DJ-1 Inhibits α-synuclein Accumulation By Regulating Chaperone-mediated Autophagy

Loss-of-function mutations of Park7/DJ-1 gene cause early-onset familial Parkinson disease(PD),which is the most common progressive neurodegenerative disorder characterized by the loss of neurons in the substantia nigra pars compacta and the presence of α-synuclein-containing Lewy bodies(LB)in surviving neurons.α-Synuclein misfolding and aggregation play an important role in the pathogenesis of PD.Previous research showed that DJ-1 could inhibit α-synuclein aggregation,and DJ-1 may function at an early step in the aggregation process.Soluble wild-type 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 can reduce α-synuclein accumulation and aggregation by CMA.DJ-1 knockout mice and DJ-1 si RNA knockdown SHSY5 Y cells were used to elucidate the mechanisms underlying the relationship between DJ-1 deficiency and α-synuclein aggregation.We confirmed DJ-1 deficiency could increase the accumulation and aggregation of α-synuclein both in vitro and in vivo,and overexpression of DJ-1 in vitro could effectively decrease α-synuclein levels.Then,α-synuclein overexpression could activate CMA by elevating the levels of the protein controlling its rate-limiting step,lysosome-associated membrane protein type-2A(LAMP-2A),but DJ-1 deficiency abolished the upregulation of LAMP-2A.Cells responded to the DJ-1 deficiency-mediated blockage of CMA by increasing the amount of lysosomal heat-shock cognate protein70 k Da(Lys-HSC 70).This increase may be an attempt to compensate for reduced activity of the pathway with DJ-1 deficiency after α-synuclein accumulation induced stress.Further mechanical studies showed that DJ-1 deficiency could accelerate LAMP-2A degradation.DJ-1 deficiency decreased LAMP-2A,supporting the view that DJ-1 is an important regulator for α-synuclein degradation by regulating CMA.Our study provides further evidence for the interplay between neurodegenerative diseaseassociated proteins and has an important implication for the understanding of the biology of DJ-1 and its role in the pathogenesis of PD.