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)

A genetic contribution to the etiology of Parkinson's disease was first suspected by Charcot and later confirmed by case control, family, and twin studies, as well as by the description of large parkinsonian families with Mendelian inheritance of the disease. Recent progress in the field of molecular neurogenetics has led to the identification of several Parkinson disease genes and gene loci. Mutations in the alpha-Synuclein gene (PARK1) and in the gene for the ubiquitin C-terminal hydrolase I (PARK5), along with two gene loci harboring currently unknown genes (PARK3 and PARK4), have been linked to very rare autosomal dominantly inherited parkinsonian syndromes. Mutations in the parkins gene (PARK2), causing autosomal recessive early-onset parkinsonism, are much more common and therefore of clinical relevance. A second gene locus for an autosomal dominantly inherited Parkinsonian syndrome was recently localized on chromosome 1 (PARK6). All three parkinson genes identified thus far imply the involvement of the ubiquitin pathway of protein degradation in the pathogenesis of Parkinson's disease.
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PMID:[The genetics of Parkinson syndrome]. 1144 21

We present the findings of a study of two large unrelated kindreds with autosomal dominant Parkinson's disease. The affected members were assessed clinically and with [(18)F]6-fluorodopa-PET and were indistinguishable from patients with the sporadic form of Parkinson's disease. In one kindred, an affected member was examined subsequently at autopsy and Lewy bodies were present in a distribution typical of sporadic Parkinson's disease. These kindreds are distinct from other Parkinsonian kindreds with identified genetic loci (PARK1-4) and provide further evidence for genetic heterogeneity in familial Parkinson's disease.
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PMID:Two large British kindreds with familial Parkinson's disease: a clinico-pathological and genetic study. 1183 92

Eight regions of the genome (PARK1-8) have been implicated in autosomal dominant and autosomal recessive forms of early-onset Parkinson's disease. These forms constitute a few of all cases. However, except for a haplotype in six families (PARK3), no study has successfully mapped a gene or described mutations that contribute to the common late-onset Parkinson's disease. Some have even suggested that a genetic component does not exist. We cross-matched our nationwide genealogy database with a population-based list of Icelandic Parkinson's disease patients to search for families with more than one patient. We performed a genomewide scan on 117 patients and 168 of their unaffected relatives within 51 families using 781 microsatellite markers. Allele-sharing, model-independent analysis of the results showed linkage to a region on chromosome 1p32 with a logarithm of odds score of 3.9 (Z(lr) = 4.2). By increasing the information content with additional microsatellite markers in this region, we found that the logarithm of odds score increased to 4.9 (Z(lr) = 4.8). This result corresponds to an unadjusted p value of 1.0 x 10(-6) and p < 0.005 after adjusting for a genomewide search. We designate this region PARK10. We therefore have successfully mapped, to genomewide significance, a susceptibility gene for late-onset Parkinson's disease using multiple families drawn across a whole population. Identification of the susceptibility gene in this region may pave the way for a better understanding of the disease process, which, in turn, may lead to improved diagnostics and therapeutics.
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PMID:A susceptibility gene for late-onset idiopathic Parkinson's disease. 1240 51

Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identification as an alpha-synuclein (PARK1) and parkin (PARK2) interacting protein. Moreover, synphilin-1 is a component of Lewy bodies (LB) in brains of sporadic PD patients. Therefore, we performed a detailed mutation analysis of the synphilin-1 gene in 328 German familial and sporadic PD patients. In two apparently sporadic PD patients we deciphered a novel C to T transition in position 1861 of the coding sequence leading to an amino acid substitution from arginine to cysteine in position 621 (R621C). This mutation was absent in a total of 702 chromosomes of healthy German controls. To define a possible role of mutant synphilin-1 in the pathogenesis of PD we performed functional analyses in SH-SY5Y cells. We found synphilin-1 capable of producing cytoplasmic inclusions in transfected cells. Moreover we observed a significantly reduced number of inclusions in cells expressing C621 synphilin-1 compared with cells expressing wild-type (wt) synphilin-1, when subjected to proteasomal inhibition. C621 synphilin-1 transfected cells were more susceptible to staurosporine-induced cell death than cells expressing wt synphilin-1. Our findings argue in favour of a causative role of the R621C mutation in the synphilin-1 gene in PD and suggest that the formation of intracellular inclusions may be beneficial to cells and that a mutation in synphilin-1 that reduces this ability may sensitize neurons to cellular stress.
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PMID:Identification and functional characterization of a novel R621C mutation in the synphilin-1 gene in Parkinson's disease. 1276 Oct 37

In this study no one of our 85 patients of Serbian origin with young-onset (</= 45 years) dopa-responsive parkinsonism (YOP), previously proved negative for PARK1 and PARK2 mutations, had either spinocerebellar ataxia type 2 (SCA2) or SCA3 mutation. These data do not prove the significance of these two mutations in either sporadic or familial YOP suggestive of Parkinson's disease.
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PMID:SCA2 and SCA3 mutations in young-onset dopa-responsive parkinsonism. 1294 Aug 46

The name synphilin-1 comes from its identification as an alpha-synuclein-interacting protein (SNCAIP) in yeast two-hybrid screens. Since alpha-synuclein ( PARK1) was the first gene identified as causing inherited forms of Parkinson's disease (PD), synphilin-1 was quickly implicated in neurodegeneration in PD. Recently, the first genetic evidence for the direct contribution of synphilin-1 in the pathogenesis of PD has been defined with the identification of an R621C mutation as a susceptibility factor for PD in two German patients. Extensive in vitro studies have determined the physiological functions of synphilin-1, identified novel synphilin-1-interacting proteins, and linked synphilin-1 to ubiquitin-mediated protein degradation. The present article provides an overview of the current concepts of the role of synphilin-1 in synaptic function and protein degradation and in the molecular mechanisms leading to neurodegeneration in PD.
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PMID:The role of synphilin-1 in synaptic function and protein degradation. 1532 16

There has been lots of progress in Parkinson's disease. First of all, in Japan, a guideline for the treatment of Parkinson's disease was published. This guideline contains both EBM based systematic review of every drugs being used in the treatment of Parkinson's disease including those drugs for the management of side effects and other problems arising during the course of the treatment and an algorithm of the practical treatment of Parkinson's disease patients. This is an official publication of Japanese Neurological Society. In the diagnosis of Parkinson's disease, many specialists in Parkinson's disease have recognized the usefulness of MIBG SPECT of the cardiac sympathetic endings. MIBG uptake shows remarkable decrease in Lewy body positive Parkinson's disease patients from the early stage except for some of the stage I patients. In the basic aspect, studies on familial forms of Parkinson's disease have contributed a lot to the understanding of the pathogenesis of sporadic Parkinson's disease. Mutations of alpha-synuclein cause autosomal dominant Parkinson's disease. Recently, triplication of one of the alpha-synuclein genes was found as the third mutation of PARK1. Thus just overproduction of normal alpha-synuclein is toxic to nigral neurons. In this form and sporadic Parkinson's disease, oxidative damage plays an important role in nigral neurodegeneration. PARK2 is caused by mutations of the parkin gene. Parkin protein is an ubiquitin-protein ligase. In this form also, oxidative damage appears to be operating in neurodegeneration. Thus a common mechanism appears to be present in different forms of Parkinson's disease. Future investigation to find neuroprotective drugs should take this concept of common mechanism into their research strategies.
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PMID:[Progress in Parkinson's disease]. 1546 71

Parkinson disease (PD) is the second most common neurodegenerative disorder. Recent studies have consistently demonstrated that in some families, disease is attributable to a mutation in a single gene. To date, genetic analyses have detected linkage to six chromosomal regions and have identified three causative genes: PARK1 (alpha-synuclein), PARK2 (parkin), and PARK7 (DJ-1). In addition, mutations in several other genes have been implicated in familial PD. Identification of the mutations in these genes has led to the recognition that the ubiquitin-proteasome system is an important pathway that may be disrupted in PD. Studies are ongoing to identify additional genes that may contribute to PD susceptibility, particularly in late-onset families without a clear pattern of disease inheritance. With the identification of mutations in particular genes and the likely role of additional genes that are important in PD risk-susceptibility, appropriate protocols must be developed so that accurate and informative genetic counseling can be offered to families in which one or more members has PD. Further diagnostic testing should be delayed until more is learned about the frequency, penetrance, and risk assessment of certain gene mutations. Important lessons can be learned from the implementation of counseling protocols for other neurodegenerative disorders, such as Huntington disease and Alzheimer disease.
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PMID:Genetics of Parkinson disease. 1571 24

Monogenic forms of Parkinson's disease (PD) provide an opportunity to examine mechanisms underlying phenotypic variation. Glutathione S-transferase (GST) has detoxification and antioxidative functions. To screen genetic variations in GST for an effect on the onset age (OA) of PD, we typed seven common genetic polymorphisms in five GST isoenzymes, M1, M3, P1, T1, and Z1, in 36 affected individuals of Italian or Greek origin with the alpha-synuclein A53T (PARK1) mutation. Mean OA was 45.2 years with a wide SD of 11.03 years, similar to that of idiopathic PD. Our allelic analysis showed that the subjects homozygous for the GSTP1 G-for-A nucleotide substitution at position 313 had a mean OA acceleration of 15.2 years (31.3 +/- 7.09 years, n = 3 vs. 46.5 +/- 10.50 years, n = 33, P = 0.020). The GSTP1 C341T substitution was associated with a 9.7-year acceleration of OA, but the significance was borderline (36.4 +/- 8.35 years vs. 46.7 +/- 10.85 years, P = 0.0519). After correction for the five genes examined, both results lose statistical significance. Nevertheless, our results suggest that further investigation in GSTP1 variants and PD pathogenesis is warranted in sporadic PD and that a search for toxins that accelerate PD OA should pay particular attention to GST-P1 substrates.
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PMID:Glutathione S-transferase polymorphisms and onset age in alpha-synuclein A53T mutant Parkinson's disease. 1703 8

Until 10 years ago, conventional wisdom held that Parkinson's disease was not a genetic disorder. Since that time, there have been a plethora of genetic findings, culminating in the cloning of several genes that derive from the loci given the nomenclature PARK1-PARK12 (OMIM 168600). Recently, these research findings have begun to impact clinical practice, and this impact is likely to increase. The primary purpose of this article is to outline these genetic advances, discuss their importance for current practice in clinical and related settings, and outline briefly how they are influencing research into the causes of and possible future treatments for this prevalent disorder.
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PMID:Genetics of Parkinson's disease and parkinsonism. 1706 89


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