ATP6V0A1 protects dopaminergic neurons via the autophagy-lysosomal pathway in Parkinson’s disease

Abstract Parkinson’s disease is the second most common neurodegenerative disorder. ATPase H+ transporting V0 subunit A1 (ATP6V0A1) is a component of vacuolar H+-ATPase (V-ATPase), an ATP-dependent proton pump. Our previous research identified an association between the ATP6V0A1 rs601999 variant and Parkinson’s disease; however, the underlying mechanisms of ATP6V0A1 in Parkinson’s disease remain elusive. In this study, we generated ATP6V0A1 knockdown and overexpression models and then examined the degeneration of dopaminergic neurons, lysosomal function, and the autophagy-lysosomal pathway using immunohistochemistry, western blotting, and transmission electron microscopy. We found that ATP6V0A1 protected against lysosomal dysfunction, regulated autophagic flux, and decreased phosphorylated α-synuclein levels in vitro. In vivo, ATP6V0A1 reduced levels of α-synuclein and phosphorylated α-synuclein proteins, mitigated degeneration of dopaminergic neurons, and improved motor dysfunction. Collectively, these findings show that ATP6V0A1 plays a protective role in Parkinson’s disease by modulating the autophagy-lysosomal pathway. A correlation between ATP6V0A1 and Parkinson’s disease susceptibility may serve as a biomarker for Parkinson’s disease, while the protective effects of ATP6V0A1 could represent a potential therapeutic target for the disease.