Pharmacological Intervention Targeting FAF1 Restores Autophagic Flux for α‑Synuclein Degradation in the Brain of a Parkinson’s Disease Mouse Model

α-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 α-synuclein accumulation through autophagy impairment in dopam...

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Published in:ACS chemical neuroscience 2022-03, Vol.13 (6), p.806-817
Main Authors: Kim, Bok-Seok, Song, Jin-A, Jang, Ki-Hong, Jang, Taeik, Jung, Bumjun, Yoo, Sung-Eun, Lee, Jae Moon, Kim, Eunhee
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - metabolism
alpha-Synuclein - metabolism
Animals
Apoptosis Regulatory Proteins - metabolism
Autophagy - physiology
Brain - metabolism
Disease Models, Animal
Dopaminergic Neurons - metabolism
Humans
Mice
Mice, Transgenic
Parkinson Disease - metabolism
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Summary:α-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 α-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 α-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 α-synuclein in neuronal cells. Furthermore, KM-819 restored the turnover rate of α-synuclein in FAF1-overexpressing SH-SY5Y cells, implicating KM-819-mediated reconstitution of the α-synuclein degradative pathway. In addition, KM-819 reconstituted autophagic flux in FAF1-transfected SH-SY5Y cells, also suppressing α-synuclein-induced mitochondrial dysfunction. Moreover, oral administration of KM-819 also interfered with α-synuclein accumulation in the midbrain of mice overexpressing FAF1 via an adeno-associated virus system. Consistently, KM-819 reduced α-synuclein accumulation in both the hippocampus and the midbrain of human A53T α-synuclein transgenic mice. Collectively, these data imply that KM-819 may have therapeutic potential for patients with PD.
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.1c00828