Frontiers in Aging Neuroscience | |
DJ-1 Inhibits α-Synuclein Aggregation by Regulating Chaperone-Mediated Autophagy | |
Li-Na Zhang1  Tian-Fang Jiang2  Chuan-Ying Xu2  Wen-Yan Kang2  Jian-Qing Ding2  Jun Liu2  Jia Zhang2  Sheng-Di Chen3  Yi-Meng Chen3  | |
[1] Department of Biostatistics, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;Department of Neurology and Collaborative Innovation Center for Brain Science, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China;Laboratory of Neurodegenerative Diseases, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China; | |
关键词: Parkinson’s disease; α-synuclein; DJ-1; chaperone-mediated autophagy; LAMP2A; | |
DOI : 10.3389/fnagi.2017.00308 | |
来源: DOAJ |
【 摘 要 】
α-Synuclein misfolding and aggregation play an important role in the pathogenesis of Parkinson’s disease (PD). Loss of function and mutation of the PARK7/DJ-1 gene cause early-onset familial PD. DJ-1 can inhibit α-synuclein aggregation, and may function at an early step in the aggregation process. Soluble wild-type (WT) α-synuclein is mainly degraded by chaperone-mediated autophagy (CMA), and impairment of CMA is closely related to the pathogenesis of PD. Here, we investigated whether DJ-1 could reduce α-synuclein accumulation and aggregation by CMA. DJ-1 knockout mice and DJ-1 siRNA knockdown SH-SY5Y cells were used to investigate the potential mechanisms underlying the relationship between DJ-1 deficiency and α-synuclein aggregation. First, we confirmed that DJ-1 deficiency increased the accumulation and aggregation of α-synuclein in both SH-SY5Y cells and PD animal models, and overexpression of DJ-1 in vitro effectively decreased α-synuclein levels. α-Synuclein overexpression activated CMA by elevating the levels of lysosome-associated membrane protein type-2A (LAMP2A), but DJ-1 deficiency suppressed upregulation of LAMP2A. DJ-1 deficiency downregulated the level of lysosomal 70 kDa heat-shock cognate protein (HSC70) but not the levels of that in homogenates. Further studies showed that DJ-1 deficiency accelerated the degradation of LAMP2A in lysosomes, leading to the aggregation of α-synuclein. Our study suggests that DJ-1 deficiency aggravates α-synuclein aggregation by inhibiting the activation of CMA and provides further evidence of the molecular interaction between PD-related proteins via the CMA pathway.
【 授权许可】
Unknown