Yasuji; Sziráki, István; Hashim, Audrey; Lafrancois, John; Sershen, Henry; Duff, Karen E
Familial Parkinson's disease (PD) has been linked to point mutations and duplication of the alpha-synuclein gene and mutant alpha-synuclein expression increases the vulnerability of neurons to exogenous insults. In this study, we analyzed the levels of dopamine and its metabolites in the olfactory bulb (OB), and nigrostriatal regions of transgenic mice expressing human, mutant A53T alpha-synuclein (alpha-syn tg) and their non-transgenic (ntg) littermates using a sub-toxic, moderate dose of MPTP to determine if mutant human alpha-synuclein sensitizes the central dopaminergic systems to oxidative stress. We observed that after a single, sub-lethal MPTP injection, dopamine levels were reduced in striatum and SN in both the alpha-syn tg and ntg mice. In the olfactory bulb, a region usually resistant to MPTP toxicity, levels were reduced only in the alpha-syn tg mice. In addition, we identified a significant increase in dopamine metabolism in the alpha-syn transgenic, but not ntg mice. Finally, MPTP treatment of alpha-syn tg mice was associated with a marked elevation in the oxidative product, 3-nitrotyrosine that co-migrated with alpha-synuclein. Cumulatively, the data support the hypothesis that mutant alpha-synuclein sensitizes dopaminergic neurons to neurotoxic insults and is associated with greater oxidative stress. The alpha-syn tg line is therefore useful to study the genetic and environmental inter-relationship in PD. PMID:17999181
Kloepper, Kathryn D.; Hartman, Kevin L.; Ladror, Daniel T.; Rienstra, Chad M.
Protein aggregation is implicated in the etiology of numerous neurodegenerative diseases. An understanding of aggregation mechanisms is enhanced by atomic-resolution structural information, of which relatively little is currently available. Lewy bodies, the pathological hallmark of Parkinson’s disease, contain large quantities of fibrillar alpha-synuclein (AS). Here we present solid-state NMR spectroscopy studies of dried AS fibrils. The spectra have high resolution and sensitivity, and the s...
Baekelandt, Veerle; Gérard, Melanie; Deleersnijder, Angélique; Schreurs, Sarah; Munck, Sebastian; Van den Haute, Chris; Taymans, Jean-Marc; Pottel, Hans; Engelborghs, Yves; Debyser, Zeger
alpha-Synuclein (alpha-SYN) is a key player in the pathogenesis of Parkinson's disease (PD). In pathological conditions, the protein is present in a fibrillar, aggregated form inside cytoplasmic inclusions called Lewy bodies. Members of the FK506 binding protein (FKBP) family are peptidyl-prolyl isomerases that were shown recently to accelerate the aggregation of alpha-SYN in vitro. We now established a neuronal cell culture model for synucleinopathy based on oxidative stress-induced alpha-SY...
Casadei, Nicolas; Pöhler, Anne-Maria; Tomás-Zapico, Cristina; Torres-Peraza, Jesús; Schwedhelm, Ivo; Witz, Annemarie; Zamolo, Irina; De Heer, Raymond; Spruijt, Berry; Noldus, Lucas P J J; Klucken, Jochen; Lucas, José J; Kahle, Philipp J; Krüger, Rejko; Riess, Olaf; Nuber, Silke
Lewy bodies and neurites are the pathological hallmark of Parkinson's disease. These structures are composed of fibrillized and ubiquitinated alpha-synuclein suggesting that impaired protein clearance is an important event in aggregate formation. The A30P mutation is known for its fast oligomerization, but slow fibrillization rate. Despite its toxicity to neurons, mechanisms involved in either clearance or conversion of A30P alpha-synuclein from its soluble state into insoluble fibrils and their effects in vivo are poorly understood. Synphilin-1 is present in Lewy bodies, interacting with alpha-synuclein in vivo and in vitro and promotes its sequestration into aggresomes, which are thought to act as cytoprotective agents facilitating protein degradation. We therefore crossed animals overexpressing A30P alpha-synuclein with synphilin-1 transgenic mice to analyze its impact on aggregation, protein clearance and phenotype progression. We observed that co-expression of synphilin-1 mildly delayed the motor phenotype caused by A30P alpha-synuclein. Additionally, the presence of N- and C-terminal truncated alpha-synuclein species and fibrils were strongly reduced in double-transgenic mice when compared with single-transgenic A30P mice. Insolubility of mutant A30P and formation of aggresomes was still detectable in aged double-transgenic mice, paralleled by an increase of ubiquitinated proteins and high autophagic activity. Hence, this study supports the notion that co-expression of synphilin-1 promotes formation of autophagic-susceptible aggresomes and consecutively the degradation of human A30P alpha-synuclein. Notably, although synphilin-1 overexpression significantly reduced formation of fibrils and astrogliosis in aged animals, a similar phenotype is present in single- and double-transgenic mice suggesting additional neurotoxic processes in disease progression. PMID:24064336
Full Text Available Alpha-synuclein is a presynaptic protein expressed throughout the central nervous system, and it is the main component of Lewy bodies, one of the histopathological features of Parkinson’s disease (PD which is a progressive and irreversible neurodegenerative disorder. The conformational flexibility of α-synuclein allows it to adopt different conformations, i.e. bound to membranes or form aggregates, the oligomers are believed to be the more toxic species. In this review, we will focus on two major features of α-synuclein, transmission and toxicity that could help to understand the pathological characteristics of PD. One important feature of α-synuclein is its ability to be transmitted from neuron to neuron using mechanisms such as endocytosis, plasma membrane penetration or through exosomes, thus propagating the Lewy body pathology to different brain regions thereby contributing to the progressiveness of PD. The second feature of α-synuclein is that it confers cytotoxicity to recipient cells, principally when it is in an oligomeric state. This form causes mitochondrial dysfunction, endoplasmic reticulum stress, oxidative stress, proteasome impairment, disruption of plasma membrane and pore formation, and lead to apoptosis pathway activation and consequent cell death. The complexity of α-synuclein oligomerization and formation of toxic species could be a major factor for the irreversibility of PD and could also explain the lack of successful therapies to halt the disease.
A. R. Esteves
Full Text Available While the etiology of Parkinson's disease remains largely elusive, there is accumulating evidence suggesting that mitochondrial dysfunction occurs prior to the onset of symptoms in Parkinson's disease. Mitochondria are remarkably primed to play a vital role in neuronal cell survival since they are key regulators of energy metabolism (as ATP producers, of intracellular calcium homeostasis, of NAD+/NADH ratio, and of endogenous reactive oxygen species production and programmed cell death. In this paper, we focus on mitochondrial dysfunction-mediated alpha-synuclein aggregation. We highlight some of the findings that provide proof of evidence for a mitochondrial metabolism control in Parkinson's disease, namely, mitochondrial regulation of microtubule-dependent cellular traffic and autophagic lysosomal pathway. The knowledge that microtubule alterations may lead to autophagic deficiency and may compromise the cellular degradation mechanisms that culminate in the progressive accumulation of aberrant protein aggregates shields new insights to the way we address Parkinson's disease. In line with this knowledge, an innovative window for new therapeutic strategies aimed to restore microtubule network may be unlocked.
Uversky, V N; Li, J; Fink, A L
Parkinson's disease involves the aggregation of alpha-synuclein to form fibrils, which are the major constituent of intracellular protein inclusions (Lewy bodies and Lewy neurites) in dopaminergic neurons of the substantia nigra. Occupational exposure to specific metals, especially manganese, copper, lead, iron, mercury, zinc, aluminum, appears to be a risk factor for Parkinson's disease based on epidemiological studies. Elevated levels of several of these metals have also been reported in the substantia nigra of Parkinson's disease subjects. We examined the effect of various metals on the kinetics of fibrillation of recombinant alpha-synuclein and in inducing conformational changes, as monitored by biophysical techniques. Several di- and trivalent metal ions caused significant accelerations in the rate of alpha-synuclein fibril formation. Aluminum was the most effective, along with copper(II), iron(III), cobalt(III), and manganese(II). The effectiveness correlated with increasing ion charge density. A correlation was noted between efficiency in stimulating fibrillation and inducing a conformational change, ascribed to formation of a partially folded intermediate. The potential for ligand bridging by polyvalent metal ions is proposed to be an important factor in the metal-induced conformational changes of alpha-synuclein. The results indicate that low concentrations of some metals can directly induce alpha-synuclein fibril formation. PMID:11553618
Georg Sebastian Nübling
Full Text Available BACKGROUND: In several neurodegenerative diseases, hyperphosphorylation at position Ser129 is found in fibrillar deposits of alpha-synuclein (asyn, implying a pathophysiological role of asyn phosphorylation in neurodegeneration. However, recent animal models applying asyn phosphorylation mimics demonstrated a protective effect of phosphorylation. Since metal-ion induced asyn oligomers were identified as a potential neurotoxic aggregate species with membrane pore-forming abilities, the current study was undertaken to determine effects of asyn phosphorylation on oligomer membrane binding. METHODS: We investigated the influence of S129 phosphorylation on interactions of metal-ion induced asyn oligomers with small unilamellar lipid vesicles (SUV composed of POPC and DPPC applying the phosphorylation mimic asyn129E. Confocal single-particle fluorescence techniques were used to monitor membrane binding at the single-particle level. RESULTS: Binding of asyn129E monomers to gel-state membranes (DPPC-SUV is slightly reduced compared to wild-type asyn, while no interactions with membranes in the liquid-crystalline state (POPC-SUV are seen for both asyn and asyn129E. Conversely, metal-ion induced oligomer formation is markedly increased in asyn129E. Surprisingly, membrane binding to POPC-SUV is nearly absent in Fe(3+ induced asyn129E oligomers and markedly reduced in Al(3+ induced oligomers. CONCLUSION: The protective effect of pseudophosphorylation seen in animal models may be due to impeded oligomer membrane binding. Phosphorylation at Ser129 may thus have a protective effect against neurotoxic asyn oligomers by preventing oligomer membrane binding and disruption of the cellular electrophysiological equilibrium. Importantly, these findings put a new complexion on experimental pharmaceutical interventions against POLO-2 kinase.
Eric J Benner
Full Text Available BACKGROUND: The neuropathology of Parkinson's disease (PD includes loss of dopaminergic neurons in the substantia nigra, nitrated alpha-synuclein (N-alpha-Syn enriched intraneuronal inclusions or Lewy bodies and neuroinflammation. While the contribution of innate microglial inflammatory activities to disease are known, evidence for how adaptive immune mechanisms may affect the course of PD remains obscure. We reasoned that PD-associated oxidative protein modifications create novel antigenic epitopes capable of peripheral adaptive T cell responses that could affect nigrostriatal degeneration. METHODS AND FINDINGS: Nitrotyrosine (NT-modified alpha-Syn was detected readily in cervical lymph nodes (CLN from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP intoxicated mice. Antigen-presenting cells within the CLN showed increased surface expression of major histocompatibility complex class II, initiating the molecular machinery necessary for efficient antigen presentation. MPTP-treated mice produced antibodies to native and nitrated alpha-Syn. Mice immunized with the NT-modified C-terminal tail fragment of alpha-Syn, but not native protein, generated robust T cell proliferative and pro-inflammatory secretory responses specific only for the modified antigen. T cells generated against the nitrated epitope do not respond to the unmodified protein. Mice deficient in T and B lymphocytes were resistant to MPTP-induced neurodegeneration. Transfer of T cells from mice immunized with N-alpha-Syn led to a robust neuroinflammatory response with accelerated dopaminergic cell loss. CONCLUSIONS: These data show that NT modifications within alpha-Syn, can bypass or break immunological tolerance and activate peripheral leukocytes in draining lymphoid tissue. A novel mechanism for disease is made in that NT modifications in alpha-Syn induce adaptive immune responses that exacerbate PD pathobiology. These results have implications for both the pathogenesis and
May, V E L; Nuber, S; Marxreiter, F; Riess, O; Winner, B; Winkler, J
Synucleinopathies including Parkinson's disease (PD) are characterized by the accumulation of alpha-synuclein (α-syn) within neural cell bodies and their processes. Transgenic mice overexpressing human wild-type or mutant forms of α-syn under the control of different promoters were developed to analyse the underlying neuropathology of PD. One of the earliest clinical symptoms associated with PD is olfactory impairment. The generation of new neurons persists up to adulthood in mammals, in particular the olfactory bulb (OB). In order to assess this process in relation to α-syn accumulation, we used mice overexpressing human wild-type α-syn under the regulatable control (tet-off) of the calcium/calmodulin-dependent protein kinase IIα-promoter (CaMKII). We observed a decrease in OB neurogenesis in transgenic animals compared to controls using 5-bromo-2'-deoxyuridine (BrdU) to label newly generated cells (neuron-specific nuclear protein; NeuN). After cessation of transgene expression we detected an increase in newly generated cells both in granular (GCL) and glomerular (GLOM) layers of the OB. This led to a rescue of newly generated neurons (BrdU(+)/NeuN(+)) within the GLOM with a distinct specificity for the dopaminergic subpopulation. In contrast, we did not detect a cell-specific rescue of neuronal cells in the GCL suggesting diverse effects of alpha-synucleinopathy in both interneuronal layers of the OB. Colabelling of BrdU with glial markers showed that a differentiation into neither astroglia nor microglia attributed to the observed phenotype in the GCL. In particular, BrdU(+) particles located within microglial cells were predominantly associated close to the membrane therefore the resembling phagocytosed nuclear fragments of BrdU(+) cells. Thus, our study further contributes insights into α-syn accumulation as a causative player in the impairment of adult neurogenesis and emphasizes its diverse role in cell renewal of distinct OB cell layers. PMID:22814000
Kulathingal, Jayanarayan; Ko, Li-wen; Cusack, Bernadette; Yen, Shu-Hui
A tetracycline inducible transfectant cell line (3D5) capable of producing soluble and sarkosyl-insoluble assemblies of wild-type human alpha-synuclein (α-Syn) upon differentiation with retinoic acid was used to study the impact of α-Syn accumulation on protein phosphorylation and glycosylation. Soluble proteins from 3D5 cells, with or without the induced α-Syn expression were analyzed by two-dimensional gel electrophoresis and staining of gels with dyes that bind to proteins (Sypro ruby), ph...
Ip, Joanna Y.; Sone, Masamitsu; Nashiki, Chieko; Pan, Qun; Kitaichi, Kiyoyuki; Yanaka, Kaori; Abe, Takaya; Takao, Keizo; Miyakawa, Tsuyoshi; Blencowe, Benjamin J.; Nakagawa, Shinichi
The long noncoding RNA Gomafu/MIAT/Rncr2 is thought to function in retinal cell specification, stem cell differentiation and the control of alternative splicing. To further investigate physiological functions of Gomafu, we created mouse knockout (KO) model that completely lacks the Gomafu gene. The KO mice did not exhibit any developmental deficits. However, behavioral tests revealed that the KO mice are hyperactive. This hyperactive behavior was enhanced when the KO mice were treated with the psychostimulant methamphetamine, which was associated with an increase in dopamine release in the nucleus accumbens. RNA sequencing analyses identified a small number of genes affected by the deficiency of Gomafu, a subset of which are known to have important neurobiological functions. These observations suggest that Gomafu modifies mouse behavior thorough a mild modulation of gene expression and/or alternative splicing of target genes. PMID:27251103
Full Text Available The relatively high co-occurrence of Parkinson's disease (PD and melanoma has been established by a large number of epidemiological studies. However, a clear biological explanation for this finding is still lacking. Ultra-violet radiation (UVR-induced skin melanin synthesis is a defense mechanism against UVR-induced damage relevant to the initiation of melanoma, whereas, increased neuromelanin (NM, the melanin synthesized in dopaminergic neurons, may enhance the susceptibility to oxidative stress-induced neuronal injury relevant to PD. SNCA is a PD-causing gene coding for alpha-Synuclein (α-Syn that expresses not only in brain, but also in skin as well as in tumors, such as melanoma. The findings that α-Syn can interact with tyrosinase (TYR and inhibit tyrosine hydroxylase (TH, both of which are enzymes involved in the biosynthesis of melanin and dopamine (DA, led us to propose that α-Syn may participate in the regulation of melanin synthesis. In this study, by applying ultraviolet B (UVB light, a physiologically relevant stimulus of melanogenesis, we detected melanin synthesis in A375 and SK-MEL-28 melanoma cells and in SH-SY5Y and PC12 dopaminergic neuronal cells and determined effects of α-Syn on melanin synthesis. Our results showed that UVB light exposure increased melanin synthesis in all 4 cell lines. However, we found that α-Syn expression reduced UVB light-induced increase of melanin synthesis and that melanin content was lower when melanoma cells were expressed with α-Syn, indicating that α-Syn may have inhibitory effects on melanin synthesis in melanoma cells. Different from melanoma cells, the melanin content was higher in α-Syn-over-expressed dopaminergic neuronal SH-SY5Y and PC12 cells, cellular models of PD, than that in non-α-Syn-expressed control cells. We concluded that α-Syn could be one of the points responsible for the positive association between PD and melanoma via its differential roles in melanin synthesis in
Hyperactivity in children is explained in relation to behavioral characteristics, precipitating factors, and stimulant medication therapy. The basic mechanism of hyperactivity is seen to be impulsive style in motility, attention, and socialization. Problems caused by impulsivity are noted to include feeding problems, school difficulties, and peer…
... is often considered more of a problem for schools and parents than it is for the child. But many hyperactive children are unhappy or even depressed. Hyperactive behavior may make a child a target for bullying, or make it harder to connect with other ...
Cabeza-Arvelaiz Yofre; Fleming Sheila M; Richter Franziska; Masliah Eliezer; Chesselet Marie-Francoise; Schiestl Robert H
Abstract Background Alpha synuclein (SNCA) has been linked to neurodegenerative diseases (synucleinopathies) that include Parkinson's disease (PD). Although the primary neurodegeneration in PD involves nigrostriatal dopaminergic neurons, more extensive yet regionally selective neurodegeneration is observed in other synucleinopathies. Furthermore, SNCA is ubiquitously expressed in neurons and numerous neuronal systems are dysfunctional in PD. Therefore it is of interest to understand how overe...
Valerie R. Osterberg
Full Text Available Aggregated alpha-synuclein inclusions are found where cell death occurs in several diseases, including Parkinson’s disease, dementia with Lewy bodies, and multiple-system atrophy. However, the relationship between inclusion formation and an individual cell’s fate has been difficult to study with conventional techniques. We developed a system that allows for in vivo imaging of the same neurons over months. We show that intracerebral injection of preformed fibrils of recombinant alpha-synuclein can seed aggregation of transgenically expressed and endogenous alpha-synuclein in neurons. Somatic inclusions undergo a stage-like maturation, with progressive compaction coinciding with decreased soluble somatic and nuclear alpha-synuclein. Mature inclusions bear the post-translational hallmarks of human Lewy pathology. Long-term imaging of inclusion-bearing neurons and neighboring neurons without inclusions demonstrates selective degeneration of inclusion-bearing cells. Our results indicate that inclusion formation is tightly correlated with cellular toxicity and that seeding may be a pathologically relevant mechanism of progressive neurodegeneration in many synucleinopathies.
Kruse, N.; Persson, S.; Alcolea, D.;
Decreased levels of alpha-synuclein (aSyn) in cerebrospinal fluid (CSF) in Parkinson's disease and related synucleinopathies have been reported, however, not consistently in all cross-sectional studies. To test the performance of one recently released human-specific enzyme-linked immunosorbent...... assay (ELISA) for the quantification of aSyn in CSF, we carried out a round robin trial with 18 participating laboratories trained in CSF ELISA analyses within the BIOMARKAPD project in the EU Joint Program -Neurodegenerative Disease Research. CSF samples (homogeneous aliquots from pools) and ELISA kits...... (one lot) were provided centrally and data reported back to one laboratory for data analysis. Our study showed that although factors such as preanalytical sample handling and lot-to-lot variability were minimized by our study design, we identified high variation in absolute values of CSF aSyn even when...
Kloepper, Kathryn D; Hartman, Kevin L; Ladror, Daniel T; Rienstra, Chad M
Protein aggregation is implicated in the etiology of numerous neurodegenerative diseases. An understanding of aggregation mechanisms is enhanced by atomic-resolution structural information, of which relatively little is currently available. Lewy bodies, the pathological hallmark of Parkinson's disease, contain large quantities of fibrillar alpha-synuclein (AS). Here we present solid-state NMR spectroscopy studies of dried AS fibrils. The spectra have high resolution and sensitivity, and the site-resolved chemical shifts agree very well with those previously observed for hydrated fibrils. The conserved chemical shifts indicate that bulk water is nonessential to the fibril core structure. Moreover, the sample preparation procedure yields major improvements in spectral sensitivity, without compromising spectral resolution. This advance will greatly assist the atomic-resolution structural analysis of AS fibrils. PMID:17985869
Full Text Available Intraneuronal inclusions containing alpha-synuclein (a-syn constitute one of the pathological hallmarks of Parkinson's disease (PD and are accompanied by severe neurodegeneration of A9 dopaminergic neurons located in the substantia nigra. Although to a lesser extent, A10 dopaminergic neurons are also affected. Neurodegeneration of other neuronal populations, such as the cholinergic, serotonergic and noradrenergic cell groups, has also been documented in PD patients. Studies in human post-mortem PD brains and in rodent models suggest that deficits in cholinergic and dopaminergic systems may be associated with the cognitive impairment seen in this disease. Here, we investigated the consequences of targeted overexpression of a-syn in the mesocorticolimbic dopaminergic and septohippocampal cholinergic pathways. Rats were injected with recombinant adeno-associated viral vectors encoding for either human wild-type a-syn or green fluorescent protein (GFP in the ventral tegmental area and the medial septum/vertical limb of the diagonal band of Broca, two regions rich in dopaminergic and cholinergic neurons, respectively. Histopathological analysis showed widespread insoluble a-syn positive inclusions in all major projections areas of the targeted nuclei, including the hippocampus, neocortex, nucleus accumbens and anteromedial striatum. In addition, the rats overexpressing human a-syn displayed an abnormal locomotor response to apomorphine injection and exhibited spatial learning and memory deficits in the Morris water maze task, in the absence of obvious spontaneous locomotor impairment. As losses in dopaminergic and cholinergic immunoreactivity in both the GFP and a-syn expressing animals were mild-to-moderate and did not differ from each other, the behavioral impairments seen in the a-syn overexpressing animals appear to be determined by the long term persisting neuropathology in the surviving neurons rather than by neurodegeneration.
Nielsen, Mette Slot; Glud, Andreas Nørgaard; Møller, Arne; Mogensen, Poul; Doudet, Doris J; Sørensen, Jens Christian Hedemann; Bjarkam, C.R.
stems including the SN were paraffin embedded and immunohistochemically stained for tyrosine hydroxylase (TH) and alpha-synuclein. Stereological examination of the SN showed progressive nigral neuron loss with increased MPTP dosages. Occasional neuronal staining confined to the cytoplasm and cell....../day, n=12) or acute MPTP intoxication for 11 days (24 mg MPTP/day, n=2) and 9 weeks of recovery. Four pigs served as normal controls. Animals were euthanized with intracardial pentobarbital injections, transcardially perfused with 5 L 4% paraformaldehyde and the brains removed. The striatae and brain...... membrane was observed in the SN but no neuronal inclusions. In the striatum, alpha-synuclein positive staining occurred in the acutely intoxicated animals and increased in intensity with increasing doses of chronic MPTP infusion. The 12 and 18 mg animals showed swollen TH-positive terminals in the striatum...
Glucocerebrosidase 1 deficient Danio rerio mirror key pathological aspects of human Gaucher disease and provide evidence of early microglial activation preceding alpha-synuclein-independent neuronal cell death
Keatinge, Marcus; Bui, Hai; Menke, Aswin; Chen, Yu-Chia; Sokol, Anna M.; Bai, Qing; Ellett, Felix; Da Costa, Marc; Burke, Derek; Gegg, Matthew; Trollope, Lisa; Payne, Thomas; McTighe, Aimee; Mortiboys, Heather; de Jager, Sarah; Nuthall, Hugh; Kuo, Ming-Shang; Fleming, Angeleen; Schapira, Anthony H.V.; Renshaw, Stephen A.; Highley, J. Robin; Chacinska, Agnieszka; Panula, Pertti; Burton, Edward A.; O'Neill, Michael J.; Bandmann, Oliver
Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's disease (GD). Heterozygous GBA1 mutations (GBA1+/−) are the most common risk factor for Parkinson's disease (PD). Previous studies typically focused on the interaction between the reduction of glucocerebrosidase (enzymatic) activity in GBA1+/− carriers and alpha-synuclein-mediated neurotoxicity. However, it is unclear whether other mechanisms also contribute to the increased risk of PD in GBA1+/− carriers. The zebrafish genome does not contain alpha-synuclein (SNCA), thus providing a unique opportunity to study pathogenic mechanisms unrelated to alpha-synuclein toxicity. Here we describe a mutant zebrafish line created by TALEN genome editing carrying a 23 bp deletion in gba1 (gba1c.1276_1298del), the zebrafish orthologue of human GBA1. Marked sphingolipid accumulation was already detected at 5 days post-fertilization with accompanying microglial activation and early, sustained up-regulation of miR-155, a master regulator of inflammation. gba1c.1276_1298del mutant zebrafish developed a rapidly worsening phenotype from 8 weeks onwards with striking reduction in motor activity by 12 weeks. Histopathologically, we observed marked Gaucher cell invasion of the brain and other organs. Dopaminergic neuronal cell count was normal through development but reduced by >30% at 12 weeks in the presence of ubiquitin-positive, intra-neuronal inclusions. This gba1c.1276_1298del zebrafish line is the first viable vertebrate model sharing key pathological features of GD in both neuronal and non-neuronal tissue. Our study also provides evidence for early microglial activation prior to alpha-synuclein-independent neuronal cell death in GBA1 deficiency and suggests upregulation of miR-155 as a common denominator across different neurodegenerative disorders. PMID:26376862
Glucocerebrosidase 1 deficient Danio rerio mirror key pathological aspects of human Gaucher disease and provide evidence of early microglial activation preceding alpha-synuclein-independent neuronal cell death
Keatinge, Marcus; Bui, Hai; Menke, Aswin; Chen, Yu-Chia; Sokol, Anna M.; Bai, Qing; Ellett, Felix; Da Costa, Marc; Burke, Derek; Gegg, Matthew; Trollope, Lisa; Payne, Thomas; McTighe, Aimee; Mortiboys, Heather; de Jager, Sarah
Autosomal recessively inherited glucocerebrosidase 1 (GBA1) mutations cause the lysosomal storage disorder Gaucher's disease (GD). Heterozygous GBA1 mutations (GBA1 +/−) are the most common risk factor for Parkinson's disease (PD). Previous studies typically focused on the interaction between the reduction of glucocerebrosidase (enzymatic) activity in GBA1 +/− carriers and alpha-synuclein-mediated neurotoxicity. However, it is unclear whether other mechanisms also contribute to the increased ...
Full Text Available Dementia with Lewy bodies (DLB and Parkinson's Disease (PD are common causes of motor and cognitive deficits and are associated with the abnormal accumulation of alpha-synuclein (α-syn. This study investigated whether passive immunization with a novel monoclonal α-syn antibody (9E4 against the C-terminus (CT of α-syn was able to cross into the CNS and ameliorate the deficits associated with α-syn accumulation. In this study we demonstrate that 9E4 was effective at reducing behavioral deficits in the water maze, moreover, immunization with 9E4 reduced the accumulation of calpain-cleaved α-syn in axons and synapses and the associated neurodegenerative deficits. In vivo studies demonstrated that 9E4 traffics into the CNS, binds to cells that display α-syn accumulation and promotes α-syn clearance via the lysosomal pathway. These results suggest that passive immunization with monoclonal antibodies against the CT of α-syn may be of therapeutic relevance in patients with PD and DLB.
Chen, Lei-Lei; Song, Ju-Xian; Lu, Jia-Hong; Yuan, Zhen-Wei; Liu, Liang-Feng; Durairajan, Siva Sundara Kumar; Li, Min
Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the accumulation of protein aggregates (namely Lewy bodies) in dopaminergic neurons in the substantia nigra region of the brain. Alpha-synuclein (α-syn) is the major component of Lewy bodies in PD patients, and impairment of the autophagy-lysosomal system has been linked to its accumulation. In our previous study, we identified an oxindole alkaloid Corynoxine B (Cory B), isolated from Uncaria rhynchophylla (Miq.) Jacks (Gouteng in Chinese), as a Beclin-1-dependent autophagy inducer. In this work, we show that Cory, an enantiomer of Cory B, also induces autophagy in different neuronal cell lines, including N2a and SHSY-5Y cells, which is paralleled with increased lysosomal enzyme cathepsin D. In vivo, Cory promotes the formation of autophagosomes in the fat bodies of Drosophila. By inducing autophagy, Cory promotes the clearance of wild-type and A53T α-syn in inducible PC12 cells. Interestingly, different from its enantiomer Cory B, Cory induces autophagy through the Akt/mTOR pathway as evidenced by the reduction in the levels of phospho-Akt, phospho-mTOR and phospho-p70 S6 Kinase. Collectively, our findings provide experimental evidence for developing Cory as a new autophagy enhancer from Chinese herbal medicine, which may have potential application in the prevention or treatment of PD. PMID:24522518
Comellas Canal, Gemma; Lemkau, Luisel R.; Nieuwkoop, Andrew J.; Kloepper, Kathryn D.; Ladror, Daniel T.; Ebisu, Reika; Woods, Wendy S.; Lipton, Andrew S.; George, Julia M.; Rienstra, Chad M.
Alpha-Synuclein (AS) fibrils constitute the major proteinaceous component of Lewy bodies (LBs), the pathological hallmark of Parkinson’s disease (PD) and other neurodegenerative diseases. Three single point mutations in the AS gene, as well as multiplication of the wild-type (WT) AS allele, have been previously identified in families with early-onset PD. Although AS fibrils have been the subject of intense study, critical details about their structure including the precise location of the B-strands and the extent of the core, the three-dimensional structure and the effects of the mutations—remain unknown. Here, we have used magic-angle spinning solid-state NMR spectroscopy to present a detailed characterization of the full-length WT AS fibrils. With improved sample preparations, isotopic labeling patterns and NMR experiments, we have confidently assigned more than 90% of the 13C and 15N backbone and sidechain chemical shifts of the detected residues from residue 39 to 97, and quantified the conformational dynamics throughout this region. Our results demonstrate that the core of AS fibrils extends with a repeated motif and that residues 30, 46 and 53-the early-onset PD mutant sites-are located in structured regions of AS fibrils.
Nuber, Silke; Franck, Thomas; Wolburg, Hartwig; Schumann, Ulrike; Casadei, Nicolas; Fischer, Kristina; Calaminus, Carsten; Pichler, Bernd J; Chanarat, Sittinan; Teismann, Peter; Schulz, Jörg B; Luft, Andreas R; Tomiuk, Jürgen; Wilbertz, Johannes; Bornemann, Antje; Krüger, Rejko; Riess, Olaf
Synphilin-1 has been identified as an interacting protein of alpha-synuclein, Parkin, and LRRK2, proteins which are mutated in familial forms of Parkinson disease (PD). Subsequently, synphilin-1 has also been shown to be an intrinsic component of Lewy bodies in sporadic PD. In order to elucidate the role of synphilin-1 in the pathogenesis of PD, we generated transgenic mice overexpressing wild-type and mutant (R621C) synphilin-1 driven by a mouse prion protein promoter. Transgenic expression of both wild-type and the R621C variant synphilin-1 resulted in increased dopamine levels of the nigrostriatal system in 3-month-old mice. Furthermore, we found pathological ubiquitin-positive inclusions in cerebellar sections and dark-cell degeneration of Purkinje cells. Both transgenic mouse lines showed significant reduction of motor skill learning and motor performance. These findings suggest a pathological role of overexpressed synphilin-1 in vivo and will help to further elucidate the mechanisms of protein aggregation and neuronal cell death. PMID:19760259
Pelkonen, Anssi; Hiltunen, Mikko; Kiianmaa, Kalervo; Yavich, Leonid
The key neurochemical systems and structures involved in the predisposition to substance abuse and preference to ethanol (EtOH) are not known in detail but clearly dopamine (DA) is an important modulator of addiction. Recent data indicate that alpha-synuclein (alpha-syn), a pre-synaptic protein, plays a role in regulation of DA release from the pre-synaptic terminals in striatum and the expression of this protein is different after drug abuse or following abstinence. In the present work, we analysed stimulated DA overflow in the dorsal and ventral striatum in EtOH naïve alko alchohol (AA) and alko non-alchohol (ANA) rats selected for more than 100 generations for their differential EtOH preference. In the same structures, we studied the expression of alpha-syn using western blotting. AA rats, in comparison with ANA rats, showed a marked reduction of stimulated peak DA overflow and higher levels of alpha-syn in the nucleus accumbens core. In the same structure, DA re-uptake was increased in AA rats in comparison with ANA rats. The effects of EtOH at low (0.1 g/kg) and higher (3 mg/kg) doses on DA overflow measured in the nucleus accumbens shell were similar in both lines. These results indicate that high expression of alpha-syn may contribute to the reduced DA overflow and the possible activation of re-uptake in the nucleus accumbens core of AA rats in comparison with ANA rats. PMID:20533994
Full Text Available BACKGROUND: Parkinson's disease (PD, the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression or the A53T missense mutation of the presynaptic protein alpha-synuclein (SNCA. PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. METHODOLOGY/PRINCIPAL FINDINGS: Here, we used two mouse lines overexpressing human A53T-SNCA and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. To characterize the progression, we employed young adult as well as old mice. Analysis of striatal neurotransmitter content demonstrated that dopamine (DA levels correlated directly with the level of expression of SNCA, an observation also made in SNCA-deficient (knockout, KO mice. However, the elevated DA levels in the striatum of old A53T-SNCA overexpressing mice may not be transmitted appropriately, in view of three observations. First, a transcriptional downregulation of the extraneural DA degradation enzyme catechol-ortho-methytransferase (COMT was found. Second, an upregulation of DA receptors was detected by immunoblots and autoradiography. Third, extensive transcriptome studies via microarrays and quantitative real-time RT-PCR (qPCR of altered transcript levels of the DA-inducible genes Atf2, Cb1, Freq, Homer1 and Pde7b indicated a progressive and genotype-dependent reduction in the postsynaptic DA response. As a functional consequence, long term depression (LTD was absent in corticostriatal slices from old transgenic mice. CONCLUSIONS/SIGNIFICANCE: Taken together, the dysfunctional neurotransmission and impaired synaptic plasticity seen in the A53T-SNCA overexpressing mice reflect early changes within the basal ganglia prior to frank neurodegeneration. As a model of preclinical stages of PD, such insights may help to develop neuroprotective therapeutic approaches.
Marxreiter, Franz; Ettle, Benjamin; May, Verena E L; Esmer, Hakan; Patrick, Christina; Kragh, Christine Lund; Klucken, Jochen; Winner, Beate; Riess, Olaf; Winkler, Jürgen; Masliah, Eliezer; Nuber, Silke
In Parkinson's disease (PD) patients, alpha-synuclein (α-syn) pathology advances in form of Lewy bodies and Lewy neurites throughout the brain. Clinically, PD is defined by motor symptoms that are predominantly attributed to the dopaminergic cell loss in the substantia nigra. However, motor deficits are frequently preceded by smell deficiency or neuropsychological symptoms, including increased anxiety and cognitive dysfunction. Accumulating evidence indicates that aggregation of α-syn impairs synaptic function and neurogenic capacity that may be associated with deficits in memory, learning and mood. Whether and how α-syn accumulation contributes to neuropathological events defining these earliest signs of PD is presently poorly understood. We used a tetracycline-suppressive (tet-off) transgenic mouse model that restricts overexpression of human A30P α-syn to neurons owing to usage of the neuron-specific CaMKIIα promoter. Abnormal accumulation of A30P correlated with a decreased survival of newly generated neurons in the hippocampus and olfactory bulb. Furthermore, when A30P α-syn expression was suppressed, we observed reduction of the human protein in neuronal soma. However, residual dox resistant A30P α-syn was detected in glial cells within the hippocampal neurogenic niche, concomitant with the failure to fully restore hippocampal neurogenesis. This finding is indicative to a potential spread of pathology from neuron to glia. In addition, mice expressing A30P α-syn show increased anxiety-related behavior that was reversed after dox treatment. This implies that glial A30P α-synucleinopathy within the dentate gyrus is part of a process leading to impaired hippocampal neuroplasticity, which is, however, not a sole critical event for circuits implicated in anxiety-related behavior. PMID:23867236
Full Text Available Parkinson’s disease (PD is the second most common progressive neurodegenerative disorder after Alzheimer's disease (AD and represents a large health burden to society. Genetic and oxidative risk factors have been proposed as possible causes, but their relative contribution remains unclear. Dysfunction of alpha-synuclein (α-syn has been associated with PD due to its increased presence, together with iron, in Lewy bodies. Brain oxidative damage caused by iron may be partly mediated by α-syn oligomerization during PD pathology. Also, α-syn gene dosage can cause familial PD and inhibition of its gene expression by blocking translation via a newly identified Iron Responsive Element-like RNA sequence in its 5’-untranslated region may provide a new PD drug target.
Full Text Available Abstract Background Alpha synuclein (SNCA has been linked to neurodegenerative diseases (synucleinopathies that include Parkinson's disease (PD. Although the primary neurodegeneration in PD involves nigrostriatal dopaminergic neurons, more extensive yet regionally selective neurodegeneration is observed in other synucleinopathies. Furthermore, SNCA is ubiquitously expressed in neurons and numerous neuronal systems are dysfunctional in PD. Therefore it is of interest to understand how overexpression of SNCA affects neuronal function in regions not directly targeted for neurodegeneration in PD. Results The present study investigated the consequences of SNCA overexpression on cellular processes and functions in the striatum of mice overexpressing wild-type, human SNCA under the Thy1 promoter (Thy1-aSyn mice by transcriptome analysis. The analysis revealed alterations in multiple biological processes in the striatum of Thy1-aSyn mice, including synaptic plasticity, signaling, transcription, apoptosis, and neurogenesis. Conclusion The results support a key role for SNCA in synaptic function and revealed an apoptotic signature in Thy1-aSyn mice, which together with specific alterations of neuroprotective genes suggest the activation of adaptive compensatory mechanisms that may protect striatal neurons in conditions of neuronal overexpression of SNCA.
Parkinson’s disease (PD) is a neurodegenerative disease with heterogeneous pathological and clinical features. Cognitive dysfunction, a frequent non-motor complication, is a risk factor for poor prognosis and shows inter-individual variation in its progression. Of the clinical studies performed to identify biomarkers of PD progression, the Parkinson’s Progression Markers Initiative (PPMI) study is the largest study that enrolled drug-naïve and very early stage PD patients. The baseline characteristics of the PPMI cohort were recently published. The diagnostic utility of cerebrospinal fluid (CSF) biomarkers, including alpha-synuclein (α-syn), total tau, phosphorylated tau at Thr181, and amyloid β1-42, was not satisfactory. However, the baseline data on CSF biomarkers in the PPMI study suggested that the measurement of the CSF biomarkers enables the prediction of future cognitive decline in PD patients, which was consistent with previous studies. To prove the hypothesis that the interaction between Alzheimer’s pathology and α-syn pathology is important to the progression of cognitive dysfunction in PD, longitudinal observational studies must be followed. In this review, the neuropathological nature of heterogeneous cognitive decline in PD is briefly discussed, followed by a summarized interpretation of baseline CSF biomarkers derived from the data in the PPMI study. The combination of clinical, biochemical, genetic and imaging biomarkers of PD constitutes a feasible strategy to predict the heterogeneous progression of PD. PMID:27240810
Full Text Available In this study, we sought evidence for alpha-synuclein (ASYN expression in oligodendrocytes, as a possible endogenous source of ASYN to explain its presence in glial inclusions found in multiple system atrophy (MSA and Parkinson’s disease (PD. We identified ASYN in oligodendrocyte lineage progenitors isolated from the rodent brain, in oligodendrocytes generated from embryonic stem cells, and in induced pluripotent stem cells produced from fibroblasts of a healthy individual and patients diagnosed with MSA or PD, in cultures in vitro. Notably, we observed a significant decrease in ΑSYN during oligodendrocyte maturation. Additionally, we show the presence of transcripts in PDGFRΑ/CD140a+ cells and SOX10+ oligodendrocyte lineage nuclei isolated by FACS from rodent and human healthy and diseased brains, respectively. Our work identifies ASYN in oligodendrocyte lineage cells, and it offers additional in vitro cellular models that should provide significant insights of the functional implication of ASYN during oligodendrocyte development and disease.
Diepenbroek, Meike; Casadei, Nicolas; Esmer, Hakan; Saido, Takaomi C; Takano, Jiro; Kahle, Philipp J; Nixon, Ralph A; Rao, Mala V; Melki, Ronald; Pieri, Laura; Helling, Stefan; Marcus, Katrin; Krueger, Rejko; Masliah, Eliezer; Riess, Olaf; Nuber, Silke
Lewy bodies, a pathological hallmark of Parkinson's disease (PD), contain aggregated alpha-synuclein (αSyn), which is found in several modified forms and can be discovered phosphorylated, ubiquitinated and truncated. Aggregation-prone truncated species of αSyn caused by aberrant cleavage of this fibrillogenic protein are hypothesized to participate in its sequestration into inclusions subsequently leading to synaptic dysfunction and neuronal death. Here, we investigated the role of calpain cleavage of αSyn in vivo by generating two opposing mouse models. We crossed into human [A30P]αSyn transgenic (i) mice deficient for calpastatin, a calpain-specific inhibitor, thus enhancing calpain activity (SynCAST(-)) and (ii) mice overexpressing human calpastatin leading to reduced calpain activity (SynCAST(+)). As anticipated, a reduced calpain activity led to a decreased number of αSyn-positive aggregates, whereas loss of calpastatin led to increased truncation of αSyn in SynCAST(-). Furthermore, overexpression of calpastatin decreased astrogliosis and the calpain-dependent degradation of synaptic proteins, potentially ameliorating the observed neuropathology in [A30P]αSyn and SynCAST(+) mice. Overall, our data further support a crucial role of calpains, particularly of calpain 1, in the pathogenesis of PD and in disease-associated aggregation of αSyn, indicating a therapeutic potential of calpain inhibition in PD. PMID:24619358
Encounters Hanne Blitz From February 1st to 12th 2016 CERN Meyrin, Main Building What is our reaction to a first encounter with a tourist attraction? Contemporary Dutch painter Hanne Blitz captures visitors' responses to art and architecture, sweeping vistas and symbolic memorials. Encounters, a series of oil paintings curated specially for this CERN exhibition, depicts tourists visiting cultural highlights around the world. A thought-provoking journey not to be missed, and a tip of the hat to CERN's large Hadron Collider.
Rasmussen, Nadja Bredo; Olesen, Mikkel Vestergaard; Brudek, Tomasz; Plenge, Per; Klein, Anders Bue; Westin, Jenny E; Fog, Karina; Wörtwein, Gitta; Aznar, Susana
The 5-HT2A receptor is highly involved in aspects of cognition and executive function and seen to be affected in neurodegenerative diseases like Alzheimer's disease and related to the disease pathology. Even though Parkinson's disease (PD) is primarily a motor disorder, reports of impaired executive function are also steadily being associated with this disease. Not much is known about the pathophysiology behind this. The aim of this study was thereby twofold: (1) to investigate 5-HT2A receptor binding levels in Parkinson's brains and (2) to investigate whether PD associated pathology, alpha-synuclein (AS) overexpression, could be associated with 5-HT2A alterations. Binding density for the 5-HT2A-specific radioligand [(3)H]-MDL 100.907 was measured in membrane suspensions of frontal cortex tissue from PD patients. Protein levels of AS were further measured using western blotting. Results showed higher AS levels accompanied by increased 5-HT2A receptor binding in PD brains. In a separate study, we looked for changes in 5-HT2A receptors in the prefrontal cortex in 52-week-old transgenic mice overexpressing human AS. We performed region-specific 5-HT2A receptor binding measurements followed by gene expression analysis. The transgenic mice showed lower 5-HT2A binding in the frontal association cortex that was not accompanied by changes in gene expression levels. This study is one of the first to look at differences in serotonin receptor levels in PD and in relation to AS overexpression. PMID:27579212
Fernando E Herrera
Full Text Available The interplay between dopamine and alpha-synuclein (AS plays a central role in Parkinson's disease (PD. PD results primarily from a severe and selective devastation of dopaminergic neurons in substantia nigra pars compacta. The neuropathological hallmark of the disease is the presence of intraneuronal proteinaceous inclusions known as Lewy bodies within the surviving neurons, enriched in filamentous AS. In vitro, dopamine inhibits AS fibril formation, but the molecular determinants of this inhibition remain obscure. Here we use molecular dynamic (MD simulations to investigate the binding of dopamine and several of its derivatives onto conformers representative of an NMR ensemble of AS structures in aqueous solution. Within the limitations inherent to MD simulations of unstructured proteins, our calculations suggest that the ligands bind to the (125YEMPS(129 region, consistent with experimental findings. The ligands are further stabilized by long-range electrostatic interactions with glutamate 83 (E83 in the NAC region. These results suggest that by forming these interactions with AS, dopamine may affect AS aggregation and fibrillization properties. To test this hypothesis, we investigated in vitro the effects of dopamine on the aggregation of mutants designed to alter or abolish these interactions. We found that point mutations in the (125YEMPS(129 region do not affect AS aggregation, which is consistent with the fact that dopamine interacts non-specifically with this region. In contrast, and consistent with our modeling studies, the replacement of glutamate by alanine at position 83 (E83A abolishes the ability of dopamine to inhibit AS fibrillization.
Nadja Bredo Rasmussen
Full Text Available The 5-HT2A receptor is highly involved in aspects of cognition and executive function and seen to be affected in neurodegenerative diseases like Alzheimer’s disease and related to the disease pathology. Even though Parkinson’s disease (PD is primarily a motor disorder, reports of impaired executive function are also steadily being associated with this disease. Not much is known about the pathophysiology behind this. The aim of this study was thereby twofold: (1 to investigate 5-HT2A receptor binding levels in Parkinson’s brains and (2 to investigate whether PD associated pathology, alpha-synuclein (AS overexpression, could be associated with 5-HT2A alterations. Binding density for the 5-HT2A-specific radioligand [3H]-MDL 100.907 was measured in membrane suspensions of frontal cortex tissue from PD patients. Protein levels of AS were further measured using western blotting. Results showed higher AS levels accompanied by increased 5-HT2A receptor binding in PD brains. In a separate study, we looked for changes in 5-HT2A receptors in the prefrontal cortex in 52-week-old transgenic mice overexpressing human AS. We performed region-specific 5-HT2A receptor binding measurements followed by gene expression analysis. The transgenic mice showed lower 5-HT2A binding in the frontal association cortex that was not accompanied by changes in gene expression levels. This study is one of the first to look at differences in serotonin receptor levels in PD and in relation to AS overexpression.
Full Text Available BACKGROUND: Diacylglycerol kinase (DGK is an enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. DGKβ is one of the subtypes of the DGK family and regulates many intracellular signaling pathways in the central nervous system. Previously, we demonstrated that DGKβ knockout (KO mice showed various dysfunctions of higher brain function, such as cognitive impairment (with lower spine density, hyperactivity, reduced anxiety, and careless behavior. In the present study, we conducted further tests on DGKβ KO mice in order to investigate the function of DGKβ in the central nervous system, especially in the pathophysiology of attention deficit hyperactivity disorder (ADHD. METHODOLOGY/PRINCIPAL FINDINGS: DGKβ KO mice showed attention-deficit behavior in the object-based attention test and it was ameliorated by methylphenidate (MPH, 30 mg/kg, i.p.. In the open field test, DGKβ KO mice displayed a decreased response to the locomotor stimulating effects of MPH (30 mg/kg, i.p., but showed a similar response to an N-methyl-d-aspartate (NMDA receptor antagonist, MK-801 (0.3 mg/kg, i.p., when compared to WT mice. Examination of the phosphorylation of extracellular signal-regulated kinase (ERK, which is involved in regulation of locomotor activity, indicated that ERK1/2 activation induced by MPH treatment was defective in the striatum of DGKβ KO mice. CONCLUSIONS/SIGNIFICANCE: These findings suggest that DGKβ KO mice showed attention-deficit and hyperactive phenotype, similar to ADHD. Furthermore, the hyporesponsiveness of DGKβ KO mice to MPH was due to dysregulation of ERK phosphorylation, and that DGKβ has a pivotal involvement in ERK regulation in the striatum.
Kragh, Christine Lund; Romero-Ramos, Marina; Halliday, Glenda M;
The perception of Parkinson’s disease (PD) as a disease centered on dopaminergic striatonigral neurodegeneration has changed fundamentally since 1997 when the first mutation in the SNCA gene (PARK1) encoding a-synuclein was discovered (Polymeropoulos et al. 1997). This discovery formed the basis...
Langford-Smith, Alex; Langford-Smith, Kia J.; Jones, Simon A.; Wynn, Robert F.; Wraith, J. E.; Wilkinson, Fiona L.; Bigger, Brian W.
Reliable behavioural tests in animal models of neurodegenerative diseases allow us to study the natural history of disease and evaluate the efficacy of novel therapies. Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo A), is a severe, neurodegenerative lysosomal storage disorder caused by a deficiency in the heparan sulphate catabolising enzyme, sulfamidase. Undegraded heparan sulphate accumulates, resulting in lysosomal enlargement and cellular dysfunction. Patients suffer a progressive loss of motor and cognitive function with severe behavioural manifestations and premature death. There is currently no treatment. A spontaneously occurring mouse model of the disease has been described, that has approximately 3% of normal enzyme activity levels. Behavioural phenotyping of the MPS IIIA mouse has been previously reported, but the results are conflicting and variable, even after full backcrossing to the C57BL/6 background. Therefore we have independently backcrossed the MPS IIIA model onto the C57BL/6J background and evaluated the behaviour of male and female MPS IIIA mice at 4, 6 and 8 months of age using the open field test, elevated plus maze, inverted screen and horizontal bar crossing at the same circadian time point. Using a 60 minute open field, we have demonstrated that female MPS IIIA mice are hyperactive, have a longer path length, display rapid exploratory behaviour and spend less time immobile than WT mice. Female MPS IIIA mice also display a reduced sense of danger and spend more time in the centre of the open field. There were no significant differences found between male WT and MPS IIIA mice and no differences in neuromuscular strength were seen with either sex. The altered natural history of behaviour that we observe in the MPS IIIA mouse will allow more accurate evaluation of novel therapeutics for MPS IIIA and potentially other neurodegenerative disorders. PMID:22028789
Full Text Available Reliable behavioural tests in animal models of neurodegenerative diseases allow us to study the natural history of disease and evaluate the efficacy of novel therapies. Mucopolysaccharidosis IIIA (MPS IIIA or Sanfilippo A, is a severe, neurodegenerative lysosomal storage disorder caused by a deficiency in the heparan sulphate catabolising enzyme, sulfamidase. Undegraded heparan sulphate accumulates, resulting in lysosomal enlargement and cellular dysfunction. Patients suffer a progressive loss of motor and cognitive function with severe behavioural manifestations and premature death. There is currently no treatment. A spontaneously occurring mouse model of the disease has been described, that has approximately 3% of normal enzyme activity levels. Behavioural phenotyping of the MPS IIIA mouse has been previously reported, but the results are conflicting and variable, even after full backcrossing to the C57BL/6 background. Therefore we have independently backcrossed the MPS IIIA model onto the C57BL/6J background and evaluated the behaviour of male and female MPS IIIA mice at 4, 6 and 8 months of age using the open field test, elevated plus maze, inverted screen and horizontal bar crossing at the same circadian time point. Using a 60 minute open field, we have demonstrated that female MPS IIIA mice are hyperactive, have a longer path length, display rapid exploratory behaviour and spend less time immobile than WT mice. Female MPS IIIA mice also display a reduced sense of danger and spend more time in the centre of the open field. There were no significant differences found between male WT and MPS IIIA mice and no differences in neuromuscular strength were seen with either sex. The altered natural history of behaviour that we observe in the MPS IIIA mouse will allow more accurate evaluation of novel therapeutics for MPS IIIA and potentially other neurodegenerative disorders.
Soulage, Christophe; Zarrouki, Bader; Soares, Anisio Francesco; Lagarde, Michel; Geloen, Alain
Lou/C obesity-resistant rat constitutes an original model to understand the phenomena of overweight and obesity. The aim of the present study was to identify metabolic causes for the outstanding leanness of Lou/C rat. To this end, the metabolic profiles (food intake, energy expenditure, and physical activity) and the cellular characteristics of white adipose tissue (lipogenesis, lipolysis, cellularity, and lipid composition) in 30-wk-old Lou/C rats were compared with age-matched Wistar rats. Lou/C rats exhibited a lower body weight (-45%), reduced adiposity (-80%), increased locomotor activity (+95%), and higher energy expenditure (+11%) than Wistar rats. Epididymal adipose tissue of Lou/C rat was twice lower than that of Wistar rat due to both a reduction in both adipocyte size (-25%) and number (three times). Basal lipolysis and sensitivity to noradrenaline were similar; however, the responsiveness to noradrenaline was lower in adipocytes from Lou/C compared with that from Wistar rats. Lipidomic analysis of plasma, adipose tissue, and liver revealed profound differences in lipid composition between the two strains. Of note, the desaturation indexes (ratio C16:1/C16:0 and C18:1/C18:0) were lower in Lou/C, indicating a blunted activity of delta-9-desaturase such as stearoyl-coenzyme A-desaturase-1. Increased physical activity, increased energy expenditure, and white adipose tissue cellularity are in good agreement with previous observations suggesting that a higher sympathetic tone in Lou/C could contribute to its lifelong leanness. PMID:18006635
Luisel R Lemkau
Full Text Available Parkinson's disease (PD is pathologically characterized by the presence of Lewy bodies (LBs in dopaminergic neurons of the substantia nigra. These intracellular inclusions are largely composed of misfolded α-synuclein (AS, a neuronal protein that is abundant in the vertebrate brain. Point mutations in AS are associated with rare, early-onset forms of PD, although aggregation of the wild-type (WT protein is observed in the more common sporadic forms of the disease. Here, we employed multidimensional solid-state NMR experiments to assess A53T and E46K mutant fibrils, in comparison to our recent description of WT AS fibrils. We made de novo chemical shift assignments for the mutants, and used these chemical shifts to empirically determine secondary structures. We observe significant perturbations in secondary structure throughout the fibril core for the E46K fibril, while the A53T fibril exhibits more localized perturbations near the mutation site. Overall, these results demonstrate that the secondary structure of A53T has some small differences from the WT and the secondary structure of E46K has significant differences, which may alter the overall structural arrangement of the fibrils.
Giehm, Lise; Lorenzen, Nikolai; Otzen, Daniel
aggregates 1. The ability to form amyloid structures has also been exploited by living systems, where proteins forming fibrils during the normal life-cycle have functional rather than disease associated properties 2; 3; 4; 5. Thus, understanding the structural features of fibrils, as well as the processes......Over the last few decades, protein aggregation gone from being an irritating side product in the test tube to becoming a subject of great interest. This has been stimulated by the realization that a large and growing number of diseases is associated with the formation and accumulation of proteins...
Hui Liu; Xiaozhong Wang
OBJECTIVE: To review the recent progresses on the studies of α-synuclein in the pathogenesis of Parkinson disease (PD) and look into the perspective of α-synuclein as a new therapy target.DATA SOURCES: To search the literatures on the progresses of PD studies, especially on the structure, gene expression of α-synuclein and the pathogenesis of PD in Medline from January 1998 to February 2007.Search terms were "Parkinson's disease, α -synuclein" in English.STUDY SELECTION: Initial check the data and choose the original and review articles directly linked to the role of α -synuclein in PD pathogenesis and screening out indirectly discussing articles. Collect the full text and trace the quoting articles and the quoted articles. Only the latest reviews were chosen in Chinese articles.DATA EXTRACTION: There were 424 articles on α-synuclein and its role in the pathogenesis of PD and 43 articles directly related with α -synuclein were chosen among which 12 were reviews.DATA SYNTHESIS: α-synuclein is a kind of soluble protein expressed in pre-synapse in central nervous system encoded by gene in homologous chromosome 4q21. It has physiological function in modulating the stability of membrane and neural plasticity. There is a close relationship between gene mutation in α -synuclein and the pathogenesis of PD. Environmental and genetic factors can induce the misfolding of α-synuclein, and secondary structural change can result in oligomer formation which induces a series of cascade reaction to damage dopaminergic system subsequently. Cell and animal transgenic and non-transgenic models are established recently and the important role of α -synuclein in the pathogenesis both of familial and sporadic PD is confirmed. Studies reveal that inhibiting the aggregation of α -synuclein can prevent its neurotoxicity;gene parkin can intercept the cell death pathway triggered by the aggregation of α -synuclein in cytoplasm.CONCLUSION: Gene mutation of α -synuclein and the impairment in its structure and function are important in the pathogenesis of PD. Intervention of the gene mutations and abnormal protein aggregation of α -synuclein may be a new strategy for preventing and treating PD.
... Quizzes Kids' Dictionary of Medical Words En Español What Other Kids Are Reading Back-to-School Butterflies? ... Got Homework? Here's Help White House Lunch Recipes What Is Hyperactivity? KidsHealth > For Kids > What Is Hyperactivity? ...
Doğangün, Burak; Yavuz, Mesut
Attention deficit hyperactivity disorder is characterized by excessive overactiviy inattention and impulsiveness It is reported that attention deficit hyperactivity disorder affects 5 12 of children worldwide It has significant negative effects on psychological and social development and academic functioning of the children if it remains nbsp; untreated The etiology of attention deficit hyperactivity disorder is unknown Genetic neurodevelopmental neurophysiological and psychosocial factors ar...
Expression of human A53T alpha-synuclein in the rat substantia nigra using a novel AAV1/2 vector produces a rapidly evolving pathology with protein aggregation, dystrophic neurite architecture and nigrostriatal degeneration with potential to model the pathology of Parkinson's disease
Full Text Available Abstract Background The pathological hallmarks of Parkinson's disease (PD include the presence of alpha-synuclein (α-syn rich Lewy bodies and neurites and the loss of dopaminergic (DA neurons of the substantia nigra (SN. Animal models of PD based on viral vector-mediated over-expression of α-syn have been developed and show evidence of DA toxicity to varying degrees depending on the type of virus used, its concentration, and the serotype of vector employed. To date these models have been variable, difficult to reproduce, and slow in their evolution to achieve a desired phenotype, hindering their use as a model for testing novel therapeutics. To address these issues we have taken a novel vector in this context, that can be prepared in high titer and which possesses an ability to produce neuronally-directed expression, with expression dynamics optimised to provide a rapid rise in gene product expression. Thus, in the current study, we have used a high titer chimeric AAV1/2 vector, to express human A53T α-syn, an empty vector control (EV, or green fluorescent protein (GFP, the latter to control for the possibility that high levels of protein in themselves might contribute to damage. Results We show that following a single 2 μl injection into the rat SN there is near complete coverage of the structure and expression of A53T α-syn or GFP appears throughout the striatum. Within 3 weeks of SN delivery of their respective vectors, aggregations of insoluble α-syn were observed in SN DA neurons. The numbers of DA neurons in the SN were significantly reduced by expression of A53T α-syn (52%, and to a lesser extent by GFP (24%, compared to EV controls (both P P Conclusions In the current implementation of the model, we recapitulate the primary pathological hallmarks of PD, although a proportion of the SN damage may relate to general protein overload and may not be specific for A53T α-syn. Future studies will thus be required to optimise the dose of
Bousset, Luc; Pieri, Laura; Ruiz-Arlandis, Gemma; Gath, Julia; Jensen, Poul Henning; Habenstein, Birgit; Madiona, Karine; Olieric, Vincent; Böckmann, Anja; Meier, Beat H.; Melki, Ronald
α-synuclein aggregation is implicated in a variety of diseases including Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. The association of protein aggregates made of a single protein with a variety of clinical phenotypes has been explained for prion diseases by the existence of different strains that propagate through the infection pathway. Here we structurally and functionally characterize two polymorphs of α-synuclein. We present evidence that the two forms indeed fulfil the molecular criteria to be identified as two strains of α-synuclein. Specifically, we show that the two strains have different structures, levels of toxicity, and in vitro and in vivo seeding and propagation properties. Such strain differences may account for differences in disease progression in different individuals/cell types and/or types of synucleinopathies.
Lili Xiong; Peng Zhao; Zhiyun Guo; Jianhua Zhang; Diqiang Li; Canquan Mao
α-synuclein,a member of the synuclein family,is predominately expressed in brain tissues,where it is the major component of Lewy bodies,the major hallmark of Parkinson's disease.We analyzed the phylogenetics,gene structure,and effects of different forms of α-synuclein on in vitro protein aggregation.The synuclein phylogenetic tree showed that sequences could be classified into α,β,and γ protein groups.The orthologous gene α-,β-and γ-synuclein showed similar evolutionary distance to the paralogous gene α-,β-and γ-synuclein.Bioinformatics analysis suggests that the amino-acid sequence of human α-synuclein can be divided into three regions: N-terminal amphipathic region(1-60),central hydrophobic non-amyloid beta component segment(61-95),and the C-terminal acidic part(96-140).The mutant site of A30P is at the second exon of α-synuclein,whereas E46K is located at the third exon of α-synuclein.α-synuclein alternative splicing results in four isomers,and five exons,all of which participate in protein coding,comprising 140 amino acids to produce the major α-synuclein in vivo.The threeα-synuclein isoforms are products of alternative splicing,α-synuclein 126,112 and 98.We also review the genetic and cellular factors that affect the aggregation of α-synuclein and compounds that inhibit aggregation.A better understanding of α-synuclein sequences,structure,and function may allow better targeted therapy and diagnosis of α-synuclein in Parkinson's disease and other neurodegenerative diseases.
... more likely to be hyperactive if they eat sugar, artificial sweeteners, or certain food colorings. Other experts ... Some people claim that eating sugar (such as sucrose), aspartame (NutraSweet), ... and other behavior problems in children. They argue ...
Dissertation focus on problems connected with ADHD and hyperkinetic disorder. First part describes ADHD, it?s symptoms, utterances in different parts of children?s evolution, diagnosis and treatment. Main part focuses on foreknowledge, right usage of term ADHD and hyperactivity of different groups of people. As next, it focuses on finding how is the situation with recognizing of ADHD and diagnosis and consecutive work with these children.
Mortensen, Marianne Foss
, and 3) a synthesis of the findings from the first two studies with findings from the literature to generate two types of results: a coherent series of suggestions for a design iteration of the studied exhibit as well as a more general normative model for exhibit engineering. Finally, another...
The immersive exhibition is a specialized exhibition genre in museums, which creates the illusion of time and place by representing key characteristics of a reference world and by integrating the visitor in this three-dimensionally reconstructed world (Mortensen 2010). A successful representation...
The exhibition Upcycle, at Athens Institute of Contemporary Art (ATHICA‘) in Athens, Georgia, USA. opens in congruence with Earth Day on April 22nd, 2012. Upcycle celebrates over twenty artists’ creative approaches to material re-use, materials destined to become landfill fodder — or worse, toxic pollution — are reborn as these artists dream them out of the waste stream. Curated by Lizzie Zucker Saltz with the assistance of Katie Faulkner, the exhibit will run through Athfest weekend, clos...
Corominas-Roso, Margarida; Palomar, Gloria; Ferrer, Roser; Real, Alberto; Nogueira, Mariana; Corrales, Montserrat; Casas, Miguel; Ramos-Quiroga, Josep Antoni
Background: Differences in the cortisol response have been reported between children exhibiting the inattentive and hyperactive/impulsive subtypes of attention deficit hyperactivity disorder. However, there is no such information about adults. The aim of the present study was to determine the possible differences between the combined and inattentive subtypes in the cortisol response to stress. Methods: Ninety-six adults with attention deficit hyperactivity disorder, 38 inattentive and 58 comb...
INDIANAPOLIS CITY ENGAGEMENT PROJECTS BY SIX INTERNATIONALLY ACTIVE ARTISTS How can you understand your city more deeply? This exhibition presents the ways in which the Indianapolis-based informal collective We Are City has answered that question over the past two years. At the center of this show are the products of We Are City’s artist-in-residence program, which has brought six internationally active artists into conversation with Indianapolis residents. Featuring these artists’ visual, a...
Over the last two decades, there have been numerous technical and methodological advances available to clinicians and researchers to better understand attention deficit hyperactivity disorder (ADHD) and its etiology. Despite the growing body of literature investigating the disorder’s pathophysiology, ADHD remains a complex psychiatric disorder to characterize. This chapter will briefly review the literature on ADHD, with a focus on its history, the current genetic insights, neurophysiologic t...
Thapar, Anita; Cooper, Miriam
Attention deficit hyperactivity disorder (ADHD) is a childhood-onset neurodevelopmental disorder with a prevalence of 1·4-3·0%. It is more common in boys than girls. Comorbidity with childhood-onset neurodevelopmental disorders and psychiatric disorders is substantial. ADHD is highly heritable and multifactorial; multiple genes and non-inherited factors contribute to the disorder. Prenatal and perinatal factors have been implicated as risks, but definite causes remain unknown. Most guidelines recommend a stepwise approach to treatment, beginning with non-drug interventions and then moving to pharmacological treatment in those most severely affected. Randomised controlled trials show short-term benefits of stimulant medication and atomoxetine. Meta-analyses of blinded trials of non-drug treatments have not yet proven the efficacy of such interventions. Longitudinal studies of ADHD show heightened risk of multiple mental health and social difficulties as well as premature mortality in adult life. PMID:26386541
Abstract Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioural disorder in childhood, affecting over 5% of children worldwide. As well as the core symptoms of inattention, hyperactivity and impulsivity, patients often exhibit learning difficulties and impairment in social functioning. The frequency of referral is higher for boys than for girls (about 2:1), and girls are generally older at the time of referral. Pharmacological therapy is considered the...
... review our exit disclaimer . Subscribe Focusing on ADHD Attention Deficit Hyperactivity Disorder Most children get restless, rowdy, or distracted at ... might be signs of a developmental disorder called attention deficit hyperactivity disorder, or ADHD. ADHD is a common brain condition ...
This podcast discusses Attention Deficit Hyperactivity Disorder, or ADHD, the most common behavioral disorder in children. Learn about symptoms, risk factors, and treatment. Created: 4/10/2014 by National Center on Birth Defects and Developmental Disabilities (NCBDDD). Date Released: 5/7/2014.
Gold, Sandra; Sherry, Lee
A review of research on the effects of alcohol consumption by pregnant women supports the U.S. Food and Drug Administration's warning about the possible negative effects (learning disabilities, hyperactivity, short attention span, and emotional liability) of children. (Author/CL)
Carlson, E A; Jacobvitz, D; Sroufe, L A
The development of inattentiveness and hyperactivity in middle childhood was investigated using a prospective longitudinal approach. Endogenous and exogenous predictors measured in infancy and in early and middle childhood were examined independently and in combination. In early childhood, quality of caregiving more powerfully predicted distractibility, an early precursor of hyperactivity, than did early biological or temperament factors. Caregiving and contextual factors together with early distractibility significantly predicted hyperactivity in middle childhood. While environmental variables also predicted hyperactivity in later elementary years, these factors did not improve the prediction beyond the influence of hyperactivity in early elementary years. The findings support a developmental view of the origins and course of hyperactivity in childhood, that is, that the emergence and persistence of AD/HD symptoms depend on developmental history along with current circumstances. PMID:7497828
Bertin; CERN PhotoLab
The United Kingdom inaugurated the Industrial Exhibitions in 1968, and it wasn't till 1971 that other countries staged exhibitions at CERN. This photo was taken in 1969, at the second British exhibition, where 16 companies were present.
@@ China's exhibition industry, often renowned as the locomotive of the tertiary industry, has developed rapidly in recent years and has become the sunrise industry and gets much concern. However, in exhibition industry circles in China, there is a saying being passed around "rushed exhibitions with bad service, property rights protection is badly needed; a low threshold with high demand, and 5 out of 10 exhibitions are disorganized." This jingle reflects many problems that currently exist in the exhibition industry in China.
Gordon, Michael; Oshman, Harvey
The Rorschach protocols of 20 boys (ages 6-11 years) rated by their teachers as hyperactive and those of 20 nonhyperactive boys were compared along 16 indices. Findings are discussed in terms of the assessment of hyperactivity within a conceptual framework which regards impulsivity as a major underlying dimension. (Author/SJL)
Den Houtter, Kathryn
Results from recent studies on the effectiveness of Ritalin for "hyperactivity" show that this treatment is dubious at best. This article presents an alternative treatment approach, placing emphasis on devising an appropriate learning situation that meets the needs of the so-called hyperactive child. (Author)
Ryan, Joseph B.; Katsiyannis, Antonis; Hughes, Elizabeth M.
Attention deficit hyperactivity disorder (ADHD) has become the most commonly diagnosed psychiatric disorder among school-age children. For more than half a century, physicians have prescribed medications to help manage behaviors such as hyperactivity, impulsivity, and inattention. Today, there is a growing consensus that ADHD is a biologically…
Wolraich, Mark L
Attention-deficit hyperactivity disorder (ADHD) is a challenging condition to diagnose and treat. For diagnosis, the clinician needs to establish the presence of ADHD on Diagnostic and Statistical Manual of Mental Disorders criteria requiring information from parents and teachers and considering both alternative diagnoses and co-occurring conditions. In the treatment of ADHD as a chronic illness, the clinician needs to educate the family about the condition and partner with them about treatment decisions. The 2 treatments with demonstrated efficacy for ADHD are medications (stimulant medications and a selective norepinephrine reuptake inhibiter) and behavior-modification programs. PMID:17178358
Evans, Steven W.; And Others
Two studies evaluated a notetaking intervention targeting the passive learning style and disruptive behaviors exhibited by adolescents with attention deficit hyperactivity disorder. Thirty teens in a summer program were able to learn notetaking strategies using a modification of the Directed Notetaking Activity training method and showed…
Today's libraries are taking advantage of cutting-edge technologies such as flat panel displays using touch, sound, and hands-free motions to design amazing exhibits using everything from simple computer hardware to advanced technologies such as the Microsoft Kinect. Libraries of all types are striving to add new interactive experiences for their patrons through exciting digital exhibits, both online and off. Digital Collections and Exhibits takes away the mystery of designing stunning digital exhibits to spotlight library trea
Vick, Randy M.
This article discusses ethical questions raised by an exhibition of work by an artist with a history of mental illness and the exhibition's relevance to art therapy and “outsider art” discourse on the subject. Considerations for how such an exhibit could be handled had the circumstances included an art therapist and art therapy client are…
Ping Yang; Guoqiang Cai; Youqing Cai; Jian Fei; Guoxiang Liu
Attention deficit/hyperactivity disorder (ADHD) is characterized by hyperactivity,impaired sustained attention,impulsivity,and is usually accompanied by varying degrees of learning difficulties and lack of motor coordination.However,the pathophysiology and etiology of ADHD remain inconclusive so far.Our previous studies have demonstrated that the gamma aminobutyric acid transporter subtype 1 (GAT1) gene knockout (ko) mouse (gat1-/-)is hyperactive and exhibited impaired memory performance in the Morris water maze.In the current study,we found that the gat1-/-mice showed low levels of attentional focusing and increased impulsivity.In addition,the gat1-/-mice displayed ataxia characterized by defects in motor coordination and balance skills.The hyperactivity in the ko mice was reduced by both methylphenidate and amphetamine.Collectively,these results suggest that GAT1 ko mouse is a new animal model for ADHD studying and GAT1 may be a new target to treat ADHD.
Tao Chen; Beisha Tang; Xiaoping Liao; Guoqiang Wen; Xinxiang Yan; Jifeng Guo; Yuhu Zhang; Feng Ouyang; Zhigang Long; Li Cao; Jing Li
BACKGROUND: Overexpression of o-synuclein can induce cell apoptosis. RNA interference (RNAi)may block specific gene function and cause gene silencing.OBJECTIVE: To construct a specific and effective RNAi plasmid for the a-synuclein gene and investigate if RNAi can block apoptosis in HEK293 cells, induced by overexpression of wild-type α-synuclein.DESIGN, TIME AND SETTING: A contrast experiment based on genetically engineered cytobiology was performed at the State Key Lab of Medical Genetics of China, Xiangya Medical College of Central South University, between October 2004 and October 2008.MATERIALS: HEK293 cells and pBSHH1 plasmid were provided by the State Key Lab of Medical Genetics of China; OligDNA sequence by Sagon Bioengineering Company, Shanghai;Lipofectamine 2000 by Invitrogen, USA;α-synuclein monoclonal antibody, Hoechst 33258, and MTT by Sigma, USA; Horseradish peroxidase-coupled goat anti-rat luG by KPL, USA; FACSan flow cytometry by BD, USA.METHODS: Four target sites were used to construct hairpin RNA pBSHH1 vectors-pSYNi-1,pSYNi-2, pSYNi-3 and pSYNi-4-which were cloned in the pBSHH1 plasmid. HEK293 cells were transfected using Lipofectamine 2000. In addition, a non-transfect group and a negative plasmid transfect group were established. The cultured HEK293 cells were processed as follows:transfection of blank plasmid (blank control group), transfection of α-synuclein-pEGFP and RNAi negative vector (negative control group), and transfection of a-synuclein-pEGFP and pSYNi-1 (transfection group). Cells in all groups were transfected with Lipofectamine 2000 for 48 hours.MAIN OUTCOME MEASURES: Expression of α-synuclein mRNA and protein were detected by RT-PCR and Western blot. Cell morphology was observed under an inverted fluorescence microscope; cell viability was measured using MTT method; and cell apoptosis was determined with Annexin V-PE flow cytometry.RESULTS: a-synuclein mRNA and protein expressions were significantly decreased in the pSYNi-1 group when compared with the non-transfect and negative plasmid transfect groups (P<0.05). The expressions were partially decreased in the pSYNi-2 group, but there was no significant difference in the pSYNi-3 and pSYNi-4 groups. Hoechst staining indicated that cell nuclei were enlarged in the negative control group, coloring was not uniform, and chromatin was accumulated and appeared spot-like. The nucleus coloring was uniform in the transfection group compared to negative control group. Cell viability in the negative control group was significantly lower than blank control group with cell apoptosis being significantly increased (P<0.05). In comparison with negative control group,cell viability was significantly increased in the transfection group and cell apoptosis was significantly decreased (P<0.05).CONCLUSION: pSYNi-1 can inhibit α-synuclein gene expression and block apoptosis of HEK293 cells induced by overexpression of wild-type a-synuclein.
Thome, Aaron D; Harms, Ashley S; Volpicelli-Daley, Laura A; Standaert, David G
Increasing evidence points to inflammation as a chief mediator of Parkinson's disease (PD), a progressive neurodegenerative disorder characterized by loss of dopamine neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein α-synuclein (α-syn). Recently, microRNAs, small, noncoding RNAs involved in regulating gene expression at the posttranscriptional level, have been recognized as important regulators of the inflammatory environment. Using an array approach, we found significant upregulation of microRNA-155 (miR-155) in an in vivo model of PD produced by adeno-associated-virus-mediated expression of α-syn. Using a mouse with a complete deletion of miR-155, we found that loss of miR-155 reduced proinflammatory responses to α-syn and blocked α-syn-induced neurodegeneration. In primary microglia from miR-155(-/-) mice, we observed a markedly reduced inflammatory response to α-syn fibrils, with attenuation of major histocompatibility complex class II (MHCII) and proinflammatory inducible nitric oxide synthase expression. Treatment of these microglia with a synthetic mimic of miR-155 restored the inflammatory response to α-syn fibrils. Our results suggest that miR-155 has a central role in the inflammatory response to α-syn in the brain and in α-syn-related neurodegeneration. These effects are at least in part due to a direct role of miR-155 on the microglial response to α-syn. These data implicate miR-155 as a potential therapeutic target for regulating the inflammatory response in PD. PMID:26911687
Tianhong Pan; Julie Zhu; Wen-Jen Hwu; Joseph Jankovic
The relatively high co-occurrence of Parkinson's disease (PD) and melanoma has been established by a large number of epidemiological studies. However, a clear biological explanation for this finding is still lacking. Ultra-violet radiation (UVR)-induced skin melanin synthesis is a defense mechanism against UVR-induced damage relevant to the initiation of melanoma, whereas, increased neuromelanin (NM), the melanin synthesized in dopaminergic neurons, may enhance the susceptibility to oxidative...
Both increased temperature and moderate concentrations of fluorinated alcohols enhance aggregation of the Parkinson's disease-associated protein α-synuclein (αS). Here, we investigate the secondary structural rearrangements induced by heating and trifluoroethanol [TFE]. At low TFE concentrations, CD spectra feature a negative peak characteristic of disordered polypeptides near 200 nm and a slight shoulder around 220 nm suggesting some polyproline-II content. Upon heating, these peaks weaken, while a weak negative signal develops at 222 nm. At high TFE concentrations, the spectra show distinct minima at 208 and 222 nm, indicative of considerable α-helical structure, which diminish upon heating. We observe a crossover between the low-TFE and high-TFE behavior near 15% TFE, where we previously showed that a partially helical intermediate is populated. We postulate that the protein is well solvated by water at low TFE concentrations and by TFE at high TFE concentrations, but may become desolvated at the crossover point. We discuss the potential roles and interplay of desolvation and helical secondary structure in driving αS aggregation. (paper)
Klucken, Jochen; Poehler, Anne-Maria; Ebrahimi-Fakhari, Darius; Schneider, Jacqueline; Nuber, Silke; Rockenstein, Edward; Schlötzer-Schrehardt, Ursula; Hyman, Bradley T; McLean, Pamela J; Masliah, Eliezer; Winkler, Juergen
Synucleinopathies like Parkinson disease and dementia with Lewy bodies (DLB) are characterized by α-synuclein aggregates within neurons (Lewy bodies) and their processes (Lewy neurites). Whereas α-synuclein has been genetically linked to the disease process, the pathological relevance of α-synuclein aggregates is still debated. Impaired degradation is considered to result in aggregation of α-synuclein. In addition to the ubiquitin-proteasome degradation, the autophagy-lysosomal pathway (ALP) is involved in intracellular degradation processes for α-synuclein. Here, we asked if modulation of ALP affects α-synuclein aggregation and toxicity. We have identified an induction of the ALP markers LAMP-2A and LC3-II in human brain tissue from DLB patients, in a transgenic mouse model of synucleinopathy, and in a cell culture model for α-synuclein aggregation. ALP inhibition using bafilomycin A 1 (BafA1) significantly potentiates toxicity of aggregated α-synuclein species in transgenic mice and in cell culture. Surprisingly, increased toxicity is paralleled by reduced aggregation in both in vivo and in vitro models. The dichotomy of effects on aggregating and nonaggregating species of α-synuclein was specifically sensitive to BafA1 and could not be reproduced by other ALP inhibitors. The present study expands on the accumulating evidence regarding the function of ALP for α-synuclein degradation by isolating an aggregation specific, BafA1-sensitive, ALP-related pathway. Our data also suggest that protein aggregation may represent a detoxifying event rather than being causal for cellular toxicity. PMID:22647715
Barkholt, Pernille; Sanchez-Guajardo, Vanesa Maria; Kirik, Denis; Romero-Ramos, Marina
We have previously shown that persistent ﰇ-sy- nuclein overexpression in ventral midbrain of marmoset leads to a distinctive neurodegenerative process and motor defects. The neurodegeneration was confined to caudate putamen dopaminergic fibers in animals overexpressing wild-type (wt) ﰇ-synuclein.......We have previously shown that persistent ﰇ-sy- nuclein overexpression in ventral midbrain of marmoset leads to a distinctive neurodegenerative process and motor defects. The neurodegeneration was confined to caudate putamen dopaminergic fibers in animals overexpressing wild-type (wt) ﰇ......-synuclein showed a long-term increase in microglia presenting macrophagic morphology. However, wt ﰇ-synuclein overexpression, despite the ab- sence of dopaminergic cell death, resulted in a permanent robust increase of the microglia population characterized by a range of distinct morphological types that persisted...... after 1 year. These results confirm that the microglial response dif- fers depending on the type of ﰇ-synuclein (wt/A53T) and/or whether ﰇ-synuclein expression results in cell death or not, suggesting that microglia may play different roles during disease progression. Furthermore, the microglial...
Devine, M.J.; Ryten, M.; Vodička, Petr; Thomson, A.J.; Burdon, T.; Houlden, H.; Cavaleri, F.; Nagano, M.; Drummond, N.J.; Taanman, J.W.; Schapira, A.H.; Gwinn, K.; Hardy, J.; Lewis, P.A.; Kunath, T.
Roč. 2, č. 440 (2011), s. 1-1. ISSN 2041-1723 Institutional research plan: CEZ:AV0Z50450515 Keywords : gene duplication * dementia * association Subject RIV: FH - Neurology Impact factor: 7.396, year: 2011
Abstract: The article analyses the new permanent exhibition in the composer Wolfgang A. Mozart’s apartment in Vienna, opened in 2006, from the curator’s perspective. The exhibition presents an approach to biographical display in which the exhibited person becomes part of a multifaceted web of contexts, and the article argues for the active deployment of the polysemic character of objects as a means of grasping the complexity of a person’s biography. Presenting a concept for the...
China's convention and exhibition industry has grown rapidly in recent years, with some of the nation's key cities becoming hubs of internationally renowned expositions, spurred by the construction of new exhibition centers.In 2003, a total of 3,298 conventions and exhibitions were held in China, up from 3,075 in the previous year. The number is estimated to have hit 4,000 in 2004.
Baijal, Shruti; Gupta, Rashmi
Recent studies suggest that training-based measures are effective in improving cognitive skills. Meditation-based training has produced lasting changes in brain and cognitive functions. This technique of mental training exhibits neuroplasticity in the attentional networks, exhibiting superior performance, especially in the domain of attention and executive control processing, which is impaired in attention deficit hyperactivity disorder (ADHD). Although intervention techniques for ADHD are we...
... this? Submit What's this? Submit Button NCHS Home Attention Deficit Hyperactivity Disorder (ADHD)* Recommend on Facebook Tweet ... physician offices, hospital outpatient and emergency departments) with attention deficit disorder as primary diagnosis: 9.0 million ( ...
This article touches on the role of Malaysian Nuclear Agency as nuclear research institutions to promote, develop and encourage the peaceful uses of nuclear technology in its agricultural, medical, manufacturing, industrial, health and environment for the development of the country running successfully. Maturity of Malaysian Nuclear Agency in dealing with nuclear technology that are very competitive and globalization cannot be denied. On this basis Malaysian Nuclear Agency was given the responsibility to strengthen the nuclear technology in Malaysia. One way is through an exhibition featuring the research, discoveries and new technology products of the nuclear technology. Through this exhibition is to promote the nuclear technology and introduce the image of the agency in the public eye. This article also states a number of exhibits entered by the Malaysian Nuclear Agency and achievements during the last exhibition. Authors hope that the exhibition can be intensified further in the future.
Behavioural characterisation of rats exposed neonatally to bisphenol-A: responses to a novel environment and to methylphenidate challenge in a putative model of attention-deficit hyperactivity disorder.
Kiguchi, M.; Fujita, S.; Oki, H.; Shimizu, N.; Cools, A.R.; Koshikawa, N.
Neonatal exposure of rats to bisphenol-A, an endocrine disruptor, has recently been proposed as a possible animal model of attention-deficit hyperactivity disorder (ADHD), because such rats exhibit motor hyperactivity. To strengthen the face validity of this animal model, the present study replicate
Carpenter, Ele; Mabb, David; Craighead, Alison; Crowe, Nick; Schuppli, Susan; Takeuchi, Kota; Erika, Kobayashi
Material Nuclear Culture is an exhibition of contemporary artists responses to the physical qualities and material traces of the aesthetics, traditions and legacy of nuclear powered submarines in the UK. Whilst the MOD is currently undertaking a public consultation process on how and where to dismantle and store Britain’s old subs the long term problems of storing radioactive waste remain unresolved. The exhibition will include new sculptural, film, sound and installation works by David ...
By means of 20 visual aids, the NOK mobile exhibition aims to illustrate how the NOK satisfies the power requirements of two million people in nine cantons. Of particular interest are the graphs of daily and annual consumption. Examples of the exhibits are a flow model which at the touch of a button demonstrates to the visitor how a pumped-storage or nuclear power station operates, and a model of power transmission. (R.S.)
An exhibition of plastic arts and two evenings of performances by sound and visual artists as part of CERN's 50th anniversary celebrations. Fifty candles for CERN, an international laboratory renowned for fundamental research, is a cause for celebration. Since March this year, Geneva and neighbouring parts of France have been the venues for a wealth of small and large-scale events, which will continue until November. Given CERN's location in the commune of Meyrin, the ForuMeyrin is hosting exhibitions of plastic arts and performances entitled: Accelerated Particles. Several works will be exhibited and performed in two 'salons'. Salon des matières: An exhibition of plastic arts From Tues 12 October to Wed 3 November 2004 Tuesdays to Fridays: 16:00 to 19:00 Saturdays: 14:00 to 18:00 Exhibition open late on performance nights, entrance free Salon des particules: Musical and visual performances Tues 12 and Mon 25 October from 20:00 to 23:00 Preview evening for both events: Tues 12 October from 18:...
To complete the revamp of CERN’s Council Chamber, a new exhibition is being installed just in time for the June Council meetings. Panels will showcase highlights of CERN’s history, using some of the content prepared for the exhibitions marking 50 years of the PS, which were displayed in the main building last November. The previous photo exhibition in the Council Chamber stopped at the 1970s. To avoid the new panels becoming quickly out of date, photos are grouped together around specific infrastructures, rather than following a classic time-line. “We have put the focus on the accelerators – the world-class facilities that CERN has been offering researchers over the years, from the well-known large colliders to the lesser-known smaller facilities,” says Emma Sanders, who worked on the content. The new exhibition will be featured in a future issue of the Bulletin with photos and an interview with Fabienne Marcastel, designer of the exhibit...
Poulsen, Lotte; Jørgensen, Siv Lykke; Dalsgaard, Søren;
INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is characterized by inattention, hyperactivity and impulsivity. The diagnostic classification is based on developmental anamnesis, objective examination, neuropsychological tests, observation of the child, and evaluation of the symptoms...
Sykes, Donald H.; And Others
Hyperactive children treated with methylphenidate (ritalin) showed a significant improvement in all aspects of performance in an experimenter-paced task when compared to a control group of hyperactive children given a placebo. (Author/WY)
http://www.cern.ch/cern50/ An exhibition of plastic arts and two evenings of performances by sound and visual artists as part of CERN's fiftieth anniversary celebrations. The fiftieth anniversary of a world famous organization like CERN, an international laboratory specializing in fundamental research, is a cause for celebration. Since March this year, Geneva and neighbouring parts of France have been the venues for a wealth of small and large-scale events, which will continue until November. Given CERN's location in the commune of Meyrin, the ForuMeyrin is hosting two "salons" consisting of an exhibition of plastic arts and evenings of music and visual arts performances with the collective title of "Accelerated Particles". Several works will be exhibited and performed. Salon des matières: An exhibition of plastic arts Until Wednesday 3 November 2004. Tuesdays to Fridays: 4.00 p.m. to 7.00 p.m. Saturdays: 2.00 p.m. to 6.00 p.m. Doors open late on the evening of the performances. Salon des ...
Adan, R A H; Hillebrand, J J G; Danner, U N; Cardona Cano, S; Kas, M J H; Verhagen, L A W
Hyperactivity in anorexia nervosa is difficult to control and negatively impacts outcome. Hyperactivity is a key driving force to starvation in an animal model named activity-based anorexia (ABA). Recent research has started unraveling what mechanisms underlie this hyperactivity. Besides a general i
Raya Trenas, Antonio Félix; Herreruzo Cabrera, Javier; Pino Osuna, María José
The present study aims to determine the relationship among factors that make up the parenting styles according to the PCRI (Parent-Child Relationship Inventory) and hyperactivity reported by parents through the BASC (Behaviour Assessment System for Children). We selected a sample of 32 children between 3 and 14 years old (23 male and 9 female) with risk scores in hyperactivity and another similar group with low scores in hyperactivity. After administering both instruments to the parents, we carried out a binomial logistic regression analysis which resulted in a prediction model for 84.4% of the sample, made up of the PCRI factors: fathers' involvement, communication and role orientation, mothers' parental support, and both parents' limit-setting and autonomy. Moreover, our analysis of the variance produced significant differences in the support perceived by the fathers and mothers of both groups. Lastly, the utility of results to propose intervention strategies within the family based on an authoritative style is discussed. PMID:18940070
Explore by yourself the issues CERN's physicists are trying to solve: given that the entire universe is made of particles, where do they come from? Why do they behave in the way they do? Discover the massive apparatus used by physicists at CERN, like the LHC, and see how each part works. And if you have more time on site, follow the LHC circuit at ground level to understand in situ this giant machine. Enter our exhibitions. Welcome!
Summer is coming - and with it, a new Microcosm exhibition showcasing CERN (see here). But while the new exhibit is preparing to enchant visitors, many have been asking about the site's former content. Will it simply be out with the old and in with the new? Not as such! The plasma ball from Microcosm is now on display at the LHCb site. As Microcosm's new content is moving in, its old content is moving up. From LHCb to IdeaSquare, former Microcosm displays and objects are being installed across the CERN site. "Microcosm featured many elements that were well suited to life outside of the exhibition," says Emma Sanders, Microcosm project leader in the EDU group. "We didn't want this popular content to go to waste, and so set out to find them new homes across CERN." The LHCb experiment has received a number of Microcosm favourites, including the Rutherford experiment, the cosmic ray display and the Thomson experiment. "We&...
Presenting the complexity of geosciences to the public via the Internet poses a number of challenges. For example, utilizing various - and sometimes redundant - Web 2.0 tools can quickly devour limited time. Do you tweet? Do you write press releases? Do you create an exhibit or concept map? The presentation will provide participants with a context for utilizing Web 2.0 tools by briefly highlighting methods of online scientific communication across several dimensions. It will address issues of: * breadth and depth (e.g. from narrow topics to well-rounded views), * presentation methods (e.g. from text to multimedia, from momentary to enduring), * sources and audiences (e.g. for experts or for the public, content developed by producers to that developed by users), * content display (e.g. from linear to non-linear, from instructive to entertaining), * barriers to entry (e.g. from an incumbent advantage to neophyte accessible, from amateur to professional), * cost and reach (e.g. from cheap to expensive), and * impact (e.g. the amount learned, from anonymity to brand awareness). Against this backdrop, the presentation will provide an overview of two methods of online information dissemination, exhibits and concept maps, using the WebExhibits online museum (www.webexhibits.org) and SpicyNodes information visualization tool (www.spicynodes.org) as examples, with tips on how geoscientists can use either to communicate their science. Richly interactive online exhibits can serve to engage a large audience, appeal to visitors with multiple learning styles, prompt exploration and discovery, and present a topic’s breadth and depth. WebExhibits, which was among the first online museums, delivers interactive information, virtual experiments, and hands-on activities to the public. While large, multidisciplinary exhibits on topics like “Color Vision and Art” or “Calendars Through the Ages” require teams of scholars, user interface experts, professional writers and editors
Cross-Villasana, Fernando; Finke, Kathrin; Hennig-Fast, Kristina;
Abstract Background: Adults with Attention Deficit/Hyperactivity Disorder (ADHD) exhibit slowed reaction times (RTs) in various attention tasks. The exact origins of this slowing, however, have not been yet established. Potential candidates are early sensory processes mediating the deployment of ...
Jitendra, Asha K.; DuPaul, George J.; Someki, Fumio; Tresco, Katy E.
Although children with Attention-Deficit Hyperactivity Disorder (ADHD) exhibit significant academic difficulties in school settings, considerably less attention is devoted to remediating their academic problems when compared to behavioral and social difficulties. The purpose of this article is to review empirically supported academic interventions…
DuPaul, George J.; Weyandt, Lisa L.
Children with Attention Deficit Hyperactivity Disorder (ADHD) exhibit significant academic, social, and behavioural difficulties in school settings. This article reviews empirical findings regarding the effects of classroom interventions for students with ADHD. Three major types of interventions are reviewed including behavioural (e.g., token…
Yerys, Benjamin E.; Wallace, Gregory L.; Sokoloff, Jennifer L.; Shook, Devon A.; James, Joette D.; Kenworthy, Lauren
Recent estimates suggest that over 30% of children with autism spectrum disorders (ASD) meet diagnostic criteria for attention deficit/hyperactivity disorder (ADHD), and another 20% of children with ASD exhibit subthreshold clinical ADHD symptoms. Presence of ADHD symptoms in the context of ASD could have a variety of effects on cognition, autistic traits, and adaptive/maladaptive behaviors including: exacerbating core ASD impairments; adding unique impairments specific to ADHD; producing new...
Albrecht, B.; Brandeis, D; Uebel, H.; Valko, L; H. Heinrich; Drechsler, R; Heise, A.; Müller, U C; Steinhausen, H.-C.; Rothenberger, A.; Banaschewski, T.
BACKGROUND: Patients with attention deficit-hyperactivity disorder (ADHD) exhibit difficulties in multiple attentional functions. Although high heritability rates suggest a strong genetic impact, aetiological pathways from genes and environmental factors to the ADHD phenotype are not well understood. Tracking the time course of deviant task processing using event-related electrophysiological brain activity should characterize the impact of familiality on the sequence of cognitive functions fr...
Context: The aim of this study was to determine the experimental evidence of treatment/intervention programs for deficits in social skills, attention, and behavioral disorder in children and adolescents with attention deficit hyperactivity disorder (ADHD). Evidence Acquisition: Meta-analysis procedures were employed to investigate whether children and adolescents with ADHD exhibit deficits in attention and social skills. A total of 17 empirical research studies published between 2000 and 2013...
enveloped by the design process but also by the end product, which is an artefact. Design is much more than a given form that serves the function of an object. I will provide an illustrative case example focuses on the processes of developing the visual and symbolic design of a small poster exhibition by...... following the design-thinking processes in detail. The fundamental concept is an introverted analysis completed by giving one person two roles, that of designer and researcher. The result is a dialogue concerning the processual experience as a reflection-in-action. The contribution to a general core of...
Miller, C L; Burmeister, M; Stevens, K E
The mouse mutants mocha (mh) and mocha2J (mh2J) result from separate mutations in the same gene (AP-3 delta) that arose independently on different backgrounds of inbred strains. They exhibit a neurological phenotype that includes hyperactivity, an epileptiform EEG and changes in the basic function of the hippocampus. Depth electrode recordings of hippocampal auditory evoked potentials revealed that the response to the first of two paired tones was significantly enhanced in mocha and mocha2J, as compared with littermate controls. The pronounced theta rhythm characteristic of unanesthetized mocha mice was not observed in these chloral-hydrate anesthetized mice, whereas spike discharge activity was frequently present in the recordings. PMID:10586974
Since January this year, a mobile atomic energy exhibition has been touring the principal cities of Mexico. In organizing this exhibition, the National Nuclear Energy Commission of Mexico was assisted by the International Atomic Energy Agency which has placed its second mobile radioisotope laboratory at the disposal of the Mexican authorities. In many States of the Republic, the visit of the mobile laboratory has given a powerful impetus to atomic training and research. Universities have made use of the laboratory for the training of young scientists in the basic isotope techniques. As a sequel to the work initiated with its aid, some universities are planning to start regular training courses in this field. The laboratory, which is a gift to the Agency from the United States, has been put to its first assignment in Mexico. It will shortly be sent to Argentina for a period of six months for use in training courses. IAEA's first mobile radioisotope unit, also donated by the United States, has been used for training purposes in Austria, the Federal Republic of Germany, Greece and Yugoslavia, and has now been sent to the Far East
Shaywitz, B A; Fletcher, J M; Shaywitz, S E
In this chapter we have reviewed the diagnosis and management of attention deficit disorder, focusing particularly on the role of stimulant therapy in ADHD. Hisorical review suggests that ADHD has roots that extend back almost a century. The definition of ADHD is based on inclusion and exclusion criteria that are established by history and reflect behavioral concerns. Attention-deficit/hyperactivity disorder is a chronic disorder affecting the child's home, school, and community life. The primary symptoms of the disorder manifest a developmental pattern: activity diminishes while attentional deficits persist. Major sources of concern are the secondary and often more resistant problems of learning difficulties, behavioral problems, lack of peer acceptance, and low self-esteem. An often frustrating and perplexing characteristic of the disorder is its marked variability-over time, across situations, and within the same child and similar situations. Educational management represents an important priority and often forms the cornerstone of all other therapies, nonpharmacologic or pharmacologic. Cognitive-behavioral therapies represent the most widely used alternative to pharmacotherapy. Although the effects of CBT alone are disappointing, recent studies suggest that such therapies may provide a useful adjunct to pharmacotherapy and may be helpful when children are tapered off medication. Psychotherapy, or a combination of psychotherapy and medication (termed multimodality therapy), may also be useful. Pharmacotherapy for ADHD originated almost 60 years ago, and at this time the ameliorative effects of medications in ADHD are well established. The general skepticism of experienced clinicians, coupled with a climate where parents are reluctant to medicare children, serves to limit their use except where indicated. Although the effects of stimulants on attention and activity seem well established, effects on cognition, conduct, and social behavior are more controversial
Somkuwar, S S; Kantak, K M; Bardo, M T; Dwoskin, L P
Impulsivity and hyperactivity are two facets of attention deficit/hyperactivity disorder (ADHD). Impulsivity is expressed as reduced response inhibition capacity, an executive control mechanism that prevents premature execution of an intermittently reinforced behavior. During methylphenidate treatment, impulsivity and hyperactivity are decreased in adolescents with ADHD, but there is little information concerning levels of impulsivity and hyperactivity in adulthood after adolescent methylphenidate treatment is discontinued. The current study evaluated impulsivity, hyperactivity as well as cocaine sensitization during adulthood after adolescent methylphenidate treatment was discontinued in the Spontaneously Hypertensive Rat (SHR) model of ADHD. Treatments consisted of oral methylphenidate (1.5mg/kg) or water vehicle provided Monday-Friday from postnatal days 28-55. During adulthood, impulsivity was measured in SHR and control strains (Wistar Kyoto and Wistar rats) using differential reinforcement of low rate (DRL) schedules. Locomotor activity and cocaine sensitization were measured using the open-field assay. Adult SHR exhibited decreased efficiency of reinforcement under the DRL30 schedule and greater levels of locomotor activity and cocaine sensitization compared to control strains. Compared to vehicle, methylphenidate treatment during adolescence reduced hyperactivity in adult SHR, maintained the lower efficiency of reinforcement, and increased burst responding under DRL30. Cocaine sensitization was not altered following adolescent methylphenidate in adult SHR. In conclusion, adolescent treatment with methylphenidate followed by discontinuation in adulthood had a positive benefit by reducing hyperactivity in adult SHR rats; however, increased burst responding under DRL compared to SHR given vehicle, i.e., elevated impulsivity, constituted an adverse consequence associated with increased risk for cocaine abuse liability. PMID:26657171
Brown, Ronald T.
Two psychoeducational procedures were investigated for their effects on impulsivity in 120 hyperactive children in two groups: those receiving stimulant drug therapy and those not receiving stimulant drug therapy. Results indicated that the use of psychoeducational treatment approaches are of value in altering the impulsive responses of…
Müller, Kathi; Fuermaier, Anselm B M; Koerts, Janneke; Tucha, Lara
Attention deficit hyperactivity disorder (ADHD) is a frequently diagnosed disorder in child- and adulthood with a high impact affecting multiple facets of social life. Therefore, patients suffering from ADHD are at high risk to be confronted with stigma, prejudices, and discrimination. A review of t
Molloy, Geoffrey N.
Thirty-two primary school children were evaluated on their problem-solving ability and attention level, immediately following either an aerobic exercise or a passive activity. Results indicated that physical activity of moderate intensity enhanced problem-solving performance; the two hyperactive children improved their ability to stay on task,…
Full Text Available On the 10th of August, 2005 in Tartu (the second biggest educational and cultural city in Estonia Stanislav Nechvolodov's exhibition was opened to show the 5-year cycle of his work, traditional for the author and his admirers. At the opening ceremony Nechvolodov said that the exhibition was the last one and appointed on his 70th anniversary.The architectural and building society in Irkutsk remembers Stanislav Nechvolodov as an architect working on dwelling and civil buildings in 1960-70s. Below are some extracts from the Estonian press.«Postimees» newspaper, December 1993. The interview «Expressionistic naturalist, conservative Nechvolodov» by journalist Eric Linnumyagi. He asks about all the details and describes the troubles experienced by Nechvolodov during the perestroika period in Estonia, for example: the Tartu University refused to install the sculpture of Socrat, the art school refused to engage him as an instructor, the sculpture of Socrat moved to Vrotzlav, Poland, and Nechvolodov moved to Poland to read lectures there.«Tartu» newspaper, November 2000. Mats Oun, artist, says in the article «Nechvolodov: a man of Renaissance»: «Nechvolodov works in Estonia, his works are placed in many local and foreign museums. Regardless some insignificant faults, he deserves a high estimation, and his manysided open exhibition can be an example for other artists. He is a man of Renaissance».
Full Text Available Collapsin response mediator protein 1 (CRMP1 is one of the CRMP family members that are involved in various aspects of neuronal development such as axonal guidance and neuronal migration. Here we provide evidence that crmp1-/- mice exhibited behavioral abnormalities related to schizophrenia. The crmp1-/- mice exhibited hyperactivity and/or impaired emotional behavioral phenotype. These mice also exhibited impaired context-dependent memory and long-term memory retention. Furthermore, crmp1-/- mice exhibited decreased prepulse inhibition, and this phenotype was rescued by administration of chlorpromazine, a typical antipsychotic drug. In addition, in vivo microdialysis revealed that the methamphetamine-induced release of dopamine in prefrontal cortex was exaggerated in crmp1-/- mice, suggesting that enhanced mesocortical dopaminergic transmission contributes to their hyperactivity phenotype. These observations suggest that impairment of CRMP1 function may be involved in the pathogenesis of schizophrenia. We propose that crmp1-/- mouse may model endophenotypes present in this neuropsychiatric disorder.
Qiu, Guozhen; Chen, Shengqiang; Guo, Jialing; Wu, Jie; Yi, Yong-Hong
Hyperactivity is a symptom found in several neurological and psychiatric disorders, including Fragile X syndrome (FXS). The animal model of FXS, fragile X mental retardation gene (Fmr1) knockout (KO) mouse, exhibits robust locomotor hyperactivity. Alpha (α)-asarone, a major bioactive component isolated from Acorus gramineus, has been shown in previous studies to improve various disease conditions including central nervous system disorders. In this study, we show that treatment with α-asarone alleviates locomotor hyperactivity in Fmr1 KO mice. To elucidate the mechanism underlying this improvement, we evaluated the expressions of various cholinergic markers, as well as acetylcholinesterase (AChE) activity and acetylcholine (ACh) levels, in the striatum of Fmr1 KO mice. We also analyzed the AChE-inhibitory activity of α-asarone. Striatal samples from Fmr1 KO mice showed decreased m1 muscarinic acetylcholine receptor (m1 mAChR) expression, increased AChE activity, and reduced ACh levels. Treatment with α-asarone improved m1 mAChR expression and ACh levels, and attenuated the increased AChE activity. In addition, α-asarone dose-dependently inhibited AChE activity in vitro. These results indicate that direct inhibition of AChE activity and up-regulation of m1 mAChR expression in the striatum might contribute to the beneficial effects of α-asarone on locomotor hyperactivity in Fmr1 KO mice. These findings might improve understanding of the neurobiological mechanisms responsible for locomotor hyperactivity. PMID:27316341
@@ The 6th China (Guangzhou) International Seasoning Exhibition Date: May 11-13 Founded in: 2003.05 Venues: Guangzhou Int'l Convention &Exhibition Center (Pazhou) Exhibits: Seasonings, food additives, relevant material,equipment, service and publications
Watfa S. Al-Mamari
Full Text Available Objectives: The estimated worldwide prevalence of learning disorders (LDs is approximately 2‒10% among school-aged children. LDs have variable clinical features and are often associated with other disorders. This study aimed to examine the comorbidity of LDs and attention deficit hyperactivity disorder (ADHD among a sample of schoolchildren in Oman. Methods: This study was conducted between January 2014 and January 2015 at the Sultan Qaboos University, Muscat, Oman. The Learning Disabilities Diagnostic Inventory (LDDI and the 28- item version of the Conners’ Teacher Rating Scale was completed by classroom teachers to determine the existence of LD and ADHD symptoms in 321 children in grades 1‒4 who had been referred to a learning support unit for LDs from elementary schools in Muscat. Results: The mean age of the students was 8.5 years. Among the cohort, 30% were reported to have symptoms of ADHD, including conduct problems (24%, hyperactivity (24% and inattentivepassive behaviours (41%. Male students reportedly exhibited greater conduct problems and hyperactivity than females. However, there were no gender differences noted between LDDI scores. Conclusion: This study suggests that Omani schoolchildren with LDs are likely to exhibit signs of ADHD. The early identification of this disorder is essential considering the chronic nature of ADHD. For interventional purposes, multidisciplinary teams are recommended, including general and special educators, clinical psychologists, school counsellors, developmental or experienced general paediatricians and child psychiatrists.
Full Text Available Attention-deficit hyperactivity disorder (ADHD/ADD is a neurobehavioral disorder of childhood onset characterized by severe, developmentally inappropriate motor hyperactivity, inattention, and impulsiveness that result in impairment in more than one setting. It affects the home, school, and community life of 39% of school-going children worldwide. There is increasing recognition that ADHD symptoms and clinically defined disorder can persist into adult life and are associated with later drug and alcohol misuse and social and work difficulties. Added to that is the extreme variability of the disorder over time, within the same individual, between individuals, and across different circumstances. Treatment with stimulants and nonstimulants has proven effective in different subgroups, with the effectiveness of specific agents most likely related to the primary neurotransmitter involved. However, stimulants with a short duration of action have been problematic for some patients. Parent training and cognitive behavioral therapies represent the most widely adjunct psychosocial interventions to pharmacotherapy.
Ariane Sroubek; Mary Kelly; Xiaobo Li
Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with a long-term impact on functioning,productivity and quality of life of patients.This impact is largely due to the symptoms of inattentiveness.However,despite its impairing role in the lives of ADHD patients,inattentiveness has been studied relatively less frequently than have symptoms of impulsivity/hyperactivity and problems with executive function.This review therefore seeks to integrate the neuropsychological theories and current findings in the research fields of neuropsychology,neurophysiology,and neuroimaging,in an attempt to gain a more complete understanding of the role that inattentiveness plays in ADHD,as well as to suggest directions for future studies.The need for a more comprehensive understanding of inattentiveness and ADHD,which integrates findings from each of the three disciplines mentioned above,is emphasized.
J Gordon Millichap
Full Text Available The Stroop effect, a measure for selective attention, on behavioral and brain activation of attention deficit hyperactivity disorder (ADHD children (9 boys, ages 9.8-14.5 years, off or on methylphenidate and 9 controls was studied using event-related functional magnetic resonance imaging (fMRI at the Institute of Mental Health, Peking University, Beijing, China, and other centers in China and at Harvard Medical School, Boston, MA, USA.
Smalley, Susan L; Loo, Sandra K.; Hale, T. Sigi; Shrestha, Anshu; Mcgough, James,; Flook, Lisa; Reise, Steven
Attention Deficit Hyperactivity Disorder (ADHD) is a disorder characterized by attentional difficulties. Mindfulness is a receptive attention to present experience. Both ADHD and mindfulness are associated with attention and personality. This study tests whether individuals with ADHD have lower mindfulness scores than controls and, if true, whether personality contributes to these differences. 105 adults (half with ADHD) were assessed for mindfulness, using the Kentucky Inventory of Mindfulne...
To date, there have been no reports of paroxysmal sympathetic hyperactivity syndrome (PSHS) associated with cerebral fat embolization. We describe the case of a young male who developed acute brain injury and acute hypoxemic respiratory failure secondary to significant fat embolization following a traumatic femur injury. Our patient demonstrated episodes of significant hypertension, tachycardia, fever and extensor posturing. Extensive evaluation lead to the diagnosis and appropriate ...
Pharmacotherapy, one of the effective modalities of treatment for attention deficit/hyperactivity disorder (ADHD), was discovered serendipitously and, until recently, consisted primarily of short-acting methylphenidate and dextroamphetamine compounds. The US Food and Drug Administration's (FDA) approval of Concerta in 2000 followed by approval of additional long-acting methylphenidate (Ritalin LA; Metadate CD) and amphetamine formulations (Adderall XR) expanded the repertoire. By providing su...
Kim, Gun-Ha; Kim, Ji Yeon; Byeon, Jung Hye; Eun, Baik-Lin; Rhie, Young Jun; Seo, Won Hee; Eun, So-Hee
It is well-known that the prevalence of attention deficit hyperactivity disorder (ADHD) is higher in epileptic children than in the general pediatric population. The aim of this study was to compare the accompaniment of ADHD in epileptic children with well-controlled seizures and no significant intellectual disability with that in healthy controls. We included epileptic children between the ages of 6 and 12 yr visiting our clinic for six consecutive months and controls without significant med...
Background: Attention deficit hyperactivity disorder (ADHD) is an inherited developmental disorder with early onset, chronically persisting in the vast majority of cases. ADHD is associated with pervasive cognitive, emotional and functional impairments, as well as an increased rate of coexisting disorders. ADHD in the presence of early disruptive behaviours increase the risk for later delinquency. ADHD is estimated to be present in about 25-45% of adult prison inmates, thus 10-times increased...
Thapar, Anita; Cooper, Miriam; Jefferies, Rachel; Stergiakouli, Evangelia
Attention deficit hyperactivity disorder (ADHD) affects around 1–3% of children. There is a high level of comorbidity with developmental and learning problems as well as with a variety of psychiatric disorders. ADHD is highly heritable, although there is no single causal risk factor and non-inherited factors also contribute to its aetiology. The genetic and environmental risk factors that have been implicated appear to be associated with a range of neurodevelopmental and neuropsychiatric outc...
Attention-deficit disorder (attention-deficit/hyperactivity disorder without hyperactivity): A neurobiologically and behaviorally distinct disorder from attention-deficit/hyperactivity disorder (with hyperactivity)
Most studies of attention-deficit/hyperactivity disorder (ADHD) have focused on the combined type and emphasized a core problem in response inhibition. It is proposed here that the core problem in the truly inattentive type of ADHD (not simply the subthreshold combined type) is in working memory. It is further proposed that laboratory measures, such as complex-span and dual-task dichotic listening tasks, can detect this. Children with the truly inattentive type of ADHD, rather than being dist...
Nihal Yurteri; A. Evren Tufan; Gizem Melissa Akgun; Ayten Erdogan
Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common neuropsychiatric disorders of childhood. Due to studies reporting that the effects of ADHD diagnosis on functioning may last throughout life, this disorder, which has great importance for child and adolescent psychiatry, started to attract greater attention recently in terms of adult psychiatry. A review, evaluating the results of studies conducted on the genetic basis of ADHD, which started to attract increasing attent...
Mueller, Anna K; Anselm B M Fuermaier; Koerts, Janneke; Tucha, Lara
Attention deficit hyperactivity disorder (ADHD) is a frequently diagnosed disorder in child- and adulthood with a high impact affecting multiple facets of social life. Therefore, patients suffering from ADHD are at high risk to be confronted with stigma, prejudices, and discrimination. A review of the empirical research in the field of ADHD with regard to stigma was performed. The findings of investigations in this field were clustered in different categories, including stigma in children wit...
Gawrilow, Caterina; Kühnhausen, Jan; Schmid, Johanna; Stadler, Gertraud
The aim of the present literature review is threefold. (1) We will review theories, models, and studies on symptomatic hyperactivity and motoric activity in attention-deficit/hyperactivity disorder (ADHD). (2) Another focus will be on assessment methods that have been proven to be effective in the detection of hyperactivity and motoric activity in children, adolescents, and adults with and without ADHD and emerging areas of research in the field of ADHD. We will compare subjective methods (i....
Full Text Available Attention Deficit Hyperactivity Disorder is one of the most common developmental disorders of childhood with a reported world-wide prevalence of 8 to 12 %. In studies conducted in our country the prevalence rates in community were reported to vary between 8.6 to 8.1 % while clinical prevalence rates were reported to vary between 8.6 to 29.44 %. Fifty to eighty percent of cases were reported to continue into adolescence while thirty to fifty percent may continue into adulthood. Attention deficit hyperactivity disorder is known to accompany subtle physical anomalies, allergic and neurologic disorders, obesity and eating disorders, traumatic injuries, risky sexual behavior, sleep disorders, substance and alcohol use, axis I and II disorders, occupational, legal and academic problems and increased treatment expenditures. Though the effects of this disorder continue throughout life, create burdens to the society along with its treatment as well as disabling the affected patients through their lives, and receive increasing attention in recent years, reviews focusing on problems associated with it are lacking. Therefore, this study aimed to summarize the results of previous studies conducted about medical comorbidities in attention deficit hyperactivity disorder.
Boileau, Richard A.; And Others
Recognition by the physical education teacher that the cardiovascular dynamics of the hyperactive child are augmented during methylphenidate (Ritalin) medication is warranted when planning strenuous physical activity. (JD)
Ji, Eun-Sang; Kim, Chang-Ju; Park, Jun Heon; Bahn, Geon Ho
Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder, and its symptoms are hyperactivity and deficits in learning and memory. Physical exercise increases dopamine synthesis and neuronal activity in various brain regions. In the present study, we investigate the duration-dependence of the treadmill exercise on hyperactivity in relation with dopamine expression in ADHD. Spontaneously hypertensive rats were used for the ADHD rats and Wistar-Kyoto rats were used fo...
COLORATION Sandra Duchêne From September 5 to 16, 2016 CERN Meyrin, Main Building La recherche de l’Universel. Après tout ! C’est de l’Amour ! What else to say ? …La couleur, l’ENERGIE de la vie…
Jan Hladky, physicien de l'Institut de Physique de l'Académie des Sciences de la République tchèque, et membre de la collaboration Alice, expose ses œuvres au Bâtiment principal du 20 avril au 6 mai. Son exposition est dédiée aux victimes du séisme de Sendai. Des copies de ses œuvres seront mises en vente et les sommes récoltées seront versées au profit des victimes.
The 15th China International Trade Fair for Apparel Fabrics and Accessories Date:October 20th–23rd,2009 Venue:Shanghai New International Expo Centre Sponsor:China National Textile & Apparel Council Organizers:The Sub-Council of Textile Industry,CCPIT
Energie sombre, matière noire J.-J. Dalmais - J. Maréchal Du 11 au 27 novembre 2014, CERN Meyrin, Bâtiment principal A l’image des particules atomiques qui ont tissé des liens pour créer la matière, deux artistes haut bugistes croisent leurs regards et conjuguent leurs expressions singulières pour faire naître une vision commune de l’univers, produit des forces primordiales. Les sculptures de Jean-Jacques Dalmais et les peintures de Jacki Maréchal se rencontrent pour la première fois et se racontent par un enrichissement mutuel la belle histoire de la Vie. Dialogue magique des œuvres en mouvement qui questionnent en écho l’énergie sombre et la matière noire. Cette harmonieuse confluence de jeux de miroir et de résonnance illumine de poésie et de sobriété l’espace expos&...
Parallels vision Astronomical subjects which evoke extrasensory kinetic visions Alberto Di Fabio From 8 to 10 October, CERN Meyrin, Main Building In the framework of Italy@cern, the Staff Association presents Alberto Di Fabio. Di Fabio’s work is inspired by the fundamental laws of the physical world, as well as organic elements and their interrelation. His paintings and works on paper merge the worlds of art and science, depicting natural forms and biological structures in vivid colour and imaginative detail. For all additional information: firstname.lastname@example.org | Tel: 022 767 28 19
Jul, Pia; Volbracht, Christiane; de Jong, Inge E M; Helboe, Lone; Elvang, Anders Brandt; Pedersen, Jan Torleif
Tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau. In addition to memory loss, patients experience behavioral symptoms such as agitation, aggression, depression, and insomnia. We explored the behavioral phenotype of a mouse model (rTg4510) carrying the human tau P301L mutation found in a familial form of FTD. We tested these mice in locomotor activity assays as well as in the Morris water maze to access spatial memory. In addition to cognitive impairments, rTg4510 mice exhibited a hyperactivity phenotype which correlated with progression of tau pathology and was dependent on P301L tau transgene expression. The hyperactive phenotype was characterized by significantly increased locomotor activity in a novel and in a simulated home cage environment together with a disturbed day/night cycle. The P301L-tau-dependent hyperactivity and agitative-like phenotype suggests that these mice may form a correlate to some of the behavioral disturbances observed in advanced AD and FTD. PMID:26519432
Full Text Available Previously thought as a childhood disorder, attention-deficit hyperactivity disorder (ADHD is reported to be spreading at an increasing rate and affecting 4% to 5% of the adult population. It is characterized by persistent problems of inattention, hyperactivity and impulsivity. We present the case of an adult ADHD patient intervened with neurocognitive psychotherapy.
This study examined links between paternal and maternal parenting factors and preschool hyperactivity in a community sample. Forty-one hyperactive and 38 comparison boys (aged 47-62 months) and their fathers and mothers were assessed on a range of interview, parent questionnaire, and observational measures of parenting and child behavior. Results…
Scheurink, Anton J. W.; Boersma, Gretha J.; Nergardh, Ricard; Sodersten, Per; Nergårdh, Ricard; Södersten, Per
Restricted food intake is associated with increased physical activity, very likely an evolutionary advantage, initially both functional and rewarding. The hyperactivity of patients with Anorexia Nervosa, however, is a main problem for recovery. This seemingly paradoxical reward of hyperactivity in A
Full Text Available It is recognized that sustained ischemia-induced hyperactivity is related to abnormalities in dopamine function. However, it is unclear that dopaminergic neurotransmission triggers such ischemia-induced hyperactivity. Therefore, the relationship between dopaminergic neurotransmission and ischemia-induced hyperactivity was investigated in an animal model using Mongolian gerbils. When haloperidol 2 mg/kg was administered i.p. 30 min after ischemia, the ischemia-induced hyperactivity at 24 h after ischemia was blocked. General behavior was similar to that of sham-operated animals. Haloperidol at doses of 0.1 and 0.2 mg/kg had no effect on locomotor activity in sham-operated animals and decreased ischemia-induced hyperactivity when the drug was administered 24 h after ischemia; these doses did not have any effect on ischemia-induced hyperactivity when the drug was administered 30 min after ischemia. On the other hand, when the animal was confined to a small, restrictive cage for the 24 h period immediately following ischemic injury, locomotor activity at 24 h after ischemia increased. Such behavior also increased in animals when they were returned to their original more permissive cages immediately after ischemia. It is conceivable that the decrease in the level of activity was not related to ischemia-induced hyperactivity. These data suggested that the inhibition of ischemia-induced hyperactivity can be induced by complete blockage of dopaminergic receptors immediately after ischemia.
Foley, Marie; McClowry, Sandra Graham; Castellanos, Francisco X.
This study examined empirical and theoretical differences and similarities between attention deficit hyperactivity disorder (ADHD) and child temperament in 32 ADHD children aged 6-11 years, and a comparison group of 23 children with similar sociodemographic characteristics. Children were assessed for ADHD symptoms (hyperactivity, impulsivity, and…
Antai-Otong, Deborah; Zimmerman, Michele L
Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children, adolescents, and adults, with a prevalence estimated from 5% to 7% across cultures and approximately 2% to 5% in adults. This lifelong disorder challenges nurses to understand the basis of ADHD, analyze symptoms, differentiate coexisting disorders, gather health information from varied sources, and implement person-centered multimodal treatment. Nurses are poised to plan, and work with patients, families, and teachers in the community and school systems to optimize academic and occupational performance and improve quality of life. Pharmacotherapy, psychoeducation, and behavioral therapies are strong components of multimodal treatment planning. PMID:27229276
Irem Yalug; Ali Evren Tufan
Attention Deficit Hyperactivity Disorder is one of the most common developmental disorders of childhood with a reported world-wide prevalence of 8 to 12 %. In studies conducted in our country the prevalence rates in community were reported to vary between 8.6 to 8.1 % while clinical prevalence rates were reported to vary between 8.6 to 29.44 %. Fifty to eighty percent of cases were reported to continue into adolescence while thirty to fifty percent may continue into adulthood. Attention defic...
Shahid, Maryam; Takamiya, Masanari; Stegmaier, Johannes; Middel, Volker; Gradl, Marion; Klüver, Nils; Mikut, Ralf; Dickmeis, Thomas; Scholz, Stefan; Rastegar, Sepand; Yang, Lixin; Strähle, Uwe
Robust and sensitive detection systems are a crucial asset for risk management of chemicals, which are produced in increasing number and diversity. To establish an in vivo biosensor system with quantitative readout for potential toxicant effects on motor function, we generated a transgenic zebrafish line TgBAC(hspb11:GFP) which expresses a GFP reporter under the control of regulatory elements of the small heat shock protein hspb11. Spatiotemporal hspb11 transgene expression in the musculature and the notochord matched closely that of endogenous hspb11 expression. Exposure to substances that interfere with motor function induced a dose-dependent increase of GFP intensity beginning at sub-micromolar concentrations, while washout of the chemicals reduced the level of hspb11 transgene expression. Simultaneously, these toxicants induced muscle hyperactivity with increased calcium spike height and frequency. The hspb11 transgene up-regulation induced by either chemicals or heat shock was eliminated after co-application of the anaesthetic MS-222. TgBAC(hspb11:GFP) zebrafish embryos provide a quantitative measure of muscle hyperactivity and represent a robust whole organism system for detecting chemicals that affect motor function. PMID:27029555
Reddy, D S
Attention deficit hyperactivity disorder (ADHD) is a neurobehavioral developmental disorder in children and adults characterized by a persistent pattern of impulsiveness, inattention and hyperactivity. It affects about 3-10% of children and 2-5% of adolescents and adults and occurs about four times more commonly in boys than girls. The cause of ADHD is unknown, but it has strong genetic and environment components. The first-line treatment options for ADHD include behavioral therapy, pharmacotherapy with stimulants or both. Methylphenidate and amphetamine salts are the stimulant drugs of choice for ADHD treatment. Amphetamines act by increasing presynaptic release of dopamine and other biogenic amines in the brain. Methylphenidate inhibits the reuptake of dopamine and norepinephrine and therefore its pharmacology is identical to that of amphetamines. Lisdex-amfetamine is a prodrug of dextroamphetamine with low feasibility for abuse. Atomoxetine, a selective norepinephrine reuptake inhibitor, is an alternative, non-stimulant drug for ADHD but it is less efficacious than stimulants. Stimulants are generally safe but are associated with adverse effects including headache, insomnia, anorexia and weight loss. There is increased awareness about serious cardiovascular and psychiatric adverse events with ADHD drugs including concern for growth suppression in children. Stimulants have a high potential for abuse and dependence, and should be handled safely to prevent misuse and abuse. PMID:24191257
A. S. Kotov
Full Text Available Attention deficit hyperactivity disorder (ADHD is a serious problem to pediatric neurologists. The prevalence of ADHD in developed countries ranges from 1 to 20 %. ADHD is characterized by a triad of symptoms: inattention, hyperactivity, and impulsivity (the International Statistical Classification of Diseases, 10th revision, codes it as F90 and it is the most common conduct disorder in children. The etiology of ADHD remains disсutable to the present day; there are a few basic concepts of the origin of this disorder. Its manifestations may be a reason for family conflicts, poor peer relationships, social and school maladjustment, learning problems, lower academic performance, accidents and injuries, smoking, psychoactive substance abuse (toxicomania, narcomania, delinquencies, deviant social behavior, thus having a negative impact on all spheres of a patient’s life. The manifestations of ADHD may continue in adulthood, resulting in work and family life problems, low self-evaluation, alcohol and psychoactive substance abuse, and other unfavorable consequences. The authors describe the etiology, pathogenesis, diagnostic principles (diagnostic scales and tests, differential diagnosis (by setting out a large group of different diseases, the manifestations of which can mimic ADHD, treatment, and prognosis of the disorder. Within its therapeutic correction framework, the authors present the definition and general principles of Montessori therapy, including recommendations for parents and relatives to deal with children with ADHD.
Influence of RNA interference on the mitochondrial subcellular localization of alpha-synuclein and on the formation of Lewy body-like inclusions in the cytoplasm of human embryonic kidney 293 cells induced by the overexpression of alpha- synuclein
Tao Chen; Xiaoping Liao; Guoqiang Wen; Yidong Deng; Min Guo; Zhigang Long; Feng Ouyang
The specific and effective α-synuclein RNA interference (RNAi) plasmids, and the α-synuclein-pEGFP recombinant plasmids were co-transfected into human embryonic kidney 293 (HEK293) cells using the lipofectamine method. Using an inverted fluorescence microscope, α-synuclein proteins were observed to aggregate in the cytoplasm and nucleus. Wild-type α-synuclein proteins co-localized with mitochondria. Hematoxylin-eosin staining revealed round eosinophilic bodies (Lewy body-like inclusions) in the cytoplasm of some cells transfected with α-synuclein-pEGFP plasmid. However, the formation of Lewy body-like inclusions was not observed following transfection with the RNAi pSYN-1 plasmid. RNAi blocked Lewy body-like inclusions in the cytoplasm of HEK293 cells induced by wild-type α-synuclein overexpression, but RNAi did not affect the subcellular localization of wild-type α-synuclein in mitochondria.
Juan A. Amador-Campos
Full Text Available Objective:To explore the temporal mechanism of attention in children with attention deficit hyperactivity disorder (ADHD and controls using a rapid serial visual presentation (RSVP task in which two letters (T1 and T2 were presented in close temporal proximity among distractors (attentional blink [AB].Method:Thirty children aged between 9 and 13 years (12 with ADHD combined type and 18 controls took part in the study. Both groups performed two kinds of RSVP task. In the single task, participants simply had to identify a target letter (T1, whereas in the dual task, they had to identify a target letter (T1 and a probe letter (T2.Results:The ADHD and control groups were equivalent in their single-task performance. However, in the dual-task condition, there were significant between-group differences in the rate of detection of the probe letter (T2 at lag + 1 and lag + 4. The ADHD group exhibited a larger overall AB compared with controls.Conclusion:Our findings provide support for a link between ADHD and attentional blink.
Ye, Minsook; Chung, Hwan-Suck; Lee, Chanju; Hyun Song, Joo; Shim, Insop; Kim, Youn-Sub; Bae, Hyunsu
α-Synuclein (α-Syn) has a critical role in microglia-mediated neuroinflammation, which leads to the development of Parkinson's disease (PD). Recent studies have shown that bee venom (BV) has beneficial effects on PD symptoms in human patients or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxin-induced PD mice. This study investigated whether treatment with BV-derived phospholipase A2 (bvPLA2) would improve the motor dysfunction and pathological features of PD in human A53T α-Syn mutant transgenic (A53T Tg) mice. The motor dysfunction of A53T Tg mice was assessed using the pole test. The levels of α-Syn, microglia and the M1/M2 phenotype in the spinal cord were evaluated by immunofluorescence. bvPLA2 treatment significantly ameliorated motor dysfunction in A53T Tg mice. In addition, bvPLA2 significantly reduced the expression of α-Syn, the activation and numbers of microglia, and the ratio of M1/M2 in A53T Tg mice. These results suggest that bvPLA2 could be a promising treatment option for PD. PMID:27388550
Frieling, Helge; Gozner, Andreas; Römer, Konstanze D.; Wilhelm, Julia; Hillemacher, Thomas; Kornhuber, Johannes; de Zwaan, Martina; Jacoby, Georg E.; Bleich, Stefan
α-Synuclein (α-Syn) is a neuronal protein involved in the regulation of brain serotonin and dopamine levels. We analyzed the peripheral expression of α-Syn mRNA and Beck Depression Inventory scores in female patients suffering from anorexia nervosa (n = 18) or bulimia nervosa (n = 24). We found a significant positive association between α-Syn mRNA expression and the total scores of the Beck Depression Inventory (linear regression; R 2 = 0.20; p = 0.003). α-Syn may play a pathophysiological ro...
Full Text Available Despite enormous efforts, our understanding the structure and dynamics of α-synuclein (ASN, a disordered protein (that plays a key role in neurodegenerative disease is far from complete. In order to better understand sequence-structure-property relationships in α-SYNUCLEIN we have developed a coarse-grained model using knowledge-based residue-residue interactions and used it to study the structure of free ASN as a function of temperature (T with a large-scale Monte Carlo simulation. Snapshots of the simulation and contour contact maps show changes in structure formation due to self-assembly as a function of temperature. Variations in the residue mobility profiles reveal clear distinction among three segments along the protein sequence. The N-terminal (1-60 and C-terminal (96-140 regions contain the least mobile residues, which are separated by the higher mobility non-amyloid component (NAC (61-95. Our analysis of the intra-protein contact profile shows a higher frequency of residue aggregation (clumping in the N-terminal region relative to that in the C-terminal region, with little or no aggregation in the NAC region. The radius of gyration (Rg of ASN decays monotonically with decreasing the temperature, consistent with the finding of Allison et al. (JACS, 2009. Our analysis of the structure function provides an insight into the mass (N distribution of ASN, and the dimensionality (D of the structure as a function of temperature. We find that the globular structure with D ≈ 3 at low T, a random coil, D ≈ 2 at high T and in between (2 ≤ D ≤ 3 at the intermediate temperatures. The magnitudes of D are in agreement with experimental estimates (J. Biological Chem 2002.
Yanjun Guo,1,2 Luning Wang,2 Mingwei Zhu,2 Honghong Zhang,3 Yazhuo Hu,3 Zhitao Han,3 Jia Liu,4 Weiqin Zhao,1 Dexin Wang11Department of Neurology, Beijing Friendship Hospital, Capital Medical University, 2Department of Geriatric Neurology, PLA General Hospital, 3Institute of Geriatrics, Chinese PLA General Hospital & Chinese PLA Medical Academy, 4Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, People’s Republic of ChinaAbstract: The aim of this ...
Follmer, Cristian; Braga, Carolina A.; Khattar, Elias; Palhano, Fernando; Freitas, Monica S.; Silva, Jerson L.; Foguel, Debora [Universidade Federal do Rio de Janeiro (UFRJ), RJ (Brazil). Inst. de Bioquimica Medica; Lara, Flavio Alves [Fundacao Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, RJ (Brazil). Lab. de Microbiologia Celular; Lashuel, Hilal [Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne (Switzerland)
Full text: Parkinson's disease (P D) is a chronic disorder characterized by the formation of intra neuronal inclusions called Le wy bodies mainly composed of a-synuclein (a-syn), a natively- unfolded protein with unknown function. Its implication in P D is due to the fact that two mutations (A30P and A53T) are linked to early-onset forms of P D. Selegiline (R(-)-deprenyl) is a noncompetitive monoamino oxidase-B inhibitor which has ne uroprotective effects. It has been administered to P D patients either as monotherapy or in combination with L-dopa. However, its mechanism is unknown. We evaluated the effect of Sel in the in vitro aggregation of A30P either in the presence or absence of amyloid seeds (small fibrils acting as a nucleus). We observed that Sel (1:0.5 or 1:1.5 protein:Sel ratio ) delays fibril formation by enhancing the nucleation phase. Sel effects on fibril formation are abolished when previously added seeds are present, suggesting that Sel interferes with nucleus formation, and is dependent of the A30P:Sel ratio. This inhibitory effect of Sel on the nucleation phase was also evaluated by using another amyloidogenic, natively- unfolded protein, Sup35, but in this case, the effect of Sel was not abolished when Sel was added after the end of the lag phase. We also observed that Sel in combination with dopamine (DA) favors fibril formation. Currently, we are mapping A30P-Sel interaction by NMR. We observed that in the presence of Sel (1:2 p tn:Sel ratio), very little changes occur in the HSQC spectra of the isotopically labeled protein. These results suggest that in the presence of DA, Sel favors the conversion of the toxic prot ofibrils into the non-toxic fibrils, alleviating the dopaminergic neurons from toxic effects. In the non-dopaminergic neurons, Sel would slow down the fibrillation process, probably by forming large spherical aggregates.
Games, Dora; Valera, Elvira; Spencer, Brian; Rockenstein, Edward; Mante, Michael; Adame, Anthony; Patrick, Christina; Ubhi, Kiren; Nuber, Silke; Sacayon, Patricia; Zago, Wagner; Seubert, Peter; Barbour, Robin; Schenk, Dale; Masliah, Eliezer
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are common neurodegenerative disorders of the aging population, characterized by progressive and abnormal accumulation of α-synuclein (α-syn). Recent studies have shown that C-terminus (CT) truncation and propagation of α-syn play a role in the pathogenesis of PD/DLB. Therefore, we explored the effect of passive immunization against the CT of α-syn in the mThy1-α-syn transgenic (tg) mouse model, which resembles the striato-nigral and motor deficits of PD. Mice were immunized with the new monoclonal antibodies 1H7, 5C1, or 5D12, all directed against the CT of α-syn. CT α-syn antibodies attenuated synaptic and axonal pathology, reduced the accumulation of CT-truncated α-syn (CT-α-syn) in axons, rescued the loss of tyrosine hydroxylase fibers in striatum, and improved motor and memory deficits. Among them, 1H7 and 5C1 were most effective at decreasing levels of CT-α-syn and higher-molecular-weight aggregates. Furthermore, in vitro studies showed that preincubation of recombinant α-syn with 1H7 and 5C1 prevented CT cleavage of α-syn. In a cell-based system, CT antibodies reduced cell-to-cell propagation of full-length α-syn, but not of the CT-α-syn that lacked the 118-126 aa recognition site needed for antibody binding. Furthermore, the results obtained after lentiviral expression of α-syn suggest that antibodies might be blocking the extracellular truncation of α-syn by calpain-1. Together, these results demonstrate that antibodies against the CT of α-syn reduce levels of CT-truncated fragments of the protein and its propagation, thus ameliorating PD-like pathology and improving behavioral and motor functions in a mouse model of this disease. PMID:25009275
Full Text Available Converging lines of evidence indicate that near-infrared light treatment, also known as photobiomodulation (PBM, may exert beneficial effects and protect against cellular toxicity and degeneration in several animal models of human pathologies, including neurodegenerative disorders. In the present study, we report that chronic PMB treatment mitigates dopaminergic loss induced by unilateral overexpression of human α-synuclein (α-syn in the substantia nigra of an AAV-based rat genetic model of Parkinson's disease (PD. In this model, daily exposure of both sides of the rat's head to 808-nm near-infrared light for 28 consecutive days alleviated α-syn-induced motor impairment, as assessed using the cylinder test. This treatment also significantly reduced dopaminergic neuronal loss in the injected substantia nigra and preserved dopaminergic fibers in the ipsilateral striatum. These beneficial effects were sustained for at least 6 weeks after discontinuing the treatment. Together, our data point to PBM as a possible therapeutic strategy for the treatment of PD and other related synucleinopathies.
Full Text Available Synucleinopathies are a broad class of neurodegenerative disorders characterized by the presence of intracellular protein aggregates containing α-synuclein protein. The aggregated α-synuclein protein is hyperphosphorylated on serine 129 (S129 compared to the unaggregated form of the protein. While the precise functional consequences of S129 hyperphosphorylation are still being clarified, numerous in vitro and in vivo studies suggest that S129 phosphorylation is an early event in α-synuclein dysfunction and aggregation. Identifying the kinases and phosphatases that regulate this critical phosphorylation event may ultimately prove beneficial by allowing pharmacological mitigation of synuclein dysfunction and toxicity in Parkinson's disease and other synucleinopathies. We report here the development of a high-content, fluorescence-based assay to quantitate levels of total and S129 phosphorylated α-synuclein protein. We have applied this assay to conduct high-throughput loss-of-function screens with siRNA libraries targeting 711 known and predicted human kinases and 206 phosphatases. Specifically, knockdown of the phosphatidylinositol 3-kinase related kinase SMG1 resulted in significant increases in the expression of pS129 phosphorylated α-synuclein (p-syn. Moreover, SMG1 protein levels were significantly reduced in brain regions with high p-syn levels in both dementia with Lewy bodies (DLB and Parkinson's disease with dementia (PDD. These findings suggest that SMG1 may play an important role in increased α-synuclein pathology during the course of PDD, DLB, and possibly other synucleinopathies.
Friis, Morten; Thomsen, Allan Randrup; Poulsen, Steen Seier;
induced hyperactivity of the endolymphatic sac. One group of rats was immunized by a single dose whereas a second group was immunized twice. Control animals were injected with Freund's adjuvant in saline only. Serum was collected from all rats by the end of the study and harvested autoantibodies were...... tested by immunohistochemistry. The endolymphatic sacs were investigated by transmission electron microscopy. Endolymphatic sac stimulation was observed in all immunized rats. Based on detailed ultrastructural observations, the degree of reactivity seemed proportional to the number of injections and the...... homogeneous substance of which many were observed to fuse with primary lysozymes. Basolateral foldings were numerous and in the subepithelial capillaries formation of multiple and apposing fenestrations were observed. No endolymphatic sac stimulation was observed in the control animals. Specific ribosome...
Tucha, Lara; Fuermaier, Anselm B M; Koerts, Janneke; Groen, Yvonne; Thome, Johannes
In recent years, there is an increasing awareness that individuals may purposely feign or exaggerate symptoms of attention deficit hyperactivity disorder (ADHD) to gain external incentives, including access to stimulant drugs or special academic accommodations. There are vast consequences of undetected feigned ADHD such as substantial costs covered by society for unnecessary assessments and treatments, unjustified occupation of limited medical resources and undermining society's trust in the existence of the disorder or the effectiveness of treatment. In times of economic crisis and cost savings in the medical sector, the detection of feigned ADHD is of importance. This review briefly describes the research on this topic with an emphasis on the approaches available for detection of feigned ADHD (i.e., self-report questionnaires, personality inventories, cognitive tests used in routine neuropsychological assessment and tests specifically designed for detecting feigned cognitive dysfunction). Promising approaches and measures are available for identifying feigned ADHD but there is an immediate need for further research. PMID:25096370
The proposed revision of the diagnostic criteria in DSM-5 for attention-deficit/hyperactivity disorder (ADHD) will not fundamentally change the concept of ADHD. This is mainly due to the fact that, DSM-5 will retain the exact DSM-IV wording of all 18 symptoms, but will add new examples that make...... changes will most likely increase the prevalence of ADHD, especially in adults and adolescents, but maybe also in children. The added examples will also result in necessary revisions and new validations of rating scales and diagnostic interviews. This review will examine each of the proposed DSM-5 changes...... and the impact they may have, and in addition, the paper will make an overview of the main characteristics of some of the international and national guidelines for assessment and treatment of ADHD and how these impact the clinical practice....
The winning photographs from the 2010 Global Particle Physics Photowalk competition will go on display at Microcosm from 11 February to 2 April. The exhibition is part of a global photography event taking place over three continents, with Photowalk exhibitions opening simultaneously at Fermilab in the US, KEK in Japan and here at CERN. DESY wire chamber - First place people's choice; second place global jury competition. Photographer: Hans-Peter Hildebrandt If you were one of the 1,300 photography lovers who voted in last year’s Photowalk competition, this exhibition is your chance to see the winning entries in print. The exhibition will take place in the downstairs gallery of Microcosm, overlooking the garden. 15 photographs will be on display, with each of the laboratories that participated in Photowalk represented by their 3 winning entries. Among them will be the “people’s choice” sunburst photo of a particle detector at DESY (Photo 1), and...
... Bar Home Current Issue Past Issues Special Section Against the Odds Exhibition Opens Past Issues / Spring 2008 ... Research in Bethesda. Photo courtesy of Bill Branson "Against the Odds" is a remarkable story of achievement ...
Full Text Available Attention Deficit Hyperactivity Disorder (ADHD is one of the most common neuropsychiatric disorders of childhood. Due to studies reporting that the effects of ADHD diagnosis on functioning may last throughout life, this disorder, which has great importance for child and adolescent psychiatry, started to attract greater attention recently in terms of adult psychiatry. A review, evaluating the results of studies conducted on the genetic basis of ADHD, which started to attract increasing attention both in our country and the world, was thought to help clinicians working in this field. PubMed and Turkish Psychiatry Index online search engines were screened using “attention deficit hyperactivity disorder”, “ADHD”, “genetics” as key words. The data obtained were combined with information gleaned from several textbooks. Based on previous studies, it could easily be concluded that ADHD is one of the most common heritable psychiatric disorder with distinguished genetic features. Despite its importance for diagnosis and treatment, the etiology of ADHD is still not clear and the disorder seems to be a complex problem arising from the effects of both genetic and environmental factors. Although previous studies revealed that ADHD displayed familial and hereditary transmission, stable patterns of Mendelian inheritance could not be discriminated by evaluation of pedigrees. Therefore, many studies have been conducted on the molecular genetic basis of ADHD recently. The previous studies did not report consistent results in identification of the genes responsible for ADHD which has been partially linked to heterogeneity of the disorder. Grouping relevant patients according to comorbidities and persistence in adolescence rather than DSM-IV subtypes could be an important alternative method for overcoming this limitation in the research studies.
The Globe’s “Universe of Particles” exhibition has recently received four prestigious awards for its avant-garde design. This external praise is great encouragement for the CERN exhibitions currently on the drawing board. The Universe of Particles exhibition has won 4 awards for its avant-garde design. Back in 2008, the design company Atelier Brückner was presented with a challenge: to design the layout of a new permanent exhibition for CERN, one that would epitomize both the Organization and its research. The brief was concise but complex: the exhibit had to be symbolic of the Organization, use modern technology, engage and immerse visitors, and, preferably, use touch-screen technology. With the help of IArt, an interactive technology firm, and based on the content provided by CERN’s Education Group, Atelier Brückner developed the “Universe of Particles” exhibit as it is today. Its principal concept centred on the s...
The Franklin Institute Science Museum provided an exhibit entitled the Greenhouse Earth: A Traveling Exhibition. This 3500 square-foot exhibit on global climate change was developed in collaboration with the Association of Science-Technology Centers. The exhibit opened at The Franklin Institute on February 14, 1992, welcoming 291,000 visitors over its three-month stay. During its three-year tour, Greenhouse Earth will travel to ten US cities, reaching two million visitors. Greenhouse Earth aims to deepen public understanding of the scientific issues of global warming and the conservation measures that can be taken to slow its effects. The exhibit features hands-on exhibitry, interactive computer programs and videos, a theater production, a ''demonstration cart,'' guided tours, and lectures. supplemental educational programs at the Institute included a teachers preview, a symposium on climate change, and a ''satellite field trip.'' The development of Greenhouse Earth included front-end and formative evaluation procedures. Evaluation includes interviews with visitors, prototypes, and summative surveys for participating museums. During its stay in Philadelphia, Greenhouse Earth was covered by the local and national press, with reviews in print and broadcast media. Greenhouse Earth is the first large-scale museum exhibit to address global climate change
Definitive diagnosis of attention deficit hyperactivity disorder is complex. David Coghill believes the condition is undertreated, but Harvey Markovitch argues that current uncertainties about diagnosis and treatment mean doctors should be cautious
Definitive diagnosis of attention deficit hyperactivity disorder is complex. David Coghill believes the condition is undertreated, but Harvey Markovitch argues that current uncertainties about diagnosis and treatment mean doctors should be cautious
Current literature on hyperactivity stresses the central role of short attention, distractibility, and impulsivity in contributing to the child's behavioral and learning difficulties. Journal availability: American Medical Association, 535 North Dearborn Street, Chicago, Illinois 60610. (Author)
Gawrilow, Caterina; Kühnhausen, Jan; Schmid, Johanna; Stadler, Gertraud
The aim of the present literature review is threefold. (1) We will review theories, models, and studies on symptomatic hyperactivity and motoric activity in attention-deficit/hyperactivity disorder (ADHD). (2) Another focus will be on assessment methods that have been proven to be effective in the detection of hyperactivity and motoric activity in children, adolescents, and adults with and without ADHD and emerging areas of research in the field of ADHD. We will compare subjective methods (i.e., rating scales) and objective methods (i.e., accelerometers). (3) Finally, physical activity intervention studies aiming at a modification of activity and overactive behavior will be summarized that seem to be promising candidates for alleviating hyperactivity symptoms in children, adolescents, and adults with ADHD. PMID:25506329
Full Text Available Carmen Sílvia Miguel, Tiffany M Chaim-Avancini, Maria Aparecida Silva, Mario Rodrigues LouzãAdult Attention Deficit Hyperactivity Disorder Program (PRODATH, Institute of Psychiatry, University of São Paulo, São Paulo, BrazilBackground: The cognitive profile of children with neurofibromatosis type 1 (NF1 and attention deficit hyperactivity disorder (ADHD has been well characterized, but few studies have evaluated the cognitive abilities of adults with NF1 and ADHD.Objectives: We investigated 1 the cognitive profile of an adult patient with NF1 and inattention problems, 2 changes in his cognition after 14 months of follow-up, and 3 whether the patient exhibited comorbid NF1 and ADHD or secondary ADHD-like symptoms.Methods: We administered neuropsychological tests of executive function, attention, verbal and visual memory, visuospatial function, and language during two evaluations separated by 14 months.Results: We found no changes in sustained attention, language, or verbal memory. Visual memory, verbal learning, selective attention inhibitory control, and problem solving declined over time, whereas visual search, psychomotor speed, visuospatial function, and mental flexibility improved.Conclusion: Our patient exhibited a cognitive profile characteristic of both NF1 and ADHD, leading to the hypothesis that the patient had comorbid ADHD instead of secondary ADHD-like symptoms. More studies are necessary to characterize the cognition of patients with NF1 and ADHD.Keywords: ADHD, executive function, NF1, low-grade pontine glioma, cognition
This dissertation, On the Other Side of Hyperactivity: an Anthropology of ADHD, provides a meta-historical and cultural perspective on the emergence and proliferation of Attention Deficit Hyperactivity Disorder (ADHD) in the United States over the last three decades. Through in-depth multi-sited ethnography (15 months in the San Francisco Bay Area) with doctors, educators, parents, and children as well as detailed archival research into the disorder's antecedents, my research explores how ADH...
Roohallah Mirzaaghas; Yegane Kohani; Hasan baniasadi; Fateme Tara
Background & aim: According to the previous studies, anxiety along with some other psychiatric disorders is common among mothers of children with attention deficit hyperactivity disorder (ADHD). Since maternal anxiety affects mother-child interactions, early treatment plays an important role in the prognosis of ADHD in children. This study aimed to determine the relationship between maternal anxiety and hyperactivity in children. Methods: This study was conducted on 112 mothers of ADHD child...
Scheurink, Anton J. W.; Boersma, Gretha J.; Nergardh, Ricard; Sodersten, Per; Nergårdh, Ricard; Södersten, Per
Restricted food intake is associated with increased physical activity, very likely an evolutionary advantage, initially both functional and rewarding. The hyperactivity of patients with Anorexia Nervosa, however, is a main problem for recovery. This seemingly paradoxical reward of hyperactivity in Anorexia Nervosa is one of the main aspects in our framework for the neurobiological changes that may underlie the development of the disorder. Here, we focus on the neurobiological basis of hyperac...
Wehrmann, Thomas; Müller, Jörg Michael
Background Objective measures of physical activity are currently not considered in clinical guidelines for the assessment of hyperactivity in the context of Attention-Deficit/Hyperactivity Disorder (ADHD) due to low and inconsistent associations between clinical ratings, missing age-related norm data and high technical requirements. Methods This pilot study introduces a new objective measure for physical activity using compressed webcam video footage, which should be less affected by age-rela...
This study aimed to investigate if an executive functions (EF) intervention could promote these skills in individuals with attention deficit and hyperactivity disorder (ADHD). Eighteen children and adolescents, 7-13 years old, divided into experimental (EG, N = 8) and control (CG, N = 10) groups, were assessed in the Block Design and Vocabulary subtests of the WISC III and seven tests of EF. Parents answered two scales, measuring EF and inattention and hyperactivity signs. EG children partici...
Majdak, Petra; Grogan, Elizabeth L; Gogola, Joseph V; Sorokina, Anastassia; Tse, Stephen; Rhodes, Justin S
Early environmental conditions are increasingly appreciated as critical in shaping behavior and cognition. Evidence suggests that stressful rearing environments can have an enduring impact on behaviors in adulthood, but few studies have explored the possibility that rearing environment could exacerbate genetic hyperactivity disorders. Uncovering a strong environmental influence on the transmission of hyperactivity could provide novel avenues for translational research. Recently we developed a selectively bred High-Active line of mice to model ADHD, providing a unique resource to address the question of environmental transmission. The High-Active line demonstrates transgenerational hyperactivity, but the influence of the postnatal environment (i.e. maternal care provided by dams) on hyperactivity had not been systemically quantified. This study employed a cross-fostering method to simultaneously address 1) whether High-Active and Control pups are provided with similar levels of care in the early environment, and 2) whether any differences in rearing environment influence hyperactive behavior. High-Active dams demonstrated impairment in all measures of maternal competence relative to Controls, which reduced survival rates and significantly reduced the body mass of offspring in early life and at weaning. While the deteriorated postnatal environment provided by High-Active dams was ultimately sufficient to depress Control activity, the hyperactivity of High-Active offspring remained unaffected by fostering condition. These data not only confirm the power of genetics to influence hyperactivity across generations, but also provide evidence that early rearing environments may not have a significant impact on the extreme end of hyperactive phenotypes. PMID:27449202
Ougrin, Dennis; Chatterton, Sandie; Banarsee, Ricky
Attention deficit hyperactivity disorder (ADHD) is characterised by impulsivity, hyperactivity and inattention. Up to 5% of primary school age children have ADHD. Both genes and environment play a role in the aetiology of ADHD. If left untreated, children with ADHD demonstrate a range of poor long-term psychosocial outcomes. The Strengths and Difficulties Questionnaire (SDQ) may be used to screen children for a range of psychiatric disorders, including ADHD.1
Attention deficit hyperactivity disorder (ADHD) is characterized by developmentally inappropriate levels of inattention, hyperactivity, and impulsivity, and is the most common neurodevelopmental disorder of childhood. This highly prevalent disorder is estimated to affect about 5% of school-age children worldwide, with a substantial degree of persistence over time. Although the specific cause of ADHD is still largely unknown, despite a long history of research, it is believed to involve multip...
Séguin, Jean R.; Nagin, Daniel; Assaad, Jean-Marc; Tremblay, Richard E.
Histories of violence and of hyperactivity are both characterized by poor cognitive–neuropsychological function. However, researchers do not know whether these histories combine in additive or interactive ways. The authors tested 303 male young adults from a community sample whose trajectories of teacher-rated physical aggression and motoric hyperactivity from kindergarten to age 15 were well defined. No significant interaction was found. In a 1st model, both histories of problem behavior wer...
From 21 October 2011 to 18 March 2012, the Fondation Cartier pour l’art contemporain will present the exhibition Mathematics: A Beautiful Elsewhere, an exhibition developed in association with the Institut des Hautes Études Scientifiques (IHÉS) and under the patronage of UNESCO. For this unprecedented event, the foundation invited mathematicians to work with artists with whom it has previously worked to create an exhibition that allows visitors to see, hear, do, interpret and think about mathematics. By bringing mathematics into its premises, the Fondation Cartier is itself undergoing the “sudden change of scenery” described by mathematician Alexandre Grothendieck. More information is available here. Fondation Cartier pour l’art contemporain 261, boulevard Raspail 75014 Paris http://fondation.cartier.com Private Visit For professors, researchers and all the staff of Mathematics departments...
Full Text Available Abstract Background Attention Deficit/Hyperactivity Disorder (ADHD, formerly regarded as a typical childhood disorder, is now known as a developmental disorder persisting over the lifespan. Starting in preschool-age, symptoms vary depending on the age group affected. Method According to the variability of ADHD-symptoms and the heterogeneity of comorbid psychiatric disorders, a broad review of recent studies was performed. These findings were summarized in a developmental psychopathological model, documenting relevant facts on a timeline. Results Based on a genetic disposition and a neuropsychological deregulation, there is evidence for factors which persist across the lifespan, change age-dependently, or show validity in a specific developmental phase. Qualitative changes can be found for children in preschool-age and adults. Conclusion These differences have implications for clinical practice as they can be used for prevention, diagnostic proceedings, and therapeutic intervention as well as for planning future studies. The present article is a translated and modified version of the German article "Entwicklungspsychopathologie der ADHS", published in Zeitschrift für Psychiatrie, Psychologie und Psychotherapie, 56, 2008, S. 265-274.
Full Text Available Attention Deficit Hyperactivity Disorder (ADHD continues to be controversial with arguments for and against its veracity being waged by individuals representing a variety of disciplines from behavioral scientists to philosophers. Our perspective focuses on the epistemological underpinnings of what is now commonly known as ADHD. Its ignominious history and current disputes may stem from a "pessimistic" epistemology, meaning that truth is only the province of persons in authority and power. The authoritative organizations that govern the diagnostic labels and criteria are the American Psychiatric Association and their Diagnostic and Statistical Manual and the World Health Organization that sponsors the International Classification of Disease. We contrast the pessimistic epistemology with criteria for truth from the scientific method. Although scientific scrutiny has been and is being applied subsequent to "authoritarian edicts" of the disorder, we opine that ADHD currently does not have status beyond that of the "hypothetical construct." Moreover, current brain-based causal models have failed to provide rigorous supporting data that comes from testing falsifiable hypotheses.
Yamamoto, Akiko; Ide, Shuhei; Iwasaki, Yuji; Kaga, Makiko; Arima, Masataka
We report the case of a 4-year-old girl who presented with paroxysmal sympathetic hyperactivity (PSH), after developing severe hypoxic-ischemic-encephalopathy because of cardiopulmonary arrest. She showed dramatic paroxysmal sympathetic activity with dystonia. She was treated with wide variety of medications against PSH, which were found to be effective in previous studies. Among them, morphine, bromocriptine, propranolol, and clonidine were effective in reducing the frequency of her attacks while gabapentin, baclofen, dantrolene, and benzodiazepine were ineffective. Though the paroxysms decreased markedly after the treatment, they could not be completely controlled beyond 500 days. Following the treatment, levels of plasma catecholamines and their urinary metabolites decreased to normal during inter- paroxysms. However, once a paroxysm had recurred, these levels were again very high. This case study is considered significant for two rea- sons. One is that PSH among children have been rarely reported, and the other is that this case of prolonged PSH delineated the transition of plasma catecholamines during the treatment. The excitatory: inhibitory ratio (EIR) model proposed by Baguley was considered while dis- cussing drug sensitivity in this case. Accumulation of similar case studies will help establish more effective treatment strategies and elucidate the pathophysiology of PSH. PMID:27149743
@@ Shanghai World Expo is widely regarded as another grand international pageant, so many people thought that the opening ceremony must be as much magnificent and brilliant as the opening ceremony for Beijing Olympics.However, it was revealed by Wan Jifei, Executive Director of the ExecutiveCommittee of the Shanghai World Expo that the opening ceremony of the Expo was not that luxurious and extravagant as that for the Beijing Olympics, but would have its own characteristics under the elaborate design and thorough arrangement conducted by the host. The veto against that luxurious opening ceremony was actually a practice echoing for the concept of Green World Expo, which would be applied for every corner from the beginning to the end of the Expo, including the construction of exhibition hall, building of exhibition stand and advertisement etc.
The purpose of the study is to determinate how the European companies may market the international trade fairs in order to attract and serve Russian business customers. The aim was to find out what kind of marketing are tools available for small companies perceiving new market opportunities with Russian business market. The study was carried out by analysing the secondary sources and a massive corpus of publications related to marketing in Russia and exhibitions. The research method was c...
Sandra Medić; Nataša Pavlović
In order to be up–to–date and give visitors a memorable and unique experience, museums are including usage of digital technologies in their exhibitions. Even though museums in Serbia are very important part of tourism offer, they still have traditional settings that are poorly interpreted. The majority of them have a scientific and historical review which is unattractive for various target groups of visitors and for museums it’s important to continually try out new ways in interpretation of t...
This exhibition of rapid-prototyped snow globes accompanies the book, Bipolar. The snow globes feature scenes of geo-engineering technologies, which are presented through the snow globe as a type of "philosophical furniture." These snow globes, which are accompanied by an informative pamphlet, enable reflection on the controversies related to large-scale planetary modification in order to address climate change. They further focus attention on the ways in which technological solutions for env...
Sebastien Pelletier explains states of matter to an enthusiastic group of youngsters during the opening of a new exhibition in Microcosm last week. The Fun with Physics workshop will be offered to all 13-14 year olds in school groups visiting CERN this year. The new Microcosm contents have been developed in collaboration with the local teaching community, and cover particles and the forces that act between them.
CERN is going out to meet those members of the general public who were unable to attend the recent Open Day. The Laboratory will be taking its "Big Science" exhibition from the Globe of Science and Innovation to the Balexert shopping centre from 19 to 31 May 2008. The exhibition, which shows the LHC and its experiments through the eyes of a photographer, features around thirty spectacular photographs measuring 4.5 metres high and 2.5 metres wide. Welcomed and guided around the exhibition by CERN volunteers, shoppers at Balexert will also have the opportunity to discover LHC components on display and watch films. "Fun with Physics" workshops will be held at certain times of the day. Main hall of the Balexert shopping centre, ground floor, from 9.00 a.m. to 7.00 p.m. Monday to Friday and from 10 a.m. to 6 p.m. on the two Saturdays. Call for volunteers All members of the CERN personnel are invited to enrol as volunteers to help welcom...
Full Text Available In order to be up–to–date and give visitors a memorable and unique experience, museums are including usage of digital technologies in their exhibitions. Even though museums in Serbia are very important part of tourism offer, they still have traditional settings that are poorly interpreted. The majority of them have a scientific and historical review which is unattractive for various target groups of visitors and for museums it’s important to continually try out new ways in interpretation of their settings. Because technology continues to rapidly change the way we communicate, cultural institutions should adapt to new ways of communication with their visitors. This paper examines mobile technologies that can be used in museums to give visitors a different experience and transfer the knowledge innovatively. In that way it will be presented the modern concept of presentation of museum exhibitions, focusing on usage of mobile devices through mobile applications and QR codes. The paper provides the broad understanding of usage mobile technologies in museum exhibitions with its advantages and limitations. The research results can help the museums management to improve interpretation and communication with visitors and enrich the visitor experience.
Hartlage, Lawrence C.; Telzrow, Cathy Fultz
Hyperactivity is defined, and the relationships among minimal brain dysfunction, cerebral stimulants, and student characteristics such as activity level, attention and learning, and behavior are discussed. Hyperactive children's responses to the use of Ritalin and methylphenidate are reported. (CJ)
Silbergeld, E.K.; Goldberg, A.M.
Although clinically lead poisoning is thought to cause several serious behavioral problems, a causal relationship between lead ingestion and behavioral dysfunction has not been shown. An animal model of lead poisoning was developed in which suckling mice were exposed to lead acetate from birth indirectly through their mothers and then directly after weaning. For the first 60 days, no deaths of offspring occurred due to lead but their growth and development were significantly retarded. Epidemiological evidence exists for the coincidence of lead exposure and hyperactivity syndromes in children. Activity of offspring was measured between 40 and 60 days of age. Treated mice were more than three times as active as agematched controls. Treated and control animals were given drugs used in the treatment and diagnosis of minimal brain dysfunction hyperactivity in children: d- and l-amphetamine, methylphenidate, phenobarbital, and chloral hydrate. Lead-treated hyperactive mice responded paradoxically to all drugs except chloral hydrate: that is, d- and l-amphetamine and methylphenidate suppressed hyperactivity, while phenobarbital increased their levels of motor activity. Chloral hydrate was an effective sedative. Implications of these findings are discussed for the study of the central effects of lead poisoning and for the relationship between lead poisoning and minimal brain dysfunction hyperactivity.
Lopez, Régis; Dauvilliers, Yves; Jaussent, Isabelle; Billieux, Joël; Bayard, Sophie
We aimed to compare adult patients with attention deficit hyperactivity disorder (ADHD) and matched controls on four dimensions of impulsivity (urgency, lack of premeditation, lack of perseverance, and sensation seeking) and to examine the association between impulsivity and ADHD symptoms. The study was conducted on 219 participants: 72 adult ADHD patients and 147 aged and gender matched controls. All participants completed questionnaires measuring the various facets of impulsivity (UPPS Impulsive Behavior Scale), ADHD and depressive symptoms severity. Patients were also assessed for ADHD subtypes, mood disorders, and addictive behaviors. ADHD patients exhibited higher urgency, lower premeditation and lower perseverance in comparison to controls. Lack of perseverance showed the strongest association with ADHD (area under curve=0.95). Patients with combined inattentive and hyperactive/impulsive subtypes reported more frequently substance abuse problems and had higher scores on urgency and sensation seeking dimensions of impulsivity than those with predominantly inattentive subtype. We report for the first time a multidimensional evaluation of impulsivity in adult ADHD patients. The UPPS Impulsive Behavior Scale may constitute a useful screening tool for ADHD in adults and may help to further understanding the psychological mechanisms underlying the differences between the ADHD subgroups. PMID:25895489
Purpose: Investigating the discriminative brain map for patients with attention-deficit/hyperactivity disorder (ADHD) based on feature selection and classifier; and identifying patients with ADHD based on the discriminative model. Materials and methods: A dataset of resting state fMRI contains 23 patients with ADHD and 23 healthy subjects were analyzed. Regional homogeneity (ReHo) was extracted from resting state fMRI signals and used as model inputs. Raw ReHo features were ranked and selected in a loop according to their p values. Selected features were trained and tested by support vector machines (SVM) in a cross validation procedure. Cross validation was repeated in feature selection loop to produce optimized model. Results: Optimized discriminative map indicated that the ADHD brains exhibit more increased activities than normal controls in bilateral occipital lobes and left front lobe. The altered brain regions included portions of basal ganglia, insula, precuneus, anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), thalamus, and cerebellum. Correlation coefficients indicated significant positive correlation of inattentive scores with bilateral cuneus and precuneus, and significant negative correlation of hyperactive/impulsive scores with bilateral insula and claustrum. Additionally, the optimized model produced total accuracy of 80% and sensitivity of 87%. Conclusion: ADHD brain regions were more activated than normal controls during resting state. Linear support vector classifier can provide useful discriminative information of altered ReHo patterns for ADHD; and feature selection can improve the performances of classification
Attention deficit hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioural disorder in childhood, affecting over 5% of children worldwide. As well as the core symptoms of inattention, hyperactivity and impulsivity, patients often exhibit learning difficulties and impairment in social functioning. The frequency of referral is higher for boys than for girls (about 2:1), and girls are generally older at the time of referral.Pharmacological therapy is considered the first-line treatment for patients with severe ADHD and severe impairment. Stimulant medications are licensed in the UK for the management of ADHD in school-age children and young people, and are effective in controlling ADHD symptoms.While immediate-release preparations of methylphenidate (MPH) have proven effective in the treatment of ADHD, there are a number of problems associated with their use, most notably compliance, stigma and medication diversion. Modified release preparations are now available that overcome the need for multiple daily dosing, and which offer different MPH release profiles, thereby enabling the physician to match the medication to the patient's particular requirements.This review describes the diagnosis, referral and treatment pathways for patients with ADHD in the UK and the practical considerations when initiating pharmacological treatment. The clinical experience of treating ADHD with a modified-release MPH preparation (Equasym XL®) is illustrated with case studies. PMID:21962224
Full Text Available Abstract Attention deficit hyperactivity disorder (ADHD is the most commonly diagnosed neurobehavioural disorder in childhood, affecting over 5% of children worldwide. As well as the core symptoms of inattention, hyperactivity and impulsivity, patients often exhibit learning difficulties and impairment in social functioning. The frequency of referral is higher for boys than for girls (about 2:1, and girls are generally older at the time of referral. Pharmacological therapy is considered the first-line treatment for patients with severe ADHD and severe impairment. Stimulant medications are licensed in the UK for the management of ADHD in school-age children and young people, and are effective in controlling ADHD symptoms. While immediate-release preparations of methylphenidate (MPH have proven effective in the treatment of ADHD, there are a number of problems associated with their use, most notably compliance, stigma and medication diversion. Modified release preparations are now available that overcome the need for multiple daily dosing, and which offer different MPH release profiles, thereby enabling the physician to match the medication to the patient's particular requirements. This review describes the diagnosis, referral and treatment pathways for patients with ADHD in the UK and the practical considerations when initiating pharmacological treatment. The clinical experience of treating ADHD with a modified-release MPH preparation (Equasym XL® is illustrated with case studies.
Peixoto, Rui T; Wang, Wengang; Croney, Donyell M; Kozorovitskiy, Yevgenia; Sabatini, Bernardo L
Some autistic individuals exhibit abnormal development of the caudate nucleus and associative cortical areas, suggesting potential dysfunction of cortico-basal ganglia (BG) circuits. Using optogenetic and electrophysiological approaches in mice, we identified a narrow postnatal period that is characterized by extensive glutamatergic synaptogenesis in striatal spiny projection neurons (SPNs) and a concomitant increase in corticostriatal circuit activity. SPNs during early development have high intrinsic excitability and respond strongly to cortical afferents despite sparse excitatory inputs. As a result, striatum and corticostriatal connectivity are highly sensitive to acute and chronic changes in cortical activity, suggesting that early imbalances in cortical function alter BG development. Indeed, a mouse model of autism with deletions in Shank3 (Shank3B(-/-)) shows early cortical hyperactivity, which triggers increased SPN excitatory synapse and corticostriatal hyperconnectivity. These results indicate that there is a tight functional coupling between cortex and striatum during early postnatal development and suggest a potential common circuit dysfunction that is caused by cortical hyperactivity. PMID:26928064
Wang, Xunheng [School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096 (China); Key Laboratory of Child Development and Learning Science (Ministry of Education), Southeast University, Nanjing 210096 (China); Jiao, Yun, E-mail: email@example.com [Jiangsu Key Laboratory of Molecular Imaging and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009 (China); Tang, Tianyu; Wang, Hui; Lu, Zuhong [School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096 (China); Key Laboratory of Child Development and Learning Science (Ministry of Education), Southeast University, Nanjing 210096 (China)
Purpose: Investigating the discriminative brain map for patients with attention-deficit/hyperactivity disorder (ADHD) based on feature selection and classifier; and identifying patients with ADHD based on the discriminative model. Materials and methods: A dataset of resting state fMRI contains 23 patients with ADHD and 23 healthy subjects were analyzed. Regional homogeneity (ReHo) was extracted from resting state fMRI signals and used as model inputs. Raw ReHo features were ranked and selected in a loop according to their p values. Selected features were trained and tested by support vector machines (SVM) in a cross validation procedure. Cross validation was repeated in feature selection loop to produce optimized model. Results: Optimized discriminative map indicated that the ADHD brains exhibit more increased activities than normal controls in bilateral occipital lobes and left front lobe. The altered brain regions included portions of basal ganglia, insula, precuneus, anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), thalamus, and cerebellum. Correlation coefficients indicated significant positive correlation of inattentive scores with bilateral cuneus and precuneus, and significant negative correlation of hyperactive/impulsive scores with bilateral insula and claustrum. Additionally, the optimized model produced total accuracy of 80% and sensitivity of 87%. Conclusion: ADHD brain regions were more activated than normal controls during resting state. Linear support vector classifier can provide useful discriminative information of altered ReHo patterns for ADHD; and feature selection can improve the performances of classification.
Visits Explore by yourself the issues CERN's physicists are trying to solve: given that the entire universe is made of particles, where do they come from? Why do they behave in the way they do? Discover the massive apparatus used by physicists at CERN, like the LHC, and see how each part works. CERN invites the public to discover the mysteries of the Universe and the work of the world's biggest physics laboratory through free of charge guided tours and permanent exhibitions. As a group, with friends, individually, on foot, on your bike, come and discover CERN or explore it virtually. Welcome!
The Museum of Contemporary Art Detroit (MOCAD) invited Chloë Brown to present the United States premiere of three pieces of work in the DEPE Space gallery: 'Dancing in the Boardroom (Turnin' My Heartbeat Up)' video, her large drawing 'From Alfred Street to Temple Street, Detroit' and the video 'Dancing in the Street', which was filmed along the route in Detroit that the drawing follows. The exhibition explores connections between the post-industrial cities of Stoke-on-Trent UK and Detroit USA...
Whalen, Carol K.; And Others
Teacher behaviors toward hyperactive boys on methylphenidate (ritalin), toward hyperactive boys on placebo, and toward normal comparison peers were compared. Teachers were more intense and controlling toward hyperactive boys on placebo, but no differences emerged between comparison and medicated groups. Need for broader monitoring of treatment…
Modesto-Lowe, Vania; Farahmand, Pantea; Chaplin, Margaret; Sarro, Lauren
Attention deficit hyperactivity disorder (ADHD) manifests by high levels of inattention, impulsiveness and hyperactivity. ADHD starts in childhood and results in impairments that continue into adulthood. While hyperactivity declines over time, inattention and executive function difficulties persist, leading to functional deficits. Adolescents and adults with ADHD have pervasive impairment in interpersonal and family relationships. They may develop addiction, delinquent behavior and comorbid psychiatric disorders. Despite advances in diagnosis and treatment, persistent residual symptoms are common, highlighting the need for novel treatment strategies. Mindfulness training, derived from Eastern meditation practices, may improve self-regulation of attention. It may also be a useful strategy to augment standard ADHD treatments and may be used as a potential tool to reduce impairments in patients with residual symptoms of ADHD. Clinically, this would manifest by an increased ability to suppress task-unrelated thoughts and distractions resulting in improved attention, completion of tasks and potential improvement in occupational and social function. PMID:26740931
Smirnova, Anna; Zorina, Zoya; Obozova, Tanya; Wasserman, Edward
Analogical reasoning is vital to advanced cognition and behavioral adaptation. Many theorists deem analogical thinking to be uniquely human and to be foundational to categorization, creative problem solving, and scientific discovery. Comparative psychologists have long been interested in the species generality of analogical reasoning, but they initially found it difficult to obtain empirical support for such thinking in nonhuman animals (for pioneering efforts, see [2, 3]). Researchers have since mustered considerable evidence and argument that relational matching-to-sample (RMTS) effectively captures the essence of analogy, in which the relevant logical arguments are presented visually. In RMTS, choice of test pair BB would be correct if the sample pair were AA, whereas choice of test pair EF would be correct if the sample pair were CD. Critically, no items in the correct test pair physically match items in the sample pair, thus demanding that only relational sameness or differentness is available to support accurate choice responding. Initial evidence suggested that only humans and apes can successfully learn RMTS with pairs of sample and test items; however, monkeys have subsequently done so. Here, we report that crows too exhibit relational matching behavior. Even more importantly, crows spontaneously display relational responding without ever having been trained on RMTS; they had only been trained on identity matching-to-sample (IMTS). Such robust and uninstructed relational matching behavior represents the most convincing evidence yet of analogical reasoning in a nonprimate species, as apes alone have spontaneously exhibited RMTS behavior after only IMTS training. PMID:25532894
A touring exhibition celebrating the centenary of Enrico Fermi's birth in 1901 will be on display at CERN (Main Building, Mezzanine) from 12-27 September. You are cordially invited to the opening celebration on Thursday 12 September at 16:00 (Main Building, Council Chamber), which will include speechs from: Luciano Maiani Welcome and Introduction Arnaldo Stefanini Celebrating Fermi's Centenary in Documents and Pictures Antonino Zichichi The New 'Centro Enrico Fermi' at Via Panisperna Ugo Amaldi Fermi at Via Panisperna and the birth of Nuclear Medicine Jack Steinberger Fermi in Chicago Valentin Telegdi A Close-up of Fermi and the screening of a documentary video about Fermi: Scienziati a Pisa: Enrico Fermi (Scientists at Pisa: Enrico Fermi) created by Francesco Andreotti for La Limonaia from early film, photographs and sound recordings (In Italian, with English subtitles - c. 30 mins). This will be followed by an aperitif on the Mezz...
Hair samples from hyperactive and control children have been analyzed for their trace elemental contents by PIXE. The main elements examined are S, K, Ca, Fe, Co, Ni, Cu, Zn, Se, Br, Hg and Pb. The significant difference between the elements in control population and in patients suffering from pathological conditions are examined. Investigations of the possible linear and multiple correlations between elements in each population are made. The work indicates that some elements do exhibit variation with pathological state. (author). 5 refs, 5 figs, 6 tabs