DJ-1 Inhibits α-Synuclein Aggregation by Regulating Chaperone-Mediated Autophagy

Frontiers in Aging Neuroscience

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