%A Xu,Chuan-Ying %A Kang,Wen-Yan %A Chen,Yi-Meng %A Jiang,Tian-Fang %A Zhang,Jia %A Zhang,Li-Na %A Ding,Jian-Qing %A Liu,Jun %A Chen,Sheng-Di %D 2017 %J Frontiers in Aging Neuroscience %C %F %G English %K Parkinson’s disease,α-Synuclein,DJ-1,Chaperone-mediated autophagy,LAMP2A %Q %R 10.3389/fnagi.2017.00308 %W %L %M %P %7 %8 2017-September-27 %9 Original Research %+ Jun Liu,Department of Neurology and Collaborative Innovation Center for Brain Science, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University,China,jly0520@hotmail.com %+ Sheng-Di Chen,Department of Neurology and Collaborative Innovation Center for Brain Science, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University,China,jly0520@hotmail.com %+ Sheng-Di Chen,Laboratory of Neurodegenerative Diseases, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences,China,jly0520@hotmail.com %# %! DJ-1 inhibits α-Synuclein Aggregation by Chaperone-Mediated Autophagy %* %< %T DJ-1 Inhibits α-Synuclein Aggregation by Regulating Chaperone-Mediated Autophagy %U https://www.frontiersin.org/articles/10.3389/fnagi.2017.00308 %V 9 %0 JOURNAL ARTICLE %@ 1663-4365 %X 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.