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

A missense mutation in the human alpha synuclein gene was recently identified in some cases of familial Parkinson's disease (FPD). We have developed an antibody that recognizes the C-terminal 12 amino acids of the human alpha synuclein protein and have demonstrated that alpha synuclein is an abundant component of the Lewy bodies found within the degenerating neurons of patients with Parkinson's disease (PD). The presence of alpha synuclein in Lewy bodies of sporadic PD patients suggests a central role for alpha synuclein in the pathogenesis of PD.
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PMID:Alpha synuclein is present in Lewy bodies in sporadic Parkinson's disease. 985 66

Recently several responsible genes for hereditary neurodegenerative disorders were identified. In some of them the gene products were found to be aggregated. In the case of Alzheimer disease beta protein and apolipoprotein E accumulated in senile plaques. In CAG repeat diseases the polyglutamine aggregates in neuronal nuclei. More recently alpha synuclein accumulates in Lewy bodies in Parkinson disease and tau protein accumulates in NFT of hereditary frontotemporal dementia with tau mutation. Those results suggested that the responsible gene products accumulates in the lesion which the products involve in. However, presenilin which is one of the genes for familial Alzheimer disease accumulates in NFT and on the other hand its mutation changes the production ratio of beta 1-42/40, suggesting that the abnormal gene products not simply accumulate the lesion that it involved. The gene products accumulate in different lesions such as in nuclei of polyglutamine diseases, extracellular plaque and cytoplasm of prion disease and extracellular plaques in Alzheimer disease. Some of them are ubiquitinated and some of them are not. Thus the accumulating process in these disorders seems apparently same but is essentially different. We should study more precisely each pathological process of those disorders.
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PMID:[Neuronal cell death--what we can see and what we cannot]. 1037 83

Synucleins are small highly conserved proteins in vertebrates, especially abundant in neurons and typically enriched at presynaptic terminals. Three genes in humans produce closely related synuclein proteins, all of which share a large amphipathic domain capable of reversible binding to lipid vesicles. Alpha synuclein has been specifically implicated in neurodegenerative disease. Two point mutations are genetically linked to familial Parkinson's disease, and alpha synuclein appears to form the major fibrillary component of Lewy bodies. Alpha synuclein also contributes to the intracellular inclusions of multiple system atrophy, and a fragment has been found in senile plaques in Alzheimer's disease. Although their normal cellular functions are unknown, several observations suggest the synucleins may serve to integrate presynaptic signaling and membrane trafficking. Alpha synuclein has been identified as a potent and selective inhibitor of phospholipase D2, which produces phosphatidic acid (to which synuclein binds) and is believed to function in the partitioning of membranes between the cell surface and intracellular stores. We outline a hypothesis whereby synuclein supports localized, experience-dependent turnover of synaptic membranes. Such a process may be important for lifelong learning and memory functions and may be especially vulnerable to disruption in aging-associated neurodegenerative diseases.
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PMID:Synucleins in synaptic plasticity and neurodegenerative disorders. 1049 77

A brief overview of the molecular pathology of dementia of the Alzheimer type (DAT), frontotemporal dementias (FTD), and Lewy body dementias (LBD) is preceded by a discussion of the evolutionary biological basis for the types of gene action responsible for the emergence of late life dementias. The beta amyloid cascade theory of the pathogenesis of DAT still predominates, but possible upstream events are being explored. Some familial forms of FTD have been shown to result from dominant mutations in the microtubular associated protein tau. A key element in pathogenesis is a shift in the ratios of various isoforms. Rare forms of Parkinson disease have been associated with dominant mutations in alpha synuclein, a protein of probable importance for synaptic plasticity. Aberrations in the metabolism of this protein (which is found in Lewy body fibrillar material) may therefore be of importance to the genesis of some LBD cases.
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PMID:Molecular mechanisms of late life dementias. 1095 31

Protein aggregation appears to be the common denominator in a series of distinct neurodegenerative diseases yet its role in the associated neuronal pathology in these various conditions remains elusive. In Parkinson's disease, localization of alpha synuclein aggregates within intracellular Lewy body occlusions represent a major hallmark of this disorder and suggest that such aggregation may play a causative role in the resulting dopaminergic cell loss. In this Viewpoint article, recent data is reviewed related to how alpha synuclein aggregation may occur, what cellular events might be responsible, and how this may interfere with normal cellular function(s). It appears likely that while aggregation of alpha synuclein may interfere with its normal function in the cell, this is not the primary cause of the related neurodegeneration.
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PMID:Alpha synuclein aggregation: is it the toxic gain of function responsible for neurodegeneration in Parkinson's disease? 1151 92

Agents potentially involved in the aetiology of idiopathic Parkinson's disease are discussed. These include factors regulating dopaminergic neurogenesis (Nurr 1, Ptx-3, and Lmx1b) and related proteins, together with genes involved in familial Parkinson's disease (alpha synuclein, parkin, and ubiquitin carboxy terminal hydroxylase L1), and endogenous and environmental agents.
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PMID:The aetiology of idiopathic Parkinson's disease. 1172 11

Polymorphism of the alpha synuclein promoter region (non-amyloid component of plaques (NACP)-Rep1) is associated with an increased risk of Parkinson's disease (PD) in three separate studies. We studied NACP-Rep1 polymorphism in two independent case control studies in our population. In study one, 104 PD and 104 age, gender and race matched controls; and in study two, 102 PD and 102 age, gender and race matched controls were examined separately. The results of both studies were analyzed independent of one another. We found three polymorphic alleles (designated 0, 1, 2). In study one, the frequency of allele 2 was significantly higher in PD patients as compared to healthy controls (0.37 versus 0.23, P=0.01, X(2)=9.98). In study two, the frequency of allele 2 was similar between PD and controls (0.31 versus 0.33, P=1.00, X(2)=0.30). There was a non-significant higher allele 2 frequency in PD when both studies were analyzed together (0.34 versus 0.28, P=0.20, X(2)=3.4). No significant differences of the various genotypes between PD and controls were found. However there were differences of the mixed dinucleotide repeats sequences for similar homozygous genotypes. Variability of the microsatellite region and potential interacting factors that could affect alpha synuclein gene transcription should be further examined.
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PMID:Alpha synuclein promoter and risk of Parkinson's disease: microsatellite and allelic size variability. 1249 4

The ubiquitin proteasome system is an important cellular pathway that ubiquitinates damaged proteins and degrades them via the 26S proteasome. Abnormalities of this pathway can result in molecular protein aggregation and have been associated with Parkinson's disease (PD). UCHL-1, an enzyme central to the system, possesses catalytic hydrolase activity that can hydrolyze peptide-ubiquitin bonds and recycle ubiquitin monomers for re-use in the same process. Recently, UCHL-1 has been shown to possess a second dimerisation-dependent ligase activity and, at least in vitro, this ligase activity promotes alpha synuclein aggregation. UCHL-1 was first implicated in PD by the discovery of an I93M mutation identified in a German sib-pair with probable autosomal dominant PD. Although no further UCHL-1 mutations have been identified, a common non-synonymous S18Y polymorphism has been suggested to reduce disease susceptibility in non-mendelian forms of PD. In vitro functional data support this protective effect, with evidence that S18Y possesses reduced ligase activity compared with wild type UCHL-1. One study has found increased hydrolase activity associated with S18Y, although another study has not. Important issues regarding UCHL-1 and its role in PD remain inconclusive, especially regarding the pathogenicity of the mendelian I93M mutation. This review tries to address some of these uncertainties.
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PMID:Genetic causes of Parkinson's disease: UCHL-1. 1522 45

A case is reported of an initially 78-year-old man whose presentation and course, closely followed over 10 years by an academic neurologist, were consistent with classic idiopathic Parkinson's disease (PD), including unilateral onset, obvious cogwheeling, and a very good prolonged response to levodopa/carbidopa (LD/CD). Yet at autopsy, there was no neuronal loss in the substantia nigra nor were there any Lewy bodies or immunochemical evidence of alpha synuclein in the multiple brain structures studied. This case does not support the hypothesis that the use of LD/CD is toxic to the substantia nigra in people. This patient had been on traditional doses of LD/CD for approximately 10 years, yet the number of cells in the substantia nigra was well within the normal range at autopsy. These findings are not unique, but point out the need to explain the occurrence of typical PD symptoms and course in the absence of any PD-related neuropathologic changes.
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PMID:Parkinson's disease without expected neuropathologic abnormality. 1553 Jan 80

British amyloid (ABri) peptide is precipitated as amyloid fibrils in pathological lesions which are characteristic of familial British dementia. Unlike for other amyloidogenic peptides which have been implicated in neurodegenerative disease, for example, Abeta in Alzheimer's disease and alpha synuclein in Parkinson's disease, nothing is yet known as to whether metals mediate the formation of ABri amyloid fibrils. We show herein that a concentration of ABri, which had not previously been shown to spontaneously form amyloid, formed fibrils when incubated for 12 months at 37 degrees C. The additional presence of Al(III), in particular, or Fe(III) increased significantly both the number and the size of the fibrillar amyloid deposits which were very similar in appearance to amyloid described in hippocampal plaques in familial British dementia. Co-incubation of ABri with either Zn(II) or Cu(II) precipitated the peptide but did not result in the formation of amyloid fibrils.
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PMID:Metal-mediated formation of fibrillar ABri amyloid. 1554 88


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