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

Impairment of protein clearance mechanisms leads to alpha-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 alpha-synuclein in PD patient brains, we investigated the existence of pathological interplay between FAF1 and alpha-synuclein. Monomeric and high-molecular-weight forms of alpha-synuclein were increased in FAF1-overexpressing SH-SY5Y cells. In particular, alpha-synuclein turnover was accelerated by genetic depletion of FAF1 in SH-SY5Y cells. Therefore, we questioned whether FAF1 is involved in the alpha-synuclein clearance process. Autophagy inhibitors, but not proteasome inhibitors, restored concurrent attenuation of alpha-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 alpha-synuclein clearance through the autophagy-lysosome pathway. Indeed, FAF1 activated the mammalian target of rapamycin (mTOR) pathway, subsequently suppressing autophagosome formation. Consistently, alpha-synuclein-mediated mitochondrial dysfunction was observed in FAF1-overexpressing SH-SY5Y cells. Furthermore, FAF1 overexpression using stereotaxic injection of adeno-associated virus led to alpha-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 alpha-synuclein clearance.

Automated summary

The impairment of protein clearance mechanisms in dopaminergic neurons leads to the accumulation of alpha-synuclein, contributing to the pathogenesis of Parkinson's disease. Fas-associated factor 1 (FAF1) was found to disrupt alpha-synuclein clearance through the autophagy-lysosome pathway, indicating a novel role as a negative regulator of autophagic alpha-synuclein clearance. This disturbance ultimately leads to alpha-synuclein accumulation and autophagy dysregulation in PD model mice.