Fas‐associated factor 1 induces the accumulation of α‐synuclein through autophagic suppression in dopaminergic neurons

Abstract Impairment of protein clearance mechanisms leads to α‐synuclein accumulation in dopaminergic neurons, contributing to the pathogenesis of Parkinson's disease (PD). Based on the finding that Fas‐associated factor 1 (FAF1), a positive modulator of PD, colocalizes with α‐synuclein in PD patient brains, we investigated the existence of pathological interplay between FAF1 and α‐synuclein. Monomeric and high‐molecular‐weight forms of α‐synuclein were increased in FAF1‐overexpressing SH‐SY5Y cells. In particular, α‐synuclein turnover was accelerated by genetic depletion of FAF1 in SH‐SY5Y cells. Therefore, we questioned whether FAF1 is involved in the α‐synuclein clearance process. Autophagy inhibitors, but not proteasome inhibitors, restored concurrent attenuation of α‐synuclein expression by FAF1 depletion in SH‐SY5Y cells. Moreover, we found alterations in autophagy markers in SH‐SY5Y cells caused by FAF1 overexpression, indicating that FAF1 disturbed α‐synuclein clearance through the autophagy‐lysosome pathway. Indeed, FAF1 activated the mammalian target of rapamycin (mTOR) pathway, subsequently suppressing autophagosome formation. Consistently, α‐synuclein‐mediated mitochondrial dysfunction was observed in FAF1‐overexpressing SH‐SY5Y cells. Furthermore, FAF1 overexpression using stereotaxic injection of adeno‐associated virus led to α‐synuclein accumulation and autophagy dysregulation in the PD model mice. Taken together, our results reveal a novel role for FAF1: that of a negative regulator of autophagic α‐synuclein clearance.