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)

Parkinson's disease (PD) is a common neurodegenerative disorder with a lifetime incidence of approximately 2 percent. A pattern of familial aggregation has been documented for the disorder, and it was recently reported that a PD susceptibility gene in a large Italian kindred is located on the long arm of human chromosome 4. A mutation was identified in the alpha-synuclein gene, which codes for a presynaptic protein thought to be involved in neuronal plasticity, in the Italian kindred and in three unrelated families of Greek origin with autosomal dominant inheritance for the PD phenotype. This finding of a specific molecular alteration associated with PD will facilitate the detailed understanding of the pathophysiology of the disorder.
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PMID:Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. 950 81

For the past 40 years, research into Parkinson's disease (PD) has been predominantly the province of epidemiologists interested in pursuing the connection between the disease and environmental factors such as viral infection or neurotoxins. Hereditary influences were actually discounted because of a high monozygotic twin discordance rate found in studies that were later shown to be inadequate and inconclusive. There has recently been a resurgence of interest in investigating hereditary factors in PD when it became more and more apparent that a positive family history was a major risk factor for the disease. Meanwhile, it also became increasingly apparent from neuropathological studies that the common, idiopathic form of Parkinson's disease had, in fact, a pathological correlate, i.e., the existence of Lewy bodies, an eosinophilic cytoplasmic inclusion body, distributed diffusely throughout the substantia nigra, hypothalamus, hippocampus, autonomic ganglia and olfactory tracts. Although candidate gene approaches to linkage in PD families have not been rewarding, a genome wide scan mapped PD to 4q21-23 in one large family with PD with diffuse Lewy bodies, where a candidate gene, alpha-synuclein, resides. This gene encodes a presynaptic protein of which a peptide fragment is known to be a constituent of Alzheimer's disease plaques. The identification of a missense mutation in the alpha-synuclein gene in four independent PD families suggests that at least some fraction of familial PD with diffuse Lewy bodies is the result of an abnormal protein that interferes with normal protein degradation leading to the development of inclusions and ultimately neuronal cell death. There may be common pathogenetic mechanisms involved in alpha-synuclein mutations in PD and beta-amyloid and presenilin gene mutations in Alzheimer's disease.
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PMID:Genetics of Parkinson's disease. 930 Jun 60

We initiated the present work in order to determine if the Ala53Thr mutation of the alpha-synuclein gene previously described by Polymeropoulos et al. [Science, 276 (1997) 2045-2047] could be detected in Spanish early onset Parkinson's disease (PD) patients. Thirty-four PD patients were evaluated. Of these, 13 were considered early onset patients (six familial and seven sporadic) and were included in the genetic study. We detected the presence of genetic anticipation in four kindreds with early onset PD members. The Ala53Thr mutation of the alpha-synuclein gene was absent in all patients. The results do not support a role for this mutation in our patients with early onset PD and, in agreement with the results previously reported, indicate that the Ala53Thr mutation of the alpha-synuclein gene is a rare cause of PD.
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PMID:Identification of Spanish familial Parkinson's disease and screening for the Ala53Thr mutation of the alpha-synuclein gene in early onset patients. 938 95

The aetiology and pathogenesis of Parkinson's disease (PD) remain unknown. There is a consensus emerging that there are likely to be multiple aetiologies that may result in the clinical and pathological abnormalities common to the majority of patients with idiopathic PD. Genetic factors have been suggested as important in either the cause of PD or in determining susceptibility. The recent linkage in one large pedigree of a gene for autosomal dominant parkinsonism to chromosome 4q21-23 and the subsequent identification of a mutation in the alpha-synuclein gene of this region are important steps towards identifying a biochemical deficiency capable of causing selective dopaminergic cell death. However, the relevance of such a defect to the majority of patients with apparent sporadic PD remains to be established. Factors that may predispose to substantia nigral cell loss, including mitochondrial dysfunction and oxidative damage, could be common to a number of separate aetiologies. A better understanding of these and their relationship to neuronal loss may provide further clues to aetiology.
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PMID:Pathogenesis of Parkinson's disease. 942 66

We studied two candidate genes, tau (tau) and alpha-synuclein (SNCA), for evidence of linkage disequilibrium on a group of unrelated individuals with progressive supranuclear palsy (PSP) and a group of age-matched control subjects. The tau alpha1 allele and the tau alpha1alpha1 genotype were overrepresented in individuals with PSP and the tau polymorphism was in linkage disequilibrium with the PSP disease locus when a recessive inheritance model was employed. We also report a lack of evidence to support linkage disequilibrium between PSP and the SNCA candidate Parkinson's disease gene on chromosome 4q21-q23.
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PMID:Progressive supranuclear gaze palsy is in linkage disequilibrium with the tau and not the alpha-synuclein gene. 944 91

The missense G209A mutation at exon 4 of the alpha-synuclein gene was recently found to be responsible for familial Parkinson's disease (PD) in a large kindred of Italian descent. We studied 100 typical PD patients with onset before age 51, both with and without a family history of PD. We did not find this alpha-synuclein missense mutation in any patient, but it was present in a symptomatic member of the Contursi family.
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PMID:Failure to find the alpha-synuclein gene missense mutation (G209A) in 100 patients with younger onset Parkinson's disease. 948 85

A mutation in exon 4 of the human alpha-synuclein gene was reported recently in four families with autosomal dominant Parkinson's disease (PD). In order to examine whether mutations in this exon or elsewhere in the gene are common in familial PD, all seven exons of the alpha-synuclein gene were amplified by PCR from index cases of 30 European and American Caucasian kindreds affected with autosomal dominant PD. Each product was sequenced directly and examined for mutations in the open reading frame. No mutations were found in any of the samples examined. We conclude that the A53T change described in the alpha-synuclein gene is a rare cause of PD or may even be a rare variant. Mutations in the regulatory or intronic regions of the gene were not excluded by this study.
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PMID:Sequencing of the alpha-synuclein gene in a large series of cases of familial Parkinson's disease fails to reveal any further mutations. The European Consortium on Genetic Susceptibility in Parkinson's Disease (GSPD). 949 30

Parkinson's disease (PD) is a common degenerative neurologic disorder, which is pathologically characterized by a selective degeneration of dopaminergic neurons of the substantia nigra pars compacta, and the presence of characteristic eosinophilic inclusions, known as Lewy-bodies in affected brain areas. The cause of PD is unknown but, in recent years, genetic factors have been implicated in the aetiology of the disease. Firstly, clinico-genetic, epidemiologic and twin studies revealed inheritable effects and questioned earlier studies which had denied such influences. Secondly, several family studies suggested autosomal-dominant inheritance of syndromes which, to variable degrees, resembled sporadic PD clinically and in some cases also neuropathologically. Recently, a disease locus has been mapped to chromosome 4q21-22 in a large Mediterranean pedigree, in which disease expression is clinically and pathologically within the spectrum of sporadic PD; being atypical only for a relatively young mean age at onset of 46 years and rapid course of 10 years from onset to death. In affected individuals of this family and of three unrelated Greek kindreds, a putative disease-causing mutation has been identified in the gene encoding alpha-synuclein. With the first variant being defined, genetic heterogeneity has become apparent, as in other families parkinsonism was not linked to the 4q-locus and was not associated with the alpha-synuclein mutation (unpublished data). We describe a different genetic locus that appears to be involved in the development of parkinsonism closely resembling sporadic PD including a similar mean age of onset (59 years in the families, 59.7 years in sporadic PD; ref. 12). This locus was detected in a group of families of European origin. In two of these families, there is genetic evidence for a common founder. The penetrance of the mutation appears to be low, most likely below 40%. This is compatible with a possible role of this locus not only in familial, but also in typical (sporadic) PD.
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PMID:A susceptibility locus for Parkinson's disease maps to chromosome 2p13. 950 May 49

A mutation in exon 4 of the alpha-synuclein (NACP) gene has been reported to explain the chromosome 4 linkage to autosomal dominant Parkinson's disease. We developed primers and methods for exonic sequencing of this gene and sequenced the entire coding region of the gene in 6 families with autosomal dominant disease and in 2 cases of lytico and bodig from Guam. In addition, we have sequenced exon 4 of this gene in 5 cases of familial disease and have screened for the specific mutation (A53T) in a 40 cases of idiopathic Parkinson's disease, 3 cases of multisystem atrophy, and 15 cases of Lewy body dementia. We have found no genetic variation in the gene. We discuss these findings with respect to both the epidemiology of Parkinson's disease and the possibility that NACP is not the chromosome 4 locus for disease.
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PMID:Low frequency of alpha-synuclein mutations in familial Parkinson's disease. 950 59

alpha-Synuclein is a highly conserved presynaptic protein of unknown function. A mutation in the protein has been causally linked to Parkinson's disease in humans, and the normal protein is an abundant component of the intraneuronal inclusions (Lewy bodies) characteristic of the disease. alpha-Synuclein is also the precursor to an intrinsic component of extracellular plaques in Alzheimer's disease. The alpha-synuclein sequence is largely composed of degenerate 11-residue repeats reminiscent of the amphipathic alpha-helical domains of the exchangeable apolipoproteins. We hypothesized that alpha-synuclein should associate with phospholipid bilayers and that this lipid association should stabilize an alpha-helical secondary structure in the protein. We report that alpha-synuclein binds to small unilamellar phospholipid vesicles containing acidic phospholipids, but not to vesicles with a net neutral charge. We further show that the protein associates preferentially with vesicles of smaller diameter (20-25 nm) as opposed to larger (approximately 125 nm) vesicles. Lipid binding is accompanied by an increase in alpha-helicity from 3% to approximately 80%. These observations are consistent with a role in vesicle function at the presynaptic terminal.
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PMID:Stabilization of alpha-synuclein secondary structure upon binding to synthetic membranes. 954 70


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