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

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.