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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
发表期刊PROTEIN & CELL
ISSN1674-800X
文章类型Article
卷号7期号:2页码:114-129
摘要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.
关键词Parkin Sequestosome1/p62 Ubiquitin Substantia Nigra
DOI10.1007/s13238-015-0230-9
收录类别SCI
语种英语
项目资助者National Basic Research Program (973 Program) from MOST(2011CB910903) ; National Natural Science Foundation of China(81130045 ; 31471300 ; 31271529 ; 301520103904)
WOS研究方向Cell Biology
WOS类目Cell Biology
WOS记录号WOS:000372541000005
WOS标题词Science & Technology ; Life Sciences & Biomedicine
关键词[WOS]AMYOTROPHIC-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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被引频次:9[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.psych.ac.cn/handle/311026/19704
专题健康与遗传心理学研究室
作者单位1.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
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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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