Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:6.3.2.19 (ubiquitin-protein ligase)
799 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal recessive juvenile parkinsonism (AR-JP), one of the most common familial forms of Parkinson disease, is characterized by selective dopaminergic neural cell death and the absence of the Lewy body, a cytoplasmic inclusion body consisting of aggregates of abnormally accumulated proteins. We previously cloned PARK2, mutations of which cause AR-JP (ref. 2), but the function of the gene product, parkin, remains unknown. We report here that parkin is involved in protein degradation as a ubiquitin-protein ligase collaborating with the ubiquitin-conjugating enzyme UbcH7, and that mutant parkins from AR-JP patients show loss of the ubiquitin-protein ligase activity. Our findings indicate that accumulation of proteins that have yet to be identified causes a selective neural cell death without formation of Lewy bodies. Our findings should enhance the exploration of the molecular mechanisms of neurodegeneration in Parkinson disease as well as in other neurodegenerative diseases that are characterized by involvement of abnormal protein ubiquitination, including Alzheimer disease, other tauopathies, CAG triplet repeat disorders and amyotrophic lateral sclerosis.
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PMID:Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. 1088 78

Autosomal recessive juvenile parkinsonism (AR-JP) is caused by mutations in the parkin gene. Parkin protein is characterized by a ubiquitin-like domain at its NH(2)-terminus and two RING finger motifs and an IBR (in between RING fingers) at its COOH terminus (RING-IBR-RING). Here, we show that Parkin is a RING-type E3 ubiquitin-protein ligase which binds to E2 ubiquitin-conjugating enzymes, including UbcH7 and UbcH8, through its RING-IBR-RING motif. Moreover, we found that unfolded protein stress induces up-regulation of both the mRNA and protein level of Parkin. Furthermore, overexpression of Parkin, but not a set of mutants without the E3 activity, specifically suppressed unfolded protein stress-induced cell death. These findings demonstrate that Parkin is an E3 enzyme and suggest that it is involved in the ubiquitination pathway for misfolded proteins derived from endoplasmic reticulum and contributes to protection from neurotoxicity induced by unfolded protein stresses.
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PMID:Parkin suppresses unfolded protein stress-induced cell death through its E3 ubiquitin-protein ligase activity. 1097 42

Parkin is the causative gene for an autosomal recessive form of Parkinson's disease. The gene was discovered in 1998. The parkin gene is a novel gene containing 12 exons spanning over 1.5 Mb and encodes a protein of 465 amino acids with a molecular mass of approximately 52,000 M(r). Various deletion mutations and point mutations have been discovered in patients with autosomal recessive Parkinson's disease. The substantia nigra and the locus coeruleus selectively undergo neurodegeneration without forming Lewy bodies. The parkin gene product, Parkin protein, has a unique structure with a ubiquitin-like domain in the amino-terminus and a RING finger motif in the carboxy terminus. The function of Parkin was not known until recently. During the year 2000, great progress was made in defining its function. First of all, Parkin was found to be a ubiquitin-protein ligase (E3), a component of the ubiquitin system, which is an important adenosine triphosphate-dependent protein degradation machinery. In addition, CDCrel-1, a synaptic vesicle associated protein, was found to be a substrate for Parkin as an E3. Although many studies still need to be performed to elucidate the molecular mechanism of the selective nigral neurodegeneration in this form of familial Parkinson's disease, it will not be too long before this is accomplished. In this review article, we evaluate the developments in this area published since 1 February 2000.
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PMID:Parkin and Parkinson's disease. 1147 Sep 64

Mutations in the PARKIN gene are associated with early-onset (juvenile) Parkinson's disease. We analyzed the coding sequence of this gene (exons 1-12) in patients from a family with three affected siblings, born to first-degree consanguineous parents, with an onset before 23 years and foot dystonia as the initial clinical symptom. The three patients were alive without cognitive impairment at ages of 70, 69, and 65 years, showing a marked response to levodopa treatment. A 2 bp-deletion at exon 11 (1276-1277 del GA) was found. The three patients were homozygous for this frameshift mutation, which would introduce a Stop at codon 394. This is a new PARKIN-mutation that would produce a truncated protein, lacking exon 12 and most the 11th. This region includes the C-terminal ring-finger domain of parkin, essential for its function as a ubiquitin-protein ligase. Compared to patients from other families with truncating mutations, our patients had an earlier onset. In addition, the three patients had dystonia at onset. In conclusion, we described a new PARKIN truncating mutation associated with an early onset parkinsonism, and the presence of foot dystonia as the initial symptom.
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PMID:Early-onset Parkinson's disease associated with a new parkin mutation in a Spanish family. 1168 52

The autosomal recessive juvenile parkinsonism is caused by the mutations of the gene encoding a novel protein called parkin. It has been reported that parkin is expressed in the central nervous system and functions as a ubiquitin-protein ligase (E3) which suppresses neuronal cell degeneration by ubiquitinating misfolded proteins. Thus far, however, it remains unknown if parkin is expressed and functions in the peripheral nervous system. In order to begin to address to this question, we investigated the expression of parkin in bovine peripheral nerve. Reverse transcription polymerase chain reaction analysis demonstrated the presence of parkin transcript in bovine peripheral nerve. The obtained bovine parkin cDNA sequence was identical to that of human except a single nucleotide. Immunoblot analysis demonstrated the expression of parkin protein in bovine peripheral nerve. Immunohistochemical analysis demonstrated the localization of parkin in the axoplasm of myelinated nerve fibers, the Schwann cell cytoplasm and the Schwann cell outer membrane. Furthermore, fractionation analysis indicated the presence of two fractions of parkin in bovine peripheral nerve, the cytosolic fraction and the cell membrane-bound fraction. All together, these results point to diverse roles of parkin in not only the central but also the peripheral nervous system.
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PMID:Characterization of parkin in bovine peripheral nerve. 1187 4

Autosomal recessive parkinsonism associated with mutations in the parkin gene represents a monogenic form of hereditary parkinsonism. We performed [(18)F]6-fluorodopa (FDOPA) positron emission tomography as a measurement of the nigrostriatal dopaminergic system as well as extensive haplotype analysis of the PARK 2 gene locus in 14 subjects with parkin mutations. In parkin subjects, the reduction of striatal FDOPA uptake increased with the number of mutated alleles and was also slightly obvious in asymptomatic parkin gene carriers in the heterozygous state. The abnormal FDOPA uptake pattern in parkin patients did not significantly differ from that of sporadic Parkinson's disease. Our data are in agreement with an enzymatic dysfunction of the gene's translational product, which has been shown to promote protein degradation as an ubiquitin-protein ligase. Thus, parkinsonism in parkin gene carriers may be related to abnormal nigral protein accumulation in the presence of a suprathreshold enzyme dysfunction.
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PMID:The striatal dopaminergic deficit is dependent on the number of mutant alleles in a family with mutations in the parkin gene: evidence for enzymatic parkin function in humans. 1191 88

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra. Several lines of evidence strongly implicate mitochondrial dysfunction as a major causative factor in PD, although the molecular mechanisms responsible for mitochondrial dysfunction are poorly understood. Recently, loss-of-function mutations in the parkin gene, which encodes a ubiquitin-protein ligase, were found to underlie a familial form of PD known as autosomal recessive juvenile parkinsonism (AR-JP). To gain insight into the molecular mechanism responsible for selective cell death in AR-JP, we have created a Drosophila model of this disorder. Drosophila parkin null mutants exhibit reduced lifespan, locomotor defects, and male sterility. The locomotor defects derive from apoptotic cell death of muscle subsets, whereas the male sterile phenotype derives from a spermatid individualization defect at a late stage of spermatogenesis. Mitochondrial pathology is the earliest manifestation of muscle degeneration and a prominent characteristic of individualizing spermatids in parkin mutants. These results indicate that the tissue-specific phenotypes observed in Drosophila parkin mutants result from mitochondrial dysfunction and raise the possibility that similar mitochondrial impairment triggers the selective cell loss observed in AR-JP.
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PMID:Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. 1264 58

An autosomal recessive juvenile-onset form of Parkinson's disease (AR-JP) is caused by loss-of-function mutations of the parkin gene, which encodes a ubiquitin-protein ligase. Three recent reports demonstrate that parkin can protect neurons from diverse cellular insults, including alpha-synuclein toxicity, proteasomal dysfunction, Pael-R accumulation, and kainate-induced excitotoxicity. These findings suggest a central role for parkin in maintaining dopaminergic neuronal integrity and strengthen the link between AR-JP and the more common sporadic form of Parkinson's disease.
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PMID:Parkin: a multipurpose neuroprotective agent? 1269 60

Parkinson's disease (PD) is a severe neurological disorder, characterized by the progressive degeneration of the dopaminergic nigrostriatal pathway and the presence of Lewy bodies (LBs). The discovery of genes responsible for familial forms of the disease has provided insights into its pathogenesis. Mutations in the parkin gene, which encodes an E3 ubiquitin-protein ligase involved in the ubiquitylation and proteasomal degradation of specific protein substrates, have been found in nearly 50% of patients with autosomal-recessive early-onset parkinsonism. The abnormal accumulation of substrates due to loss of Parkin function may be the cause of neurodegeneration in parkin-related parkinsonism. Here, we demonstrate that Parkin interacts with, ubiquitylates and promotes the degradation of p38, a key structural component of the mammalian aminoacyl-tRNA synthetase complex. We found that the ubiquitylation of p38 is abrogated by truncated variants of Parkin lacking essential functional domains, but not by the pathogenic Lys161Asn point mutant. Expression of p38 in COS7 cells resulted in the formation of aggresome-like inclusions in which Parkin was systematically sequestered. In the human dopaminergic neuroblastoma-derived SH-SY5Y cell line, Parkin promoted the formation of ubiquitylated p38-positive inclusions. Moreover, the overexpression of p38 in SH-SY5Y cells caused significant cell death against which Parkin provided protection. Analysis of p38 expression in the human adult midbrain revealed strong immunoreactivity in normal dopaminergic neurons and the labeling of LBs in idiopathic PD. This suggests that p38 plays a role in the pathogenesis of PD, opening the way for a detailed examination of its potential non-canonical role in neurodegeneration.
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PMID:The p38 subunit of the aminoacyl-tRNA synthetase complex is a Parkin substrate: linking protein biosynthesis and neurodegeneration. 1278 50

To date, nine forms of familial Parkinson's disease (PD) have been mapped to different chromosome loci. Among them, Park 2, which is an autosomal recessive form (AR-JP) by parkin gene mutations, is the most common form of familial PD. Indeed, this form of familial PD distributed in the world wide such as European, North American, Turkish, Japanese families. Moreover, we know that the role of parkin protein in the brains is to break down misfolded proteins as an ubiquitin-protein ligase. Very recently, although the presence of Lewy bodies have been reported in one case, the lack of Lewy bodies in parkin-mutated brains suggests us a fundamental pathology for Lewy bodies. Therefore, the parkin function could be essential for the Lewy body formation. Thus, the elucidation of the exact role of parkin protein provides us the mechanisms of the formation of Lewy bodies in common forms of sporadic PD. Therefore, it is important to detect the substrates for the parkin protein. Recently, several candidate substrates have been reported including CDCrel-1, synphilin-1, alpha-synuclein-22 (o-glycosylated alpha-synuclein), and Peal-receptor. The question is accumulation of which substrates are responsible for the nigral neuronal death in Park 2 linked brain.
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PMID:[Parkin gene: its mutations and function]. 1278 70


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