| First Author | Xu CY | Year | 2017 |
| Journal | Front Aging Neurosci | Volume | 9 |
| Pages | 308 | PubMed ID | 29021755 |
| Mgi Jnum | J:313562 | Mgi Id | MGI:6790883 |
| Doi | 10.3389/fnagi.2017.00308 | Citation | Xu CY, et al. (2017) DJ-1 Inhibits alpha-Synuclein Aggregation by Regulating Chaperone-Mediated Autophagy. Front Aging Neurosci 9:308 |
| abstractText | alpha-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 alpha-synuclein aggregation, and may function at an early step in the aggregation process. Soluble wild-type (WT) alpha-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 alpha-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 alpha-synuclein aggregation. First, we confirmed that DJ-1 deficiency increased the accumulation and aggregation of alpha-synuclein in both SH-SY5Y cells and PD animal models, and overexpression of DJ-1 in vitro effectively decreased alpha-synuclein levels. alpha-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 alpha-synuclein. Our study suggests that DJ-1 deficiency aggravates alpha-synuclein aggregation by inhibiting the activation of CMA and provides further evidence of the molecular interaction between PD-related proteins via the CMA pathway. |
