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

Mutations in the alpha-synuclein gene (SNCA) have been implicated in familial Parkinson's disease (PD) while certain polymorphic alleles at a microsatellite repeat, NACP-Rep1, located approximately 10 kb upstream of the gene, have been associated with sporadic PD. In order to study the regulation of the human alpha-synuclein gene, we performed a deletion analysis of 10.7 kb upstream of the translational start site, using the luciferase reporter assay in 293T cells and the neuroblastoma cell line SH-SY5Y. The shortest fragment, 400 bp upstream of the transcriptional start site, was sufficient for transcription in both cell lines. The other constructs led to variable expression levels, with some showing maximum expression and others showing nearly complete extinction of expression. An 880 bp fragment located approximately 10 kb upstream of the gene and containing the NACP-Rep1 polymorphism, was shown to be necessary for normal expression. Additional analysis of the NACP-Rep1 locus and surrounding DNA suggested that two domains flanking the repeat interact to enhance expression while the repeat acts as a negative modulator. Next, we measured the activity of the entire 10.7 kb upstream region in the luciferase reporter assay when each of our different NACP-Rep1 alleles were present. The expression levels varied very significantly among the different alleles over a 3-fold range in the SH-SY5Y cells but showed little or no significant variation in the 293T cells. Given that even small changes in alpha-synuclein expression may, over many decades, predispose to PD, the association of different NACP-Rep1 alleles with PD may be a consequence of polymorphic differences in transcriptional regulation of alpha-synuclein expression resulting from different NACP-Rep1 alleles.
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PMID:Effect of allelic variation at the NACP-Rep1 repeat upstream of the alpha-synuclein gene (SNCA) on transcription in a cell culture luciferase reporter system. 1175 92

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

A specific allele of the NACP-Rep1 polymorphism within the alpha-synuclein promoter was found to be associated both with Parkinson's disease and essential tremor. We repeated the association study on a large series of Italian patients with essential tremor using a panel of polymorphisms within the alpha-synuclein gene. Our results did not confirm the association reported previously and failed to identify a alpha-synuclein specific haplotype as susceptibility factor for essential tremor.
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PMID:Essential tremor is not associated with alpha-synuclein gene haplotypes. 1281 63

NACP-Rep1, a polymorphic microsatellite upstream of the alpha-synuclein gene ( SNCA), consisting of the nucleotides (TC)(x)(T)(2)(TC)(y)(TA)(z)(CA)(w), has five alleles originally defined by 2-bp differences in (CA)(w). Different NACP-Rep1 alleles have been associated with sporadic Parkinson's disease in some, but not all, studies and can effect expression driven by the SNCA promoter over a three-fold range in the neuroblastoma cell line, SH-SY5Y. By analyzing children in CEPH families in which parents appeared to be homozygous for a NACP-Rep1 allele, we found that there are sequence differences within same-sized NACP-Rep1 alleles, contributed mainly by variation of the (TC)(y)(TA)(z) portion of the microsatellite repeat. To test whether these sequence differences might impact on promoter function we determined the effect of two sequence variant alleles, both of size "1", using the luciferase reporter system. There was only a very small expression difference between these two variant alleles. This finding implies that the overall length of the NACP-Rep1 allele plays the main role in the transcription regulation by the NACP-Rep1 element and suggests that functional differences due to sequence heterogeneity within NACP-Rep1 alleles of the same length are probably not confounding factors in association studies based on alleles defined by length.
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PMID:Functional analysis of intra-allelic variation at NACP-Rep1 in the alpha-synuclein gene. 1292 82

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

Contradictory evidence has been reported on the role of the polymorphic mixed dinucleotide repeat (NACP-REP1) of the alpha-synuclein gene as a risk factor for sporadic Parkinson's disease (PD). In the present study we genotyped the NACP-REP1 polymorphism in 189 PD patients from southern Italy and 182 healthy control subjects. We failed to demonstrate an association of any NACP-REP1 allele with PD.
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PMID:NACP-REP1 polymorphism is not involved in Parkinson's disease: a case-control study in a population sample from southern Italy. 1458 85

The authors examined four- and six-loci haplotype constructs (from five single nucleotide polymorphisms and three microsatellite regions) of the alpha-synuclein gene in patients with Parkinson's disease (PD) and controls in an ethnic Chinese population. Logistic regression analysis demonstrated an association of NACP-Rep1 (p = 0.002) and L478 (p < 0.0001) with risk of PD after correction for the effects of age, sex, and the other polymorphic loci. Specific four-loci and six-loci haplotypes were significantly associated with an increased or decreased risk of PD.
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PMID:Alpha-synuclein haplotypes implicated in risk of Parkinson's disease. 1471 15


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