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)

Dominant mutations in the gene for alpha-synuclein, a small presynaptic protein, can cause Parkinson's disease. Although there is still substantial debate about the precise mechanisms, alpha-synuclein is toxic to vulnerable neurons, probably as a result of its tendency to aggregate. Opposing this is another gene product that, when mutated, causes a recessive form of parkinsonism, parkin. Parkin has been recently shown to protect cells against alpha-synuclein toxicity. However, the precise details of the mechanism are unclear. This review will discuss the concept that there are multiple neuronal functions that are targeted by mutant alpha-synuclein, and in many cases, there is evidence that parkin can protect cells against damage to the same systems. The authors will also discuss ways in which to test some of these ideas, by using newly identified genes such as DJ-1 that cause similar phenotypes.
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PMID:Parkin and alpha-synuclein: opponent actions in the pathogenesis of Parkinson's disease. 1498 49

We examined the distribution of Pael-R, a newly identified substrate for Parkin, in Parkinson's disease (PD) and multiple system atrophy (MSA). Pael-R, Parkin, alpha-synuclein, and ubiquitin accumulated in Lewy bodies (LBs) and neurites. Pael-R was localized in the core of LBs. Parkin and alpha-synuclein accumulated in the halo, neuronal cell bodies, and processes. These findings potentially suggest the involvement of Pael-R in LB formation, and protection role of Parkin in Pael-R-mediated neurotoxicity in PD. The absence of Pael-R and Parkin in glial cytoplasmic inclusions (GCIs) in MSA implies a distinct pathway involved in the formation of LBs and GCIs.
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PMID:Pael-R is accumulated in Lewy bodies of Parkinson's disease. 1499 25

The mouse mutant quaking(viable) ( qk(v)) has been studied for almost four decades as a model for dysmyelination of the central nervous system (CNS). The genetic lesion associated with the qk(v) phenotype is a large deletion of approximately 1 Megabase on mouse Chromosome (Chr) 17. This deficiency alters the expression of transcripts from the qkI locus in oligodendrocytes, resulting in improper myelination of the CNS in animals homozygous for the deletion. To determine whether other genes within the deletion contribute to the quaking(viable) phenotype, we physically mapped and sequenced the deleted interval. We determined that the mouse Parkin gene, as well as the Parkin co-regulated gene ( Pacrg), lies within the qk(v) deletion. We determined that qk(v) mutants completely lack the expression of the Parkin gene product. Loss-of-function mutations in the human PARKIN gene cause autosomal juvenile Parkinson's disease (AR-JP). Our studies show that the deletion of Parkin in qk(v) brains does not result in the loss of dopaminergic neurons typical of AR-JP patients. Also, alpha-synuclein, a target of Parkin-dependent ubiquitination, does not accumulate in qk(v) mutant brains. Despite the lack of AR-JP-like neuropathology in qk(v) mice, this mutant may constitute a readily available model for the study of the cellular function of Parkin. This is the first report of a gene distinct from qkI affected by the qk(v) deletion. The discovery of the multigenic nature of this classical mouse mutation calls for the re-evaluation of its phenotypic characterization.
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PMID:The neurological mutant quaking(viable) is Parkin deficient. 1501 70

Mutations in the parkin gene are common in early-onset and familial Parkinson's disease (PD), and the parkin protein interacts in the ubiquitin-proteasome system as an E3 ligase. However, the regulatory pathways that govern parkin expression are unknown. In this study, we showed that a phylogenetically conserved N-myc binding site in the bi-directional parkin promoter interacted with myc-family transcription factors in reporter assays, and N-myc bound to the parkin promoter in chromatin immunoprecipitation assays and repressed transcription activity. Parkin expression was inversely correlated with N-myc levels in the developing mouse and human brain, in human neuroblastoma cell lines with various levels of n-myc amplification, and in an inducible N-myc cell line. Although parkin and N-myc expression were dramatically altered upon retinoic acid-induced differentiation of a human neuroblastoma cell line, modulation of parkin expression did not significantly affect either rates of cellular proliferation or levels of cyclin E. Analysis of additional genes associated with familial PD revealed a shared basis of transcription regulation mediated by N-myc and the cell cycle. Our results, in combination with functional knowledge of the proteins encoded by these genes, suggest a common pathway linking together PD, the ubiquitin-proteasome system, and cell cycle control.
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PMID:N-myc regulates parkin expression. 1507 80

The authors studied whether olfactory dysfunction is present in parkin disease using the University of Pennsylvania Smell Identification Test (UPSIT). The mean UPSIT score in parkin patients was 27.3 (95% CI 24.4 to 30.2). This did not differ from the normal group mean of 29.4 (95% CI 28.0 to 30.7; p = 0.22) but was higher than the Parkinson disease group (mean 14.3; 95% CI 12.2 to 19.5; p < 0.0001) and the parkin-negative group (mean 17.1; 95% CI 14.8 to 16.3; p < 0.0001) values. Parkin disease may be a distinct and separate entity from Parkinson disease.
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PMID:Olfaction differentiates parkin disease from early-onset parkinsonism and Parkinson disease. 1507 34

Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). We show that parkin is S-nitrosylated in vitro, as well as in vivo in a mouse model of PD and in brains of patients with PD and diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's ubiquitin E3 ligase activity and its protective function. The inhibition of parkin's ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates.
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PMID:S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function. 1597 89

Mutations in the Parkin (PARK2) and the DJ1 (PARK7) gene cause early-onset Parkinson disease (EOPD). We tested 75 Serbian EOPD patients for mutations in both genes by conventional mutational screening (SSCP/dHPLC/sequencing) to detect small sequence alterations and by gene dosage studies (quantitative PCR) to reveal deletions or multiplications of one or more exons. A compound heterozygous Parkin mutation (exon deletion and point mutation; [c.836_972del]+[c.1411C>T]; +1 is first nucleotide of GenBank AB009973.1) was identified in a patient who showed a relatively benign course after a disease onset at 41 years. Another case had a heterozygous exon deletion in DJ1 ([c.253_322del]+[?]) and presented with an age at onset of 45 years and a rapid disease course. In conclusion, Parkin mutations are surprisingly rare in our Serbian EOPD sample, suggesting that the mutation rate depends on the ethnic origin of the patients. Although DJ1 mutations appear to be rare, we confirm their role in EOPD and demonstrate the importance of gene dosage studies.
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PMID:Detection of Parkin (PARK2) and DJ1 (PARK7) mutations in early-onset Parkinson disease: Parkin mutation frequency depends on ethnic origin of patients. 1510 93

The gene product responsible for autosomal recessive juvenile Parkinsonism, Parkin, has been observed to have ubiquitin ligase activity. This finding has changed the direction of studies on Parkinson's disease by suggesting that abnormal protein turnover might be involved in its pathogenesis. A number of potentially neurotoxic Parkin-specific substrates have been identified. Further investigation of Parkin knockout mice will hopefully provide new evidence in the search for Parkin's substrates and further clarify their role in Parkinson's disease.
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PMID:How do Parkin mutations result in neurodegeneration? 1519 20

Parkinson's disease (PD) is characterized by the selective degeneration of dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc). A combination of genetic and environmental factors contributes to such a specific loss. Among the five PD-linked genes identified so far, parkin, a protein-ubiquitin E3 ligase, appears to be the most prevalent genetic factor in PD. Although a variety of substrates have been identified for parkin, none of them is selectively expressed in nigral DA neurons. It remains unclear how accumulation of these substrates in the absence of functional parkin may cause the selective death of DA neurons in SNpc. Here, we show that overexpression of parkin protected human DA neuroblastoma cell line (SH-SY5Y) against apoptosis induced by DA or 6-OHDA, but not by H(2)O(2) or rotenone. Parkin significantly attenuated dopamine-induced activation of c-Jun N-terminal kinase (JNK) and caspase-3. It also decreased the level of reactive oxygen species (ROS) and protein carbonyls in the cell. Inhibiting DA uptake through dopamine transporter or treating the cell with antioxidants significantly reduced oxidative stress and dopamine toxicity. Furthermore, PD-linked mutations of parkin significantly abrogated the protective effect of wild-type parkin, as well as its ability to suppress ROS and protein carbonylation. These results suggest that parkin protects against dopamine toxicity by decreasing oxidative stress and ensuing activation of apoptotic programs such as the JNK/caspase pathway. This protective function of parkin, which is greatly attenuated by its PD-linked mutations, may be uniquely important for the survival of DA neurons, as they are constantly threatened by oxyradicals produced during dopamine oxidation.
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PMID:Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis. 1519 87

Aggresomes are associated with many neurodegenerative disorders, including Parkinson's disease, and polyglutamine disorders such as Huntington's disease. These inclusions commonly contain ubiquitylated proteins. The stage at which these proteins are ubiquitylated remains unclear. A malfunction of the ubiquitin/proteasome system (UPS) may be associated with their formation. Conversely, it may reflect an unsuccessful attempt by the cell to remove them. Previously, we demonstrated that overexpression of Parkin, a ubiquitin-protein ligase associated with autosomal recessive juvenile Parkinsonism, generates aggresome-like inclusions in UPS compromised cells. Mutations in the de-ubiquitylating enzyme, UCH-L1, cause a rare form of Parkinsonism. We now demonstrate that overexpression of UCH-L1 also forms ribbon-like aggresomes in response to proteasomal inhibition. Disease-associated mutations, which affect enzymatic activities, significantly increased the number of inclusions. UCH-L1 aggresomes co-localized with ubiquitylated proteins, HSP70, gamma-tubulin and, to a lesser extent, the 20S proteasome and the chaperone BiP. Similar to Parkin inclusions, we found UCH-L1 aggresomes to be surrounded by a tubulin rather than a vimentin cage-like structure. Furthermore, UCH-L1 aggregates with Parkin and alpha-synuclein in some, but not all inclusions, suggesting the heterogeneous nature of these inclusion bodies. This study provides additional evidence that aggregation-prone proteins are likely to recruit UPS components in an attempt to clear proteins from failing proteasomes. Furthermore, UCH-L1 accumulation is likely to play a pathological role in inclusion formation in Parkinson's disease.
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PMID:UCH-L1 aggresome formation in response to proteasome impairment indicates a role in inclusion formation in Parkinson's disease. 1522 95


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