Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the warburg effect cen zhanga, meihua lina, rui wua, xiaowen wanga, bo yangb, arnold j. In cell culture models, parkin is recruited to acutely depolarised mitochondria by pink1. The gene codes for a 465 amino acid e3 ubiquitin ligase capable of mediating mono or polyubiquitination using. Ubiquitination is a posttranslational modification that typically marks proteins for degradation through the covalent attachment of ubiquitin and. Pdf parkin inactivation links parkinsons disease to. Pdf prevalence of homozygous deletions of the parkin. Parkin is recruited selectively to impaired mitochondria. Although most cases are sporadic, several genes have been recently linked to familial parkinsons disease, and lossoffunction mutations in park2, the gene coding for the ubiquitin ligase parkin, represent the most common recessive cause kitada et al.
Parkincatalyzed ubiquitinester transfer is triggered by. In vertebrates, this gene is linked in a headtohead arrangement with the adjacent parkin gene. Identification of mutations in the parkin gene in indian patients. Association between earlyonset parkinsons disease and mutations in the parkin gene article pdf available in new england journal of medicine 34221. The pink1 gene provides instructions for making a protein called pten induced putative kinase 1. Parkin has also been linked to cancer suppression but the mechanisms are unclear. More than 180 causative variants in the parkin gene. Pdf measuring excitatory postsynaptic potentials in. Therefore, we investigated its physiological function in drosophila. Diseases associated with prkn include parkinson disease 2, autosomal recessive juvenile and ovarian cancer. Among its related pathways are metabolism of proteins and pink parkin mediated mitophagy. Highcontent genomewide rnai screens identify regulators. Prkn parkin rbr e3 ubiquitin protein ligase is a protein coding gene. Parkin belongs to a family of proteins with conserved ubiquitinlike domain ubl and really interesting new gene ring finger motifs 15.
In addition to degradation via the proteasome, ubiquitination can act as a signal for autophagy 17 degradation via. Pdf parkin, pink1, and dj1 form a ubiquitin e3 ligase. Microeconomics 12th edition pearson series in economics by michael parkin pdf free. Prevalence of homozygous deletions of the parkin gene in a cohort of patients with sporadic and familial parkinsons disease. Thus, mutations in the parkin gene were detected in 36 of 73 families 49 percent, including 12 previously described families. Quantitative proteomic analysis of parkin substrates in.
Parkin, a protein involved in mitochondria clearance by autophagy, is often mutated in earlyonset familial parkinsons disease. Mutants which carry mutations in genes encoding mitochondrial ligases mul1 and parkin are convenient drosophila models of parkinsons disease pd. Pdf association between earlyonset parkinsons disease. Pink1 is a mitochondrial serthr kinase, whereas parkin functions as an e3 ubiquitin ligase. An intronic polymorphism of the tau gene is associated with sporadic sros and mutations of the tau gene. Park2 omim 602544 is the parkin gene that may cause a form of autosomal recessive juvenile parkinson disease omim 600116 due to a mutation in the parkin protein. Landscape of the parkindependent ubiquitylome in response. Olszewski syndrome sros is a neurodegenerative disorder of unknown aetiology, most frequently sporadic. While charging of the ring2 with ub could be shown for hhari wenzel et al, 2011 and hoip smit et al, 2012.
Parkin mutation affects clock genedependent energy metabolism. Parkinsons disease pd is the second most common neurodegenerative disease, and is characterized by involuntary shaking, muscle rigidity, and the progressive loss of dopaminergic neurons. Parkin gene in japanese families with autosomal recessive juvenile parkin sonism. Pink1 and parkin target miro for phosphorylation and. Parkin gene has been identified as a tumor suppressor gene in the pathogenesis of various cancers. Mutations in the parkin gene are the most common cause of autosomal recessive pd 4, 5, 7. The pink1parkin pathway is involved in the regulation of. Institute of molecular, cell and systems biology, university of glasgow, university avenue, glasgow g12 8qq, uk. Parkin was initially identified as a cytosolic e3 ubiquitin ligase that is mutated in familial forms of pd kitada et al.
Association study of parkin gene polymorphisms with. Richard youles lab contains the insert parkin and is published in j cell biol. Mitophagy is the elimination of damaged mitochondria by the autophagosome regulated by the ubiquitin ligase, parkin and the kinase pink1. Parkin is the name of both the gene and the protein it produces. Parkin park2 is an e3 ubiquitin ligase that is commonly mutated in familial parkinsons disease pd.
More than 180 causative variants in the parkin gene have been identified. Measuring excitatory postsynaptic potentials in response to differential pink1 and parkin gene expression and various concentrations of dopamine releasing agents. The pink1 parkin pathway induces miro degradation and releases kinesin from mitochondria. They represent two completely distinct kinds of unit and we shall be hopelessly confused unless we recognize the distinction. Because parkin fra6e has genomic similarities to fhitfra3b and wwoxfra16d, two other large tumor. Mutations in the parkin gene, encoding an e3 ubiquitinprotein ligase, are a frequent cause of autosomal recessive parkinsonism and are also involved in sporadic parkinsons disease. Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25q27. The contribution of individual parkin domains in ubiquitination activity is however still unclear since a construct spanning ibr and ring2 but lacking the e2interacting ring1 domain shows high in vitro activity, which depends on cys431 in ring2 chew et al, 2011. The prkn gene spans part of a region on chromosome 6 known as fra6e.
Progression of breast cancer involves both genetic and epigenetic factors. The prkn gene, one of the largest human genes, provides instructions for making a protein called parkin. Two groups have studied the equivalent gene in the fruitfly drosophila, and find that it. Parkin gene alterations in hepatocellular carcinoma wang. Mutations in parkin cause autosomal recessive parkinsons disease arpd 10. Background previously, we detected linkage of idiopathic parkinson disease pd to the region on chromosome 6 that contains the parkin gene d6s305. Microeconomics 12th edition pearson series in economics by michael parkin epub download. In particular, mitochondrial quality control and bioenergetics have been proven.
Parkin facilitates proteasome inhibitorinduced apoptosis. This protein is found in cells throughout the body, with highest levels in the heart, muscles. Chemistry for environmental engineering and science by. Changes involving the fra6e region have been reported in several forms of human cancer, including glioblastoma a form of brain cancer, colorectal cancer, lung cancer, and ovarian cancer. Parkin plays a role in the cell machinery that breaks down. Nevertheless, the putative role of parkin in breast cancer remains largely unknown. Pdf single nucleotide polymorphisms of the parkin gene. In addition, mutations in parkin may play a role in sporadic pd 1618. This established without a shadow of a doubt that parkin.
Pink1 and parkin are causal genes for autosomal recessive familial parkinsonism. Parkin is an e3 ubiquitin ligase involved in parkinsons disease. Because parkin is an e3 ubiquitin ligase, we hypothesized that mitochondrial arrest. In support of that study, we found that endogenous parkin was barely detectable in hela cells even when prk8, the bestcharacterized specific anti parkin. Association between earlyonset parkinsons disease and. Mutations in the parkin gene chromosome 6q2527 were first described in 1998 in families with juvenile autosomal recessive parkinsonism.
Pink1 stabilized by mitochondrial depolarization recruits. Mutations in parkin are the most common cause of arpd 16, 17. Ubiquitination is a posttranslational modification that typically marks proteins for degradation through the covalent attachment of ubiquitin and ubiquitin chains to lysine residues or the nterminal amino group of a substrate protein 16. Pink1 and parkinmediated mitophagy at a glance journal. Introduction of the mutant gene into cancer cell lines promoted cell growth, whereas the wildtype gene reduced it. Parkinsons disease is the most common neurodegenerative movement disorder. Parkin is the most causative gene of familial parkinson disease fpd by mutations in the park2 gene on chromosome 6q25. Parkin coregulated gene protein is a protein that in humans is encoded by the pacrg gene this gene encodes a protein that is conserved across metazoans. Mutations in the protein parkin are associated with parkinsons disease pd, the second most common neurodegenerative disease in men. Park2 designates the type of parkinsons disease caused by a genetic defect in the parkin gene. We initially sought to study the subcellular localization and e3 activity of parkin using hela cells, which reportedly lack a functional parkin gene denison et al. Microeconomics 12th edition pearson series in economics by michael parkin. Growing evidence highlights a tight connection between circadian rhythms, molecular clockworks, and mitochondrial function. Due to the complex etiology of pd, there is possibility that single nucleotide polymorphisms snp in parkin gene.
Chemistry for environmental engineering and science by clair n. Mitochondrial dysfunction in drosophila pink1 mutants is. This region is known as a fragile area because it is unstable and prone to breakage and rearrangement. Effects of mul1 and parkin on the circadian clock, brain. Parkin, a p53 target gene, mediates the role of p53 in. However, it is still not known what this pathway does in the mitochondria.
Parkin, pink1, and dj1 form a ubiquitin e3 ligase complex promoting unfolded protein degradation. Microeconomics 12th edition pearson series in economics pdf by michael parkin. The two parkinsons disease pd genes, pteninduced kinase 1 pink1 and parkin, are linked in a common pathway which affects mitochondrial integrity and function. One example is earlyonset autosomal recessive pd arpd, for which the majority of cases are linked to. Parkinsons disease pd is the second most common progressive neurodegenerative brain disorder after alzheimers disease. Is parkin parkinsonism a cancer predisposition syndrome. The role of parkin in familial and sporadic parkinsons.
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