DJ-1 Inhibits α-Synuclein Aggregation by Regulating Chaperone-Mediated Autophagy
Autor: | Sheng-Di Chen, Yi-Meng Chen, Chuan-Ying Xu, Tian-Fang Jiang, Jun Liu, Jianqing Ding, Wenyan Kang, Lina Zhang, Jia Zhang |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2017 |
Předmět: |
0301 basic medicine
Aging DJ-1 Cognitive Neuroscience Biology medicine.disease_cause lcsh:RC321-571 LAMP2A Pathogenesis 03 medical and health sciences Chaperone-mediated autophagy α-synuclein Downregulation and upregulation medicine chaperone-mediated autophagy lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Original Research Mutation Autophagy PARK7 Molecular biology nervous system diseases 030104 developmental biology Membrane protein Knockout mouse Parkinson’s disease Neuroscience |
Zdroj: | Frontiers in Aging Neuroscience Frontiers in Aging Neuroscience, Vol 9 (2017) |
ISSN: | 1663-4365 |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |