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Parkin promotes proteasomal degradation of p62: implication of selective vulnerability of neuronal cells in the pathogenesis of Parkinson's disease
Song, Pingping1; Li, Shanshan1; Wu, Hao2; Gao, Ruize1; Rao, Guanhua1; Wang, Dongmei3; Chen, Ziheng2; Ma, Biao1; Wang, Hongxia1; Sui, Nan3; Deng, Haiteng4; Zhang, Zhuohua5; Tang, Tieshan2; Tan, Zheng2; Han, Zehan6; Lu, Tieyuan6; Zhu, Yushan1; Chen, Quan1,2
2016-02-01
Source PublicationPROTEIN & CELL
ISSN1674-800X
SubtypeArticle
Volume7Issue:2Pages:114-129
AbstractMutations 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.
KeywordParkin Sequestosome1/p62 Ubiquitin Substantia Nigra
DOI10.1007/s13238-015-0230-9
Indexed BySCI
Language英语
Funding OrganizationNational Basic Research Program (973 Program) from MOST(2011CB910903) ; National Natural Science Foundation of China(81130045 ; 31471300 ; 31271529 ; 301520103904)
WOS Research AreaCell Biology
WOS SubjectCell Biology
WOS IDWOS:000372541000005
WOS HeadingsScience & Technology ; Life Sciences & Biomedicine
WOS KeywordAMYOTROPHIC-LATERAL-SCLEROSIS ; ALPHA-SYNUCLEIN ; DEFICIENT MICE ; MITOCHONDRIAL DEPOLARIZATION ; JUVENILE PARKINSONISM ; DAMAGED MITOCHONDRIA ; MOLECULAR PATHWAYS ; SEQUESTOSOME 1/P62 ; MEDIATE MITOPHAGY ; SQSTM1 MUTATIONS
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Cited Times:14[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.psych.ac.cn/handle/311026/19704
Collection健康与遗传心理学研究室
Affiliation1.Nankai Univ, Tianjin Key Lab Prot Sci, Coll Life Sci, State Key Lab Med Chem Biol, Tianjin 300071, Peoples R China
2.Chinese Acad Sci, Inst Zool, State Key Lab Biomembrane & Membrane Biotechnol, Beijing 100101, Peoples R China
3.Chinese Acad Sci, Inst Psychol, Beijing 100101, Peoples R China
4.Tsinghua Univ, Coll Life Sci, Beijing 100084, Peoples R China
5.Cent S Univ, Xiangya Med Sch, State Key Lab Med Genet, Changsha 410078, Hunan, Peoples R China
6.Tianjin Univ Sport, Dept Hlth & Sports Sci, Tianjin 300381, Peoples R China
Recommended Citation
GB/T 7714
Song, Pingping,Li, Shanshan,Wu, Hao,et al. Parkin promotes proteasomal degradation of p62: implication of selective vulnerability of neuronal cells in the pathogenesis of Parkinson's disease[J]. PROTEIN & CELL,2016,7(2):114-129.
APA Song, Pingping.,Li, Shanshan.,Wu, Hao.,Gao, Ruize.,Rao, Guanhua.,...&Chen, Quan.(2016).Parkin promotes proteasomal degradation of p62: implication of selective vulnerability of neuronal cells in the pathogenesis of Parkinson's disease.PROTEIN & CELL,7(2),114-129.
MLA Song, Pingping,et al."Parkin promotes proteasomal degradation of p62: implication of selective vulnerability of neuronal cells in the pathogenesis of Parkinson's disease".PROTEIN & CELL 7.2(2016):114-129.
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