Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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To date, 11 gene loci that contribute to familial Parkinson's disease (PD) are known. Of these, mutations in six genes have been identified, allowing genetic testing and more accurate phenotypic characterization of genetically defined disease subtypes. In particular, mutations in Parkin, DJ-1, and Pink1 genes are associated with autosomal recessive PD and may also play a major role in early onset PD (EOPD). However, genetic testing for sequence alterations in these genes remains laborious. Therefore, our aim was to develop a flexible, rapid, high-throughput screening procedure using matrix-assisted laser desorption ionization/time of flight technology and homogeneous mass cleave assays. Using this novel approach, we screened all 27 coding exons of the Parkin, DJ-1, and Pink1 genes in 31 patients with EOPD, a total of 367,195 nucleotides. Four positive controls with known autosomal recessive PD mutations that had previously been screened by denaturing high performance liquid chromatography in combination with sequencing were also tested. All known alterations were detected by matrix-assisted laser desorption ionization/time of flight mass spectrometer, as well as additional polymorphisms in formerly unscreened regions. Overall, two previously described mutations in three patients with EOPD, 27 known polymorphisms with 386 occurrences, and eight unknown variants with 21 occurrences were detected. In total, we identified 410 sequence alterations in 31 patients with EOPD. In conclusion, this is the first study using matrix-assisted laser desorption ionization/time of flight mass spectrometry and homogeneous mass cleave assay for high-throughput mutation screening.
J Mol Diagn 2008 May
PMID:High-throughput homogeneous mass cleave assay technology for the diagnosis of autosomal recessive Parkinson's disease. 1840 12

Changes in tau (tau) metabolism comprise important pathological landmarks in the tauopathies with parkinsonism as well as Parkinson's disease and Alzheimer's disease. Mutations in the parkin gene are associated with Parkinson's disease. Deposits of amyloid proteins, including Abeta and alpha-synuclein coexist in the brains of patients with dementia with Lewy bodies; however, it is not known how either of them interacts with tau to provoke neurofibrillary tangle formation across the tauopathies. Here, we show a role for parkin against tau pathology in the presence of intracellular Abeta or alpha-synuclein. Parkin attenuates four-repeat human tau, but not mutant P301L, hyperphosphorylation in the presence of intracellular Abeta(1-42), or alpha-synuclein and decreases GSK-3beta activity in amyloid-stressed M17 human neuroblastoma cells. These data suggest that parkin may counteract the alteration of tau metabolism in certain neurodegenerative diseases with tau cytopathy and parkinsonism.
J Mol Neurosci 2009 Jan
PMID:Parkin attenuates wild-type tau modification in the presence of beta-amyloid and alpha-synuclein. 1856 Oct 34

Mutations in parkin cause autosomal recessive forms of Parkinson's disease (PD), with an early age of onset and similar pathological phenotype to the idiopathic disease. Parkin has been identified as an E3 ubiquitin ligase that mediates different types of ubiquitination, which has made the search for substrates an intriguing possibility to identify pathological mechanisms linked to PD. In this study, we present PLCgamma1 as a novel substrate for parkin. This association was found in non-transfected human neuroblastoma SH-SY5Y cells as well as in stable cell lines expressing parkin WT and familial mutants R42P and G328E. Analysis of cortical, striatal and nigral human brain homogenates revealed that the interaction between parkin and PLCgamma1 is consistent throughout these regions, suggesting that the interaction is likely to have a physiological relevance for humans. Unlike many of the previously identified substrates, we could also show that the steady-state levels of PLCgamma1 is significantly higher in parkin KO mice and lower in parkin WT human neuroblastoma cells, suggesting that parkin ubiquitination of PLCgamma1 is required for proteasomal degradation. In line with this idea, we show that the ability to ubiquitinate PLCgamma1 in vitro differs significantly between WT and familial mutant parkin. In this study, we demonstrate that parkin interacts with PLCgamma1, affecting PLCgamma1 steady state protein levels in human and murine models with manipulated parkin function and expression levels. This finding could be of relevance for finding novel pathogenic mechanisms leading to PD.
J Cell Mol Med 2009 Sep
PMID:Parkin-mediated ubiquitination regulates phospholipase C-gamma1. 1867 61

CHIP (carboxy terminus of Hsc70-interacting protein) an E3 ubiquitin ligase that binds to Hsp70 and Hsp90, promotes degradation of several Hsp90-regulated signaling proteins and disease-causing proteins containing expanded glutamine tracts. In polyglutamine disease models, CHIP has been considered a primary protection factor by promoting degradation of these misfolded proteins. Here, we show that two CHIP substrates, the glucocorticoid receptor (GR), a classic Hsp90-regulated signaling protein, and the expanded glutamine androgen receptor (AR112Q), are degraded at the same rate in CHIP(-/-) and CHIP(+/+) mouse embryonic fibroblasts after treatment with the Hsp90 inhibitor geldanamycin. CHIP(-/-) cytosol has the same ability as CHIP(+/+) cytosol to ubiquitinate purified neuronal nitric oxide synthase (nNOS), another established CHIP substrate. To determine whether other E3 ubiquitin ligases that bind to Hsp70 (Parkin) or Hsp90 (Mdm2) act on CHIP substrates, each E3 ligase was co-expressed with the GR, nNOS, AR112Q or Q78 ataxin-3. CHIP lowered the levels of all four proteins, Parkin acted on nNOS and Q78 ataxin-3 but not on the steroid receptors, and Mdm2 did not affect any of the co-expressed proteins. Moreover, both CHIP and Parkin co-localized to aggregates of the expanded glutamine AR formed in cell culture and in a knock-in mouse model of spinal and bulbar muscular atrophy. These observations establish that CHIP does not play an exclusive role in regulating the turnover of Hsp90 client signaling proteins or expanded glutamine tract proteins, and show that the Hsp70-dependent E3 ligase Parkin acts redundantly to CHIP on some substrates.
Hum Mol Genet 2008 Dec 15
PMID:CHIP deletion reveals functional redundancy of E3 ligases in promoting degradation of both signaling proteins and expanded glutamine proteins. 1878 77

Parkinson's disease (PD) is characterized by the deterioration of dopaminergic neurons in the pars compacta of substantia nigra and the formation of intraneuronal protein inclusions. The etiology of PD is not known, but the recent identification of several mutation genes in familial PD has provided a rich understanding of the molecular mechanisms of PD pathology. Mutations in PTEN-induced putative kinase 1 (PINK1) and parkin are linked to early-onset autosomal recessive forms of familial PD. Here we show molecular and functional interactions between parkin and PINK1. Parkin selectively binds to PINK1 and upregulates PINK1 levels. In addition, PINK1 reduces the solubility of parkin, which induces the formation of microtubule-dependent cytoplasmic aggresomes. Our findings reveal that parkin and PINK1 affect each other's stability, solubility and tendency to form aggresomes, and have important implications regarding the formation of Lewy bodies.
Mol Cell Neurosci 2009 Apr
PMID:Molecular interaction between parkin and PINK1 in mammalian neuronal cells. 1916 1

Research in Parkinson's disease (PD) genetics has been extremely prolific over the past decade. More than 13 loci and 9 genes have been identified, but their implication in PD is not always certain. Point mutations, duplications and triplications in the alpha-synuclein (SNCA) gene cause a rare dominant form of PD in familial and sporadic cases. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a more frequent cause of autosomal dominant PD, particularly in certain ethnic groups. Loss-of-function mutations in Parkin, PINK1, DJ-1 and ATP13A2 cause autosomal recessive parkinsonism with early-onset. Identification of other Mendelian forms of PD will be a main challenge for the next decade. In addition, susceptibility variants that contribute to PD have been identified in several populations, such as polymorphisms in the SNCA, LRRK2 genes and heterozygous mutations in the beta-glucocerebrosidase (GBA) gene. Genome-wide associations and re-sequencing projects, together with gene-environment interaction studies, are expected to further define the causal role of genetic determinants in the pathogenesis of PD, and improve prevention and treatment.
Hum Mol Genet 2009 Apr 15
PMID:Parkinson's disease: from monogenic forms to genetic susceptibility factors. 1929 1

A genetic marker screening panel, ParkScreen, optimized for simultaneous marker amplification, was constructed to test or exclude linkage in families with parkinsonism or Parkinson's disease, using only a few affected individuals per family. ParkScreen functionality was proven by detection of linkage to PARK2 in a family with known Parkin mutations, exclusion of linkage to several of the known loci, and detection of suggestive linkage to PARK8, PARK3, and PARK11 in some families. In a novel approach, we also tested the ability of ParkScreen to screen patients originating from isolated populations. Using apparently sporadic patients from geographically isolated Alpine villages, suggestive linkage to PARK11 was found in one village. ParkScreen is a useful and inexpensive tool that allows the rapid screening of patients in families suitable for clinical follow-up and further characterization in order to identify specific mutations or novel genes.
J Mol Neurosci 2009 Sep
PMID:ParkScreen: a low-cost rapid linkage marker panel for Parkinson's disease. 1931

Alzheimer's disease and Parkinson's disease are common neurodegenerative diseases that may share some underlying mechanisms of pathogenesis. Abeta(1-42) fragments are found intracellularly, and extracellularly as amyloid plaques, in Alzheimer's disease and in dementia with Lewy Bodies. Parkin is an E3-ubiquitin ligase involved in proteasomal degradation of intracellular proteins. Mutations in parkin, which result in loss of parkin function, lead to early onset Parkinsonism. Here we tested whether the ubiquitin ligase activity of parkin could lead to reduction in intracellular human Abeta(1-42). Lentiviral constructs encoding either human parkin or human Abeta(1-42) were used to infect M17 neuroblastoma cells. Parkin expression resulted in reduction of intracellular human Abeta(1-42) levels and protected against its toxicity in M17 cells. Co-injection of lentiviral constructs into control rat primary motor cortex demonstrated that parkin co-expression reduced human Abeta(1-42) levels and Abeta(1-42)-induced neuronal degeneration in vivo. Parkin increased proteasomal activity, and proteasomal inhibition blocked the effects of parkin on reducing Abeta(1-42) levels. Incubation of Abeta(1-42) cell lysates with ubiquitin, in the presence of parkin, demonstrated the generation of Abeta-ubiquitin complexes. These data indicate that parkin promotes ubiquitination and proteasomal degradation of intracellular Abeta(1-42) and demonstrate a protective effect in neurodegenerative diseases with Abeta deposits.
Hum Mol Genet 2009 Sep 01
PMID:Parkin promotes intracellular Abeta1-42 clearance. 1948 98

The patterns of emergence and disappearance in animal species of genes encoding RBR ubiquitin ligases are described. RBR genes can be classified into subfamilies (Parkin, Ariadne, Dorfin, ARA54, etc.) according to sequence and structural data. Here, I show that most animal-specific RBR subfamilies emerged early in animal evolution, and that ancient animals, before the cnidarian/bilaterian split, had a set of RBR genes, which was as complex as the one currently found in mammals. However, some lineages (nematodes, dipteran insects) have recently suffered multiple losses, leading to a highly simplified set of RBR genes. Genes of a particular RBR subfamily, characterized by containing a helicase domain and so far found only in plants, are present also in some animal species. The meaning of these patterns of diversification and streamlining are discussed at the light of functional data. Extreme evolutionary conservation may be related to gene products having housekeeping functions.
J Mol Evol 2009 Jul
PMID:RBR ubiquitin ligases: Diversification and streamlining in animal lineages. 1952 89

Mutations in the parkin gene are the most common cause of recessive familial Parkinson disease (PD). Parkin has been initially characterized as an ubiquitin E3 ligase, but the pathological relevance of this activity remains uncertain. Recently, an impressive amount of evidence has accumulated that parkin is involved in the maintenance of mitochondrial function and biogenesis. We used a human neuroblastoma cell line as a model to study the influence of endogenous parkin on mitochondrial genomic integrity. Using an unbiased chromatin immunoprecipitation approach, we found that parkin is associated physically with mitochondrial DNA (mtDNA) in proliferating as well as in differentiated SH-SY5Y cells. In vivo, the association of parkin with mtDNA could be confirmed in brain tissue of mouse and human origin. Replication and transcription of mtDNA were enhanced in SH-SY5Y cells over-expressing the parkin gene. The ability of parkin to support mtDNA-metabolism was impaired by pathogenic parkin point mutations. Most importantly, we show that parkin protects mtDNA from oxidative damage and stimulates mtDNA repair. Moreover, higher susceptibility of mtDNA to reactive oxygen species and reduced mtDNA repair capacity was observed in parkin-deleted fibroblasts of a PD patient. Our data indicate a novel role for parkin in directly supporting mitochondrial function and protecting mitochondrial genomic integrity from oxidative stress.
Hum Mol Genet 2009 Oct 15
PMID:Parkin protects mitochondrial genome integrity and supports mitochondrial DNA repair. 1961 36


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