title: Parkin ubiquitinates Drp1 for proteasome-dependent degradation: implication of dysregulated mitochondrial dynamics in Parkinson disease.
abstract: Mutations in Parkin, an E3 ubiquitin ligase that regulates protein turnover, represent one of the major causes of familial Parkinson disease, a neurodegenerative disorder characterized by the loss of dopaminergic neurons and impaired mitochondrial functions. The underlying mechanism by which pathogenic Parkin mutations induce mitochondrial abnormality is not fully understood. Here, we demonstrate that Parkin interacts with and subsequently ubiquitinates dynamin-related protein 1 (Drp1), for promoting its proteasome-dependent degradation. Pathogenic mutation or knockdown of Parkin inhibits the ubiquitination and degradation of Drp1, leading to an increased level of Drp1 for mitochondrial fragmentation. These results identify Drp1 as a novel substrate of Parkin and suggest a potential mechanism linking abnormal Parkin expression to mitochondrial dysfunction in the pathogenesis of Parkinson disease.
authors.affiliation: Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Wang
authors.forename: Pingping
authors.initials: P
authors.lastname: Song
authors.forename: Lei
authors.initials: L
authors.lastname: Du
authors.forename: Weili
authors.initials: W
authors.lastname: Tian
authors.forename: Wen
authors.initials: W
authors.lastname: Yue
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: Dengwen
authors.initials: D
authors.lastname: Li
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Yushan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Cheng
authors.initials: C
authors.lastname: Cao
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
mesh_terms: D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis* / Q000235:genetics; D054875:Ubiquitination
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins