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 neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD.
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PMID:Hereditary early-onset Parkinson's disease caused by mutations in PINK1. 1515 38

Recessively inherited mutations in parkin, DJ-1, and PINK1 have recently been linked to familial forms of parkinsonism. These syndromes are often clinically indistinguishable from Parkinson's disease, as similar neuronal groups, notably dopaminergic neurons, are selectively affected. Studies of the functions of these gene products may provide insights into the pathogenic mechanisms underlying the selective degeneration of dopaminergic neurons. Emerging evidence that one or several of these genes play important roles in mitochondrial function and the dopaminergic system suggests that these events may be early steps of the pathophysiological changes of the disease. This review will summarize recent advances in our understanding of these gene products, with emphasis on the surprising convergence of their functions.
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PMID:Mitochondria and dopamine: new insights into recessive parkinsonism. 1529 38

Mutations in the PINK1 gene (PARK6), a putative serine-threonine kinase, cause autosomal recessive Parkinson's disease. PINK1 functions as a protein kinase and confers protective effects in the mitochondria, where it is primarily located. We assessed in a population of European ancestry whether common genetic variation in this novel gene influences nonmendelian forms of Parkinson's disease. We defined the linkage disequilibrium structure of PINK1 and used this to identify a set of tagging single nucleotide polymorphisms that we estimate will efficiently represent all of the common DNA variation in the entire gene. Genotyping these tags in a set of 576 Parkinson's disease patients and 514 controls did not demonstrate a case-control partition for allele or for haplotype and thus provides evidence against the existence of a common functional variants in PINK1 that has a strong influence on PD risk.
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PMID:The gene responsible for PARK6 Parkinson's disease, PINK1, does not influence common forms of parkinsonism. 1534 59

Parkinson's disease (PD) is the second most common neurodegenerative disorders. Recently, several forms of familial PD have been reported so far. Among them, several causative genes such as alpha-synuclein, UCH-L1, PINK1, and DJ-1 have been identified. Functional analysis on these causative genes may help us to explore the molecular mechanisms of nigral neuronal death in not only FPD but also sporadic form of PD. Thus, the identification of FPD gives us good information of etiologies of PD.
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PMID:[Molecular biology for familial Parkinson's disease]. 1546 74

The identification of Mendelian mutations in rare forms of familial Parkinson's disease (PD) have provided significant insights into the molecular pathogenesis of this common complex disorder. DJ-1 is the third of four genes known to be definitively causal in familial PD, the three others being alpha-synuclein, parkin and the recently identified PINK1. Mutations in the DJ-1 gene were identified in two European families, a Dutch kindred harbouring a large homozygous genomic deletion encompassing exons 1-5 of the gene and an Italian kindred with a homozygous L166P missense mutation. The clinical phenotype of the two families was similar to that of parkin cases. Age of onset was in the mid-thirties with good responsiveness to l-dopa and slow disease progression. Focal dystonias and blepharospasm were also evident as were behavioural disturbances early in the course of the disease. To date, there are no studies of pathological material from known DJ-1 patients. It therefore remains to be determined whether these patients form Lewy bodies and/or Lewy neurites, the eosinophilic fibrillary inclusions that contain predominantly alpha-synuclein and that are the pathological hallmark of PD.
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PMID:Causes of Parkinson's disease: genetics of DJ-1. 1550 54

Parkinson's disease (PD) is a common neurodegenerative disorder of adulthood characterized clinically by rigidity, bradykinesia, resting tremor, and postural instability. The annual incidence of PD ranges between 16 and 19 individuals per 100,000 (Twelves et al., Mov Disord 2003;18:19-31). Historically, PD has been commonly viewed as an idiopathic or environmentally triggered condition. However, as is true with most common conditions, there have been several families reported with PD who demonstrate a classic Mendelian pattern of inheritance. To date, nine genetic loci have been reported and four pathogenic genes have been identified: alpha-synuclein, parkin, DJ1, and PINK1. Families with alterations in these genes or linked sites demonstrate either recessive or dominant inheritance patterns and may have typical and/or atypical symptoms, with an age of onset extending from the second to the sixth decade. Commercial tests for parkin and alpha-synuclein mutations are now available. We predict that physicians, particularly neurologists, increasingly will be approached for information and referrals regarding genetic testing. To assist patients and their families, physicians will not only need to know when such testing is likely to yield a meaningful result but also be aware of the possible social and emotional consequences of testing. The following is a review of what is currently known about the genetics of PD within this context. We discuss what is known about genetic testing for Huntington's disease, a well-described model for genetic testing in a neurodegenerative disorder. We explore the utility, appropriateness, and possible implications of genetic testing for diagnostic and presymptomatic purposes.
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PMID:Genetic testing in Parkinson's disease. 1550 1

Mutations in the PINK1 gene have recently been shown to cause autosomal recessive Parkinson disease (PD). The authors assessed the prevalence of PINK1 gene mutations in 290 well-characterized early- and late-onset PD patients from Ireland. In a 51-year-old PD patient with a family history of PD, the authors identified a novel heterozygous mutation (R147H) in exon 2 of the PINK1 gene. Overall, these data indicate that PINK1 mutations are a rare cause of PD in Ireland.
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PMID:PINK1 (PARK6) associated Parkinson disease in Ireland. 1550 46

The identification of rare monogenic forms of Parkinson's disease (PD) has provided tremendous insight into the molecular pathogenesis of this disorder. Heritable mutations in alpha-synuclein, parkin, DJ-1 and PINK1 cause familial forms of PD. In the more common sporadic form of PD, oxidative stress and derangements in mitochondrial complex-I function are considered to play a prominent role in disease pathogenesis. However, the relationship of DJ-1 with other PD-linked genes and oxidative stress has not been explored. Here, we show that pathogenic mutant forms of DJ-1 specifically but differentially associate with parkin, an E3 ubiquitin ligase. Chemical cross-linking shows that pathogenic DJ-1 mutants exhibit impairments in homo-dimer formation, suggesting that parkin may bind to monomeric DJ-1. Parkin fails to specifically ubiquitinate and enhance the degradation of L166P and M26I mutant DJ-1, but instead promotes their stability in cultured cells. The interaction of parkin with L166P DJ-1 may involve a larger protein complex that contains CHIP and Hsp70, perhaps accounting for the lack of parkin-mediated ubiquitination. Oxidative stress also promotes an interaction between DJ-1 and parkin, but this does not result in the ubiquitination or degradation of DJ-1. Parkin-mediated alterations in DJ-1 protein stability may be pathogenically relevant as DJ-1 levels are dramatically increased in the detergent-insoluble fraction from sporadic PD/DLB brains, but are reduced in the insoluble fraction from parkin-linked autosomal recessive juvenile-onset PD brains. These data potentially link DJ-1 and parkin in a common molecular pathway at multiple levels that may have important implications for understanding the pathogenesis of inherited and sporadic PD.
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PMID:Association of DJ-1 and parkin mediated by pathogenic DJ-1 mutations and oxidative stress. 1552 61

Parkinson's disease (PD) is the most common neurodegenerative movement disorder with a substantial genetic component (which is more pronounced in earlier onset cases). In addition to three well-confirmed PD genes (SNCA, parkin and DJ-1), mutations in the PTEN Induced Kinase (PINK1) gene have recently been identified in families with recessive early onset PD. We tested the hypothesis that three common coding variations (Leu63Leu, Ala340Thr and Asn521Thr) could increase the risk of PD. We performed a case control association study in a series of 91 PD cases (Caucasian of Canadian origin) and 182 normal controls. The patients were largely pre-selected for having an early age of onset (<50 years) and/or a positive family history. Our results did not reveal any evidence of association between PD and any of the three SNPs at the allelic or genotypic levels (p > 0.25). Furthermore, we did not detect a modifying effect for any genotype upon the age of onset in the PD group (p > 0.19). Nevertheless, it remains to be evaluated whether PINK1 variations contribute to the risk of common late onset sporadic PD.
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PMID:Genetic association study of PINK1 coding polymorphisms in Parkinson's disease. 1554 45

The recent identification of genes (parkin, DJ-1, and PINK1) involved in recessive autosomal parkinsonism, and the indications that these proteins may have protective effects on the mitochondria, has led to the reemergence of the notion that mitochondrial dysfunction might play a central role in the etiology of sporadic Parkinson's disease (PD). This idea has previously been supported by biochemical analyses showing reduced mitochondrial activity in PD patients and in animal models of PD generated by the selective inhibition of mitochondria activity. However, the involvement of DJ-1 or PINK1 loss of function in classical idiopathic PD, characterized by pathological inclusions composed of aggregated alpha-synuclein protein, has still not been evaluated. More detailed studies of the possible interactions between parkin, DJ-1, PINK1, and alpha-synuclein and their effects on mitochondria are needed to more adequately define the biological pathways that may convergently or independently lead to parkinsonism.
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PMID:Mitochondrial injury: a hot spot for parkinsonism and Parkinson's disease? 1557 21


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