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 ...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 phosphorylatedα-synuclein levels in vitro.In vivo,ATP6V0A1 reduced levels ofα-synuclein and phosphorylatedα-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.展开更多
基金supported by the Youth Program of the National Natural Science Foundation of China,Nos.81901282(to XC),82101326(to WG),81870992(to PX),and 81870856the Guangdong Basic and Applied Basic Research Foundation of the Science Foundation,Nos.2024A1515012919(to XC)and 2019A1515011189(to XC)+5 种基金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)the Basic Research Program of the Guangzhou Science and Technology Bureau Jointly-funded Dengfeng Hospital Project,No.20232031(to XC).
文摘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 phosphorylatedα-synuclein levels in vitro.In vivo,ATP6V0A1 reduced levels ofα-synuclein and phosphorylatedα-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.
