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)

In the majority of patients with Parkinson's disease (PD), it is now clear that genetic factors contribute to the pathogenesis of PD, although the contribution of genetic and environmental factors remained to be elucidated. Recently, several genes for familial PD (FPD) based on the single gene defects have been mapped and identified. Alpha-synuclein and UCH-L1 are involved in the dominant form of FPD. In contrast, parkin, DJ-1, and PINK1 are responsible for the recessive form of FPD. The presence of different loci or different causative genes indicates that PD is not a single entity but a highly heterogeneous disorder. However, the functions of causative genes may share common pathways such as an ubiquitin-proteasome pathway, oxidative stress, and mitochondrial dysfunction. Thus, the identification and elucidation of the causative genes should enhance our understanding of the pathogenesis of not only FPD, but also sporadic PD.
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PMID:[The gene products for familial Parkinson's disease provide us hints to elucidate the mechanisms of nigral degeneration]. 1565 2

Over the last few years, several genes for rare, monogenically inherited forms of Parkinson's disease (PD) have been mapped and/or cloned. In dominant families, mutations have been identified in the gene for alpha-synuclein. Aggregation of this protein in intracellular inclusions (Lewy bodies) may be crucial in the molecular pathogenesis of the disease. Three genes have been identified to cause autosomal-recessive early-onset parkinsonism: parkin, DJ1, and PINK1. These genes are thought to be involved in the proteasomal protein degradation pathway, in the cell's response to oxidative stress, and in mitochondrial function, respectively. It is therefore concluded that these cellular mechanisms may play an important role in the degenerative process of PD. There is also accumulating evidence that genetic factors play a role in the common sporadic form of PD, however their precise nature remains unknown.
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PMID:New aspects of genetic contributions to Parkinson's disease. 1565 63

A G309D mutation in the PINK1 gene in a consanguineous Spanish kindred with seven siblings, three of whom are clinically affected, has recently been shown to be a cause of the PARK6 form of autosomal-recessive Parkinson's syndrome. In this family, we studied pre- and postsynaptic dopaminergic function using 123I-FP-CIT- and 123I-iodobenzamide-SPECT to determine binding to the presynaptic dopamine transporter (DAT) and postsynaptic D2 receptors respectively. All three PARK6 patients showed reduced striatal DAT binding with posterior preponderance similar to sporadic idiopathic PD, but only one patient showed significant striatal asymmetry. In two of the siblings, DAT binding was markedly increased. IBZM-SPECT was normal in both patients and sibs. Our findings indicate that 123I-FP-CIT-SPECT shows similar DAT binding in PARK6 patients compared to idiopathic Parkinson's disease. The increased DAT binding in heterozygous PARK6 carriers may be a new very early preclinical finding, but its significance is still unclear.
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PMID:Dopaminergic function in a family with the PARK6 form of autosomal recessive Parkinson's syndrome. 1578 66

Several genes have been identified for monogenic disorders that variably resemble Parkinson's disease. Dominant mutations in the gene encoding alpha-synuclein enhance the propensity of this protein to aggregate. As a consequence, these patients have a widespread disease with protein inclusion bodies in several brain areas. In contrast, mutations in several recessive genes (parkin, DJ-1, and PINK1) produce neuronal cell loss but generally without protein aggregation pathology. Progress has been made in understanding some of the mechanisms of toxicity: Parkin is an E3 ubiquitin ligase and DJ-1 and PINK1 appear to protect against mitochondrial damage. However, we have not yet fully resolved how the recessive genes relate to alpha-synuclein, or whether they represent different ways to induce a similar phenotype.
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PMID:The biochemistry of Parkinson's disease. 1595 80

The authors performed PINK1 mutation analysis of 51 families with autosomal recessive Parkinson disease (ARPD). They found two novel PINK1 mutations: one was a homozygous deletion (13516-18118del) and the other a homozygous missense mutation (C388R). Clinically, the patients with the deletion had dementia. Thus, early-onset PD with dementia may be considered PINK1-linked parkinsonism. Furthermore, patients with PINK1 mutations form 8.9% of parkin- and DJ-1-negative ARPD families.
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PMID:Clinicogenetic study of PINK1 mutations in autosomal recessive early-onset parkinsonism. 1595 53

Mutations in the PINK1 gene cause autosomal recessive parkinsonism characterized by early onset and a variable phenotypic presentation. A patient homozygous for the Ala168Pro mutation has been fully characterized clinically. Apart from onset at age 39 years and the excellent and sustained response to levodopa, all clinical and laboratory features, including SPECT and assessment of autonomic function, were indistinguishable from typical idiopathic Parkinson disease.
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PMID:The PINK1 phenotype can be indistinguishable from idiopathic Parkinson disease. 1595 54

Recessively inherited early-onset parkinsonism (EOP) has been associated with mutations in the Parkin, DJ-1, and PINK1 genes. We studied the prevalence of mutations in all three genes in 65 Italian patients (mean age of onset: 43.2+/-5.4 years, 62 sporadic, three familial), selected by age at onset equal or younger than 51 years. Clinical features were compatible with idiopathic Parkinson's disease in all cases. To detect small sequence alterations in Parkin, DJ-1, and PINK1, we performed a conventional mutational analysis (SSCP/dHPLC/sequencing) of all coding exons of these genes. To test for the presence of exon rearrangements in PINK1, we established a new quantitative duplex PCR assay. Gene dosage alterations in Parkin and DJ-1 were excluded using previously reported protocols. Five patients (8%; one woman/four men; mean age at onset: 38.2+/-9.7 (range 25-49) years) carried mutations in one of the genes studied: three cases had novel PINK1 mutations, one of which occurred twice (homozygous c.1602_1603insCAA; heterozygous c.1602_1603insCAA; heterozygous c.836G>A), and two patients had known Parkin mutations (heterozygous c.734A>T and c.924C>T; heterozygous c.924C>T). Family history was negative for all mutation carriers, but one with a history of tremor. Additionally, we detected one novel polymorphism (c.344A>T) and four novel PINK1 changes of unknown pathogenic significance (-21G/A; IVS1+97A/G; IVS3+38_40delTTT; c.852C>T), but no exon rearrangements. No mutations were found in the DJ-1 gene. The number of mutation carriers in both the Parkin and the PINK1 gene in our cohort is low but comparable, suggesting that PINK1 has to be considered in EOP.
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PMID:PINK1, Parkin, and DJ-1 mutations in Italian patients with early-onset parkinsonism. 1597 Sep 50

Dissecting the genetics of Alzheimer's disease (AD) and Parkinson's disease (PD) has contributed significantly to our understanding of the pathogenesis of neurodegeneration in these two complex disorders. For AD, three highly penetrant genes (amyloid precursor protein (APP, PSEN1 and PSEN2) and one susceptibility gene (APOE) have been identified. For PD, seven genes (SNCA, Parkin, UCHL1, NR4A2, DJ1, PINK1 and LRRK2) have been found. These genes explain only a small proportion of AD and PD patients and are mostly associated with an early onset presentation of the disease. APOE remains the only common gene, which increases the risk of both rare early and late onset AD. The ongoing challenge is to unravel the genetics of the most frequent forms of these complex disorders. In the present paper, we briefly review the state of the art in the genetics of AD and PD. We also discuss the prospects of finding new genes associated with common forms of these diseases in light of two hypotheses concerning the genetic variation of complex diseases: common disease/common variants and common disease/rare variants.
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PMID:In search of genes involved in neurodegenerative disorders. 1600 83

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

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease. Some debate still exists as to whether PD is predominantly environmental or genetic in etiology. The genetic hypothesis of PD etiology has been driven recently by the identification of a number of PD loci. This review deals with each of these loci, discussing the latest data and evidence available. Of particular interest are the recently described mutations in the PINK1 (PARK6) and LRRK2 (PARK8) genes. We also consider the impact of these latest developments on our understanding of sporadic PD and on our everyday practice with PD patients.
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PMID:Genetics of parkinsonism. 1613 23


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