Pharmacological Intervention Targeting FAF1 Restores Autophagic Flux for alpha-Synuclein Degradation in the Brain of a Parkinson's Disease Mouse Model

alpha-Synuclein accumulation is implicated in the pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). Previously, we reported that Fas-associated factor 1 (FAF1), which plays a role in PD pathogenesis, potentiates alpha-synuclein accumulation through autophagy impairment in dopaminergic neurons. In this study, we show that KM-819, a FAF1-targeting compound, which has completed phase I clinical trials, interferes with alpha-synuclein accumulation in the mouse brain, as well as in human neuronal cells (SH-SY5Ys). KM-819 suppressed the accumulation of monomeric, oligomeric, and aggregated forms of alpha-synuclein in neuronal cells. Furthermore, KM-819 restored the turnover rate of alpha-synuclein in FAF1-overexpressing SH-SY5Y cells, implicating KM-819-mediated reconstitution of the alpha-synuclein degradative pathway. In addition, KM-819 reconstituted autophagic flux in FAF1-transfected SH-SY5Y cells, also suppressing alpha-synuclein-induced mitochondrial dysfunction. Moreover, oral administration of KM-819 also interfered with alpha-synuclein accumulation in the midbrain of mice overexpressing FAF1 via an adenoassociated virus system. Consistently, KM-819 reduced alpha-synuclein accumulation in both the hippocampus and the midbrain of human A53T alpha-synuclein transgenic mice. Collectively, these data imply that KM-819 may have therapeutic potential for patients with PD.