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

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

PD (Parkinson's disease) is an aetiologically heterogeneous disorder characterized by a clinical phenotype consisting of resting tremor, rigidity and bradykinesia. Motor symptoms are associated with a progressive loss of dopaminergic neurons, with Lewy body inclusions within surviving neurons. Although heritability studies have shown evidence of familial aggregation, twin studies have provided limited support for a genetic aetiology. Nevertheless, classical linkage methods have nominated 11 regions of the genome and pathogenic mutations have been identified in several genes, including alpha-synuclein, parkin, ubiquitin C-terminal hydrolase L1, oncogene DJ-1, PTEN-induced protein kinase 1 and microtubule-associated protein tau. Most recently, heterozygous mutations in LRRK2 (leucine-rich repeat kinase 2) were found to cause late-onset, autosomal-dominant PD. Despite their consistent clinical phenotype, family members with LRRK2 mutations can have variable alpha-synuclein and tau pathologies. Lrrk2 is a member of the Roc (Ras of complex proteins) family, with Ras GTPase and MAPKKK (mitogen-activated protein kinase kinase kinase) catalytic domains. Thus its discovery highlights vesicle dynamics and secondary-messenger signalling in disease pathophysiology. To diagnose a disease accurately and effectively treat it, requires an understanding of its molecular pathogenesis. Herein, we provide an overview of the genetics of PD, how these discoveries are revolutionizing long-held beliefs and more importantly how this knowledge may be translated into patient therapy.
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PMID:Pathophysiology, pleiotrophy and paradigm shifts: genetic lessons from Parkinson's disease. 1604 50

Recent data has demonstrated that mutations in PINK1, encoding PTEN-induced kinase 1, are a cause of early onset recessive parkinsonism (PARK6 locus). Common variability in genes implicated in hereditary forms of parkinsonism may be a predisposing factor in sporadic Parkinson's disease (PD). We analyzed whether six different genetic variants within and surrounding PINK1 contribute to the risk of sporadic PD in a Finnish case-control series. Our results indicate that this gene does not play a major role in the genetic predisposition to PD in this population.
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PMID:Assessment of PINK1 (PARK6) polymorphisms in Finnish PD. 1604 32

Mutations in the PTEN-induced kinase 1 (PINK1) gene have recently been implicated in autosomal recessive early onset Parkinson Disease (1, 2). To investigate the role of PINK1 in neurodegeneration, we designed human and murine neuronal cell lines expressing either wild-type PINK1 or PINK1 bearing a mutation associated with Parkinson Disease. We show that under basal and staurosporine-induced conditions, the number of terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive cells was lower in wild-type PINK1 expressing SH-SY5Y cells than in mock-transfected cells. This phenotype was due to a PINK1-mediated reduction in cytochrome c release from mitochondria, which prevents subsequent caspase-3 activation. We show that overexpression of wild-type PINK1 strongly reduced both basal and staurosporine-induced caspase 3 activity. Overexpression of wild-type PINK1 also reduced the levels of cleaved caspase-9, caspase-3, caspase-7, and activated poly(ADP-ribose) polymerase under both basal and staurosporine-induced conditions. In contrast, Parkinson disease-related mutations and a kinase-inactive mutation in PINK1 abrogated the protective effect of PINK1. Together, these results suggest that PINK1 reduces the basal neuronal pro-apoptotic activity and protects neurons from staurosporine-induced apoptosis. Loss of this protective function may therefore underlie the degeneration of nigral dopaminergic neurons in patients with PINK1 mutations.
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PMID:Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. 1607 29

Parkinson's disease is a frequent disorder caused primarily by the loss of dopaminergic neurons of the substantia nigra. Mutations in the PTEN-induced kinase (PINK1) gene, in addition to those in parkin and DJ-1, have been found in families with recessive early-onset Parkinson's disease. We screened for parkin and PINK1 mutations in a panel of 177 autosomal recessive Parkinson's disease families with ages at onset < or =60 years, mostly from Europe. In 7 unrelated families, we identified 10 pathogenic PINK1 mutations (5 missense, 2 nonsense and 3 frameshift deletion mutations), 8 of which were novel. All the mutations were in the homozygous or compound heterozygous states. Interestingly, pseudo-dominant inheritance was observed in a family with two different mutations. The clinical characteristics of 12 PINK1 patients and 114 parkin patients were similar, even for signs such as dystonia at onset and increased reflexes, which were thought to be specific to parkin. In contrast, onset in patients with PINK1 mutations was earlier and increased reflexes were found more frequently than in patients without PINK1 or parkin mutations. These results suggest that PINK1 is the second most frequent causative gene in early-onset Parkinson's disease with a slowly progressive phenotype, indistinguishable from early-onset patients with parkin mutations.
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PMID:Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa. 1640 16

The deposition of alpha-synuclein (aS), a product of pathogenic gene for dominantly inherited familial Parkinson's disease (PD; park1), as fibrillary aggregates like Lewy bodies (LB), is a hallmark lesion of a set of neurodegenerative disorders termed synucleinopathies, including sporadic PD and dementia with Lewy bodies (DLB). We found that aS is the major component of LBs and further identified a specific phosphorylation of Ser129 of insoluble aS by mass spectrometric analysis. The roles of DJ-1 and PINK-1, products of pathogenic genes for autosomal recessive forms of early-onset parkinsonism, have subsequently been examined. Overexpression of DJ-1 conferred cultured cells resistance to oxidative stress, suggesting an antioxidant function of DJ-1. We also confirmed the anti-PTEN function of DJ-1 that may promote cell survival, showing decreased phosphorylation of Akt through upregulation of PTEN activity upon siRNA knockdown for DJ-1. PINK-1, that had been identified as a gene upregulated by PTEN overexpression, turned out to be a protein kinase localized in mitochondria. Collectively, information derived from studies on pathogenic genes for familial PD will open up the way toward the clarification of the pathogenesis of PD, underscoring the roles of protein aggregation, proteolysis, oxidative stress and protein phosphorylation in PD.
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PMID:[Pathogenesis of Parkinson's disease: implications from familial Parkinson's disease]. 1644 57

Mutations of the tumour suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10) are seen in many human cancers. However, dysregulation of PTEN may be involved in other disease states such as Parkinson's disease. This minireview describes recent work examining PTEN regulation and its implications for the development of both cancer and neurodegenerative disease.
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PMID:Tumours and tremors: how PTEN regulation underlies both. 1649 27

The identification of several monogenic forms has established Parkinson disease (PD) as a movement disorder with a considerable genetic origin in at least a subset of patients. Four of the known forms, Parkin-, PINK1 (PTEN-induced putative kinase 1)-, DJ1-, and LRRK2 (leucine-rich repeat kinase 2)-linked PD, may present clinically as "idiopathic PD" and account for at least 1% of all cases of PD. However, all known monogenic forms combined explain about only 20% of early-onset PD and less than 3% of late-onset PD at best. Although the individual clinical course cannot be predicted, overall, many cases of genetic PD will progress more slowly and respond better to treatment than patients without mutations. Genetic testing frequently yields inconclusive results, is expensive, and should be used for diagnostic purposes only after careful consideration in selected cases at specialty centers. While genetic findings have greatly advanced our understanding of the pathophysiology of PD, we are faced with many novel challenges. These include the definition of the phenotypic and genotypic spectrum of the monogenic forms, a revised terminology and classification of parkinsonian syndromes, identification of genetic susceptibility factors, and development of guidelines for genetic testing and of new treatment options for PD.
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PMID:Implications of genetics on the diagnosis and care of patients with Parkinson disease. 1653 59

We report the first case of early-onset Parkinson's disease (EOP) with the PTEN-induced kinase 1 (PINK1) gene deletion in 62 years old Japanese female. The symptoms were started with unstable gait at the age 38. Parkinsonian symptoms became apparent in 45 years old. L-Dopa was markedly effective on her parkinsonian symptoms. However, equinovarus foot induced by L-Dopa intake appeared three months prior to the admission. On admission, she presented with mild cognitive impairment, severe depression, marked retropulsion, resting tremor in the left upper limb and mild hyperreflexia in the four limbs. Rigidity was not present. Mutational analysis revealed homozygous deletion from exon 6 to 8 in the PINK1 gene. An ethnic diversity in PINK1 mutation is suggested.
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PMID:[A 62-year-old woman with early-onset Parkinson's disease associated with the PINKi gene deletion]. 1664 30


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