Abstract
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.
Highlights
Loss-of-function mutations of the PARK7/DJ-1 gene cause early-onset familial Parkinson’s disease (PD)
Further studies showed that DJ-1 deficiency accelerated the degradation of lysosome-associated membrane protein type-2A (LAMP2A) in lysosomes, leading to the aggregation of α-synuclein
We studied the relationship between DJ-1 and α-synuclein in PD animal models (Figures 2A–H)
Summary
Loss-of-function mutations of the PARK7/DJ-1 gene cause early-onset familial Parkinson’s disease (PD). Point mutations (A53T, A30P and E46K; Polymeropoulos et al, 1997; Krüger et al, 1998; Zarranz et al, 2004) or multiplications (Chartier-Harlin et al, 2004) of the α-synuclein gene locus result in autosomal-dominant familial PD, whereas polymorphisms within the α-synuclein locus (Simón-Sánchez et al, 2009) confer an increased risk of sporadic PD. These findings demonstrate the critical role of increased levels of α-synuclein with the exception of gene mutations in the pathogenesis of PD. Macroautophagy is mainly responsible for the removal of oligomeric α-synuclein (Lee et al, 2004), whereas CMA predominantly degrades wild-type (WT) monomeric α-synuclein (Cuervo et al, 2004; Vogiatzi et al, 2008)
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