Neural Regeneration Research ›› 2026, Vol. 21 ›› Issue (8): 3797-3806.doi: 10.4103/NRR.NRR-D-24-01420

Previous Articles     Next Articles

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

Yuwan Lin1, #, Zixin Tan1, #, Wenfeng Ye1, #, Weimin Li1, Hao Chen1, Yuping Lin1, Miaomiao Zhou2, Hanqun Liu3, Qin Liu1, Zhiling Zhang1, Weixin Kong1, Zongtang Xu1, Hao Lin1, Mingshu Mo1, Wenyuan Guo1, Keye Lin4, Jiaxin Tang4, Yueying Zheng4, Wenlong Zhang1, *, Pingyi Xu1, *, Xiang Chen1, *   

  1. 1Department of Neurology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong Province, China; 
    2Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; 
    3Department of Geriatrics, Guangzhou First People’s Hospital, Guangzhou, Guangdong Province, China; 
    4Department of Neurology, Guangzhou Medical University, Guangzhou, Guangdong Province, China
  • Online:2026-08-18 Published:2026-04-28
  • Contact: Wenlong Zhang, MD, 925992744@qq.com; Pingyi Xu, MD, pingyixu@sina.com; Xiang Chen, MD, Wuliancx@163.com.
  • Supported by:
    This work was supported by the Youth Program of the National Natural Science Foundation of China, Nos. 81901282 (to XC), 82101326 (to WG), 81870992 (to PX), and 81870856; the Guangdong Basic and Applied Basic Research Foundation of the Science Foundation, Nos. 2024A1515012919 (to XC) and 2019A1515011189 (to XC); the Central Government Guiding Local Science and Technology Development Projects, No. ZYYD2022C17 (to PX); the Key Project of the Guangzhou Health Commission, No. 2019-ZD-09 (to PX); the Basic and Applied Basic Research of the City and School Jointly Funded Projects, No. 20220102397 (to QL); the Guangdong College Students Innovation and Entrepreneurship Training Program, No. S202310570017 (to WY); the Science and Technology Planning Project of Guangzhou, Nos. 2023B03J0631 (to PX), 2024A03J1152 (to XC), and 202102010010 (to PX); and the Basic Research Program of the Guangzhou Science and Technology Bureau Jointly-funded Dengfeng Hospital Project, No. 20232031 (to XC). 

PDF

11

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. 

Key words: ATP6V0A1, autophagy, dopaminergic neurons, lysosome, mTORC, Parkinson’s disease, vacuolar H+-ATPase, α-synuclein