Dysregulation of the TFEB-ATP6V0C axis in microglia exacerbates α-synuclein pathology through impaired lysosomal acidification in Parkinson’s disease

Emerging evidence suggests that microglia exhibit dual regulatory roles in the pathogenesis of Parkinson's disease (PD); however, their precise function in α-synuclein clearance remains incompletely understood. Here, we provide compelling evidence that α-synuclein preformed fibrils (α-syn PFF) impair lysosomal acidification in microglia, leading to defective autophagic flux and disrupted α-syn degradation. This dysfunction further promotes the secretion of microglial extracellular vesicles (EVs), exacerbating disease pathology. Mechanistic investigations uncover that α-syn PFF directly interacts with ATP6V0C, a pivotal V0 subunit of V-ATPase. This interaction sterically hinders V0-V1 domain assembly, disrupting proton pump complex formation and reducing ATP6V0C expression. Functionally, ATP6V0C overexpression rescues lysosomal acidification deficits and facilitates α-syn degradation in vitro, while in vivo, ATP6V0C overexpression alleviates neurotoxicity and reduces phosphorylated α-syn aggregation in α-syn PFF mouse models. Further investigation identifies the PI3K-AKT-mTOR-TFEB pathway as a key regulatory axis of ATP6V0C-mediated lysosomal acidification in microglia. Notably, both TFEB activation and mTOR inhibition restore lysosomal acidity and upregulate ATP6V0C expression, thereby enhancing α-syn clearance. These findings establish the TFEB-ATP6V0C axis as a key determinant of microglial proteostasis, proposing targeted activation of this pathway as a promising strategy to mitigate PD progression.