Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alzheimer's disease (AD) and Lewy body disease (LBD) are the most common causes of dementia in the elderly population. Previous studies have shown that cognitive alterations in these disorders are associated with synaptic loss. Injury and loss of synapses might be associated with altered function of synaptic proteins. Among them, recent studies have shown that abnormal aggregation and accumulation of synaptic proteins, such as alpha-synuclein, might be associated with plaque formation in AD and Lewy body formation in LBD. Further reinforcing the hypothesis that alpha-synuclein plays a major role in the pathogenesis of these disorders, recent work has shown that mutations that alter the conformation of this molecule are associated with familial forms of Parkinson's disease. The mechanisms by which altered function or aggregation of alpha-synuclein might lead to neurodegeneration are not completely clear; however, new evidence points to a potential role for this molecule in synaptic damage and neurotoxicity via amyloid-like fibril formation and mitochondrial dysfunction. In this manuscript we review the data linking alpha-synuclein to the pathogenesis of AD and LBD.
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PMID:Alpha-synuclein in Lewy body disease and Alzheimer's disease. 1051 9

The precursor of the non-Abeta-component of Alzheimer's disease (AD) amyloid (NACP, alpha-synuclein) aggregates into insoluble filaments of Lewy bodies (LBs) in Parkinson's disease (PD) and dementia with LBs (DLB). The microtubule-associated protein tau is an integral component of filaments of neurofibrillary tangles (NFTs). NFTs are occasionally found in brains of PD and DLB; however, the presence of NFTs or tau-epitopes within LB-containing neurons is rare. Double-immunofluorescence study and peroxidase-immunohistochemical study in serial sections, performed to examine the co-localization of tau- and NACP-epitopes in the brainstem of PD and DLB, demonstrated that four different epitopes of tau including phosphorylation-dependent and independent ones were present in a minority of LBs, but more often than previously considered. A tau (tau2)-epitope was localized to filaments in the outer layers of brainstem-type LBs by immunoelectron microscopy. Therefore, we conclude that tau is incorporated into filaments in certain LBs. Extensive investigation has enabled us to classify this co-localization into four types: type 1, LBs with ring-shaped tau-immunoreactivity; type 2, LBs surrounded by NFTs; type 3, NACP- and tau-immunoreactive filamentous and granular masses; and type 4, NACP- and tau-immunoreactive dystrophic neurites. This study raises a new question whether aggregation and hyperphosphorylation of tau in PD and DLB are triggered by the collapse of intraneuronal organization of microtubules due to NACP-filament aggregation in neuronal perikarya and axons.
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PMID:Cellular co-localization of phosphorylated tau- and NACP/alpha-synuclein-epitopes in lewy bodies in sporadic Parkinson's disease and in dementia with Lewy bodies. 1052 10

Immunohistochemical studies have shown that oligodendroglial inclusions in multiple system atrophy contain alpha-synuclein, a synaptic protein also found in Lewy bodies in Parkinson's disease. We have now used density gradient enrichment and an anti-alpha-synuclein immunomagnetic technique to isolate pure and morphologically intact oligodendroglial inclusions from brain white matter of patients dying with multiple system atrophy. Filamentous inclusion structures were obtained only from multiple system atrophy tissue, but not from normal brain tissues, or from multiple system atrophy tissue processed without anti-alpha-synuclein antibody. We confirmed the purity and morphology of isolated inclusions by electron microscopy. The inclusions comprised multiple protein bands after separation by polyacrylamide gel electrophoresis. Immunoblotting demonstrated that these proteins included alpha-synuclein, alphaB-crystallin, tubulins, ubiquitin, and prominent, possibly truncated alpha-synuclein species as high-molecular-weight aggregates. Our study provides the first biochemical evidence that oligodendroglial inclusion filaments consist of multiple protein components, suggesting that these inclusions may form as a result of multiprotein interactions with alpha-synuclein.
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PMID:Alpha-synuclein immunoisolation of glial inclusions from multiple system atrophy brain tissue reveals multiprotein components. 1053 69

Immunostaining with anti-alpha-synuclein is used to detect Lewy bodies and Lewy neurites in cases of Parkinson's disease and related disorders. To prove that the result of a modern silver method is equivalent to that achieved with immunoreactions for alpha-synuclein, individual sections were successively processed using both methods. The silver-stained sections showed all of the immunoreactive Lewy bodies, and thin Lewy neurites were detected equally well by both techniques. The present study, therefore, points to the capabilities of a modern silver-staining method which is less time consuming and less expensive than immunocytochemical techniques.
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PMID:Alpha-synuclein immunoreactive Lewy bodies and Lewy neurites in Parkinson's disease are detectable by an advanced silver-staining technique. 1054 68

Abnormal protein aggregation has been postulated to explain the molecular basis for many neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and prion diseases, as well as trinucleotide repeat disorders. The recent findings that mutations in alpha-synuclein lead to autosomal-dominant, early-onset Parkinson's disease in some families and that alpha-synuclein is found in Lewy bodies of all Parkinson's disease patients prompted the hypothesis that the pathophysiology of all Parkinson's disease patients starts with an abnormal folding of alpha-synuclein, producing excessive aggregation that overwhelms the antiaggregation mechanisms of the cell. The genetics of Parkinson's disease and polyglutamine repeat disorders and the evidence of abnormal processing and aggregation of the respective target proteins for the aetiology and pathogenesis in these diseases are reviewed.
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PMID:Molecular pathogenesis of movement disorders: are protein aggregates a common link in neuronal degeneration? 1055 32

Pathogenic alpha-synuclein (alphaS) gene mutations occur in rare familial Parkinson's disease (PD) kindreds, and wild-type alphaS is a major component of Lewy bodies (LBs) in sporadic PD, dementia with LBs (DLB), and the LB variant of Alzheimer's disease, but beta-synuclein (betaS) and gamma-synuclein (gammaS) have not yet been implicated in neurological disorders. Here we show that in PD and DLB, but not normal brains, antibodies to alphaS and betaS reveal novel presynaptic axon terminal pathology in the hippocampal dentate, hilar, and CA2/3 regions, whereas antibodies to gammaS detect previously unrecognized axonal spheroid-like lesions in the hippocampal dentate molecular layer. The aggregation of other synaptic proteins and synaptic vesicle-like structures in the alphaS- and betaS-labeled hilar dystrophic neurites suggests that synaptic dysfunction may result from these lesions. Our findings broaden the concept of neurodegenerative "synucleinopathies" by implicating betaS and gammaS, in addition to alphaS, in the onset/progression of PD and DLB.
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PMID:Axon pathology in Parkinson's disease and Lewy body dementia hippocampus contains alpha-, beta-, and gamma-synuclein. 1055 41

Synucleins are abundant nerve terminal proteins of hitherto unknown function. In diseases with Lewy bodies, human alpha-synuclein concentrates in these lesions in the cell body and mutations in alpha-synuclein lead to heritable Parkinson's disease with Lewy bodies. This indicates that changes in the normal metabolism and axonal transport of alpha-synuclein is perturbed in these diseases. To investigate the normal axonal transport of synucleins we studied the rat visual system by nerve crush operations and metabolic labelling of the retinal ganglion cells followed by immunoprecipitation of nerve segments. We found by immunofluorescence microscopy of the crush-operated nerves that synucleins are transported by fast antero- and retrograde transport and colocalize with synaptophysin and SNAP-25 around the lesion. The metabolic labelling studies demonstrated that synucleins were moved through the nerve with all the rate components, the fast component and the slow components a and b, with component b predominating. Two-dimensional gel electrophoresis revealed that both alpha- and beta-synuclein migrate through the nerve by slow component b in a ratio of 2:1.
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PMID:Axonal transport of synucleins is mediated by all rate components. 1056 44

Alpha-Synuclein (originally called precursor of the non-Abeta component of Alzheimer's disease amyloid-NACP) is a presynaptic nerve terminal protein and is now known to be a major component of Lewy bodies (LBs) in Parkinson's disease. Previous studies have shown that LBs are occasionally found in patients with Hallervorden-Spatz disease (HSD), a hereditary or sporadic neuroaxonal dystrophy. Therefore, an immunocytochemical examination of the brain tissues from two patients with HSD for alpha-synuclein/NACP was performed. In both cases, LBs were observed in the substantia nigra, locus ceruleus and other subcortical nuclei. These LBs were strongly immunolabelled with anti-alpha-synuclein/NACP. Moreover, abnormal alpha-synuclein/NACP-immunoreactive structures in the neuronal somata and processes were found in the cerebral neocortex, hippocampus, basal ganglia, thalamus, pontine and inferior olivary nuclei, spinal grey matter, and peripheral sympathetic ganglia. Although numerous dystrophic axons (spheroids) were found throughout the brain, either none or only a few were positive for alpha-synuclein/NACP. These findings suggest that widespread accumulation of alpha-synuclein/NACP is a pathological feature in patients suffering from HSD with LBs, and that this phenomenon is unrelated to axonal spheroid formation.
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PMID:Widespread occurrence of alpha-synuclein/NACP-immunoreactive neuronal inclusions in juvenile and adult-onset Hallervorden-Spatz disease with Lewy bodies. 1056 25

Mutations in alpha-synuclein are known to be associated with Parkinson's disease (PD). The coexistence of this neuronal protein with ubiquitin and proteasome subunits in Lewy bodies in sporadic disease suggests that alterations of alpha-synuclein catabolism may contribute to the pathogenesis of PD. The degradation pathway of alpha-synuclein has not been identified nor has the kinetics of this process been described. We investigated the degradation kinetics of both wild-type and A53T mutant 6XHis-tagged alpha-synuclein in transiently transfected SH-SY5Y cells. Degradation of both isoforms followed first-order kinetics over 24 h as monitored by the pulse-chase method. However, the t((1)/(2)) of mutant alpha-synuclein was 50% longer than that of the wild-type protein (p < 0.01). The degradation of both recombinant proteins and endogenous alpha-synuclein in these cells was blocked by the selective proteasome inhibitor beta-lactone (40 microM), indicating that both wild-type and A53T mutant alpha-synuclein are degraded by the ubiquitin-proteasome pathway. The slower degradation of mutant alpha-synuclein provides a kinetic basis for its intracellular accumulation, thus favoring its aggregation.
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PMID:Degradation of alpha-synuclein by proteasome. 1056 43

A G209A mutation in the alpha-synuclein gene was recently discovered in a large Italian kindred and three unrelated Greek kindreds with autosomal dominant Parkinson's disease (PD). Subsequently, another mutation in the gene (G88C) was also identified in a German family with autosomal PD. These results indicate that the alpha-synuclein gene may have an important role in the pathogenesis of PD. This study was designed to screen the existence of both mutations of the alpha-synuclein gene among 100 Chinese patients with PD, including 80 with sporadic and 20 with familial PD. Results showed that none of our patients, both sporadic and familial PD, had either of the two mutations of this gene. We therefore conclude that although of great interest, these two mutations are not relevant for the pathogenesis of PD in a Han Chinese population.
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PMID:Absence of G209A and G88C mutations in the alpha-synuclein gene of Parkinson's disease in a Chinese population. 1056 18


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