title: Parkin promotes proteasomal degradation of p62: implication of selective vulnerability of neuronal cells in the pathogenesis of Parkinson's disease.
abstract: Mutations or inactivation of parkin, an E3 ubiquitin ligase, are associated with familial form or sporadic Parkinson's disease (PD), respectively, which manifested with the selective vulnerability of neuronal cells in substantia nigra (SN) and striatum (STR) regions. However, the underlying molecular mechanism linking parkin with the etiology of PD remains elusive. Here we report that p62, a critical regulator for protein quality control, inclusion body formation, selective autophagy and diverse signaling pathways, is a new substrate of parkin. P62 levels were increased in the SN and STR regions, but not in other brain regions in parkin knockout mice. Parkin directly interacts with and ubiquitinates p62 at the K13 to promote proteasomal degradation of p62 even in the absence of ATG5. Pathogenic mutations, knockdown of parkin or mutation of p62 at K13 prevented the degradation of p62. We further showed that parkin deficiency mice have pronounced loss of tyrosine hydroxylase positive neurons and have worse performance in motor test when treated with 6-hydroxydopamine hydrochloride in aged mice. These results suggest that, in addition to their critical role in regulating autophagy, p62 are subjected to parkin mediated proteasomal degradation and implicate that the dysregulation of parkin/p62 axis may involve in the selective vulnerability of neuronal cells during the onset of PD pathogenesis.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, 300071, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Song
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, 300071, China.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, 300071, China.
authors.forename: Ruize
authors.initials: R
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, 300071, China.
authors.forename: Guanhua
authors.initials: G
authors.lastname: Rao
authors.affiliation: Institute of Psychology, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Ziheng
authors.initials: Z
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, 300071, China.
authors.forename: Biao
authors.initials: B
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, 300071, China.
authors.forename: Hongxia
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute of Psychology, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Sui
authors.affiliation: College of Life Sciences, Tsinghua University, Beijing, 100084, China.
authors.forename: Haiteng
authors.initials: H
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Changsha, 410078, China.
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Tieshan
authors.initials: T
authors.lastname: Tang
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Department of Health and Sports Science, Tianjin University of Sport, Tianjin, 300381, China.
authors.forename: Zehan
authors.initials: Z
authors.lastname: Han
authors.affiliation: Department of Health and Sports Science, Tianjin University of Sport, Tianjin, 300381, China. tjlutieyuan@aliyun.com.
authors.forename: Tieyuan
authors.initials: T
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, 300071, China. zhuys@nankai.edu.cn.
authors.forename: Yushan
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin, 300071, China. chenq@ioz.ac.cn.|State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China. chenq@ioz.ac.cn.
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016627:Oxidopamine / Q000494:pharmacology; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D055550:Protein Stability; D059748:Proteolysis / Q000187:drug effects; D000071456:Sequestosome-1 Protein; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D016627:Oxidopamine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex; D008239:Lysine
keywords: parkin; sequestosome1/p62; substantia nigra; ubiquitin