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

• Main Authors: Chuan-Ying Xu, Wen-Yan Kang, Yi-Meng Chen, Tian-Fang Jiang, Jia Zhang, Li-Na Zhang, Jian-Qing Ding, Jun Liu, Sheng-Di Chen
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2017-09-01
• Series: Frontiers in Aging Neuroscience
• Subjects: Parkinson’s disease; α-synuclein; DJ-1; chaperone-mediated autophagy; LAMP2A
• Online Access: http://journal.frontiersin.org/article/10.3389/fnagi.2017.00308/full

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.