Irgm1 Promotes Microglial Clearance of α-Synuclein via the TFEB-Dependent Autophagy- Lysosome Pathway in Parkinson’s Disease

Abstract Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of nigral dopaminergic neurons and abnormal α-synuclein (α-syn) aggregation. Growing evidence indicates that impaired autophagy–lysosome pathway (ALP) activity in microglia exacerbates the pathological process; however, the precise regulatory mechanisms involved remain elusive. In this study, we found that Irgm1, a key autophagy regulator, was markedly upregulated in the midbrains of PD mice. Irgm1-deficient mice exhibited accelerated PD progression, more severe motor deficits, greater TH⁺ neuronal loss, increased α-syn deposition and aggravated ALP damage, indicating a neuroprotective role for Irgm1. Moreover, Irgm1 was selectively enriched in the microglia of PD mice, and Irgm1 knockdown amplifiedα-syn-preformed fibril (PFF)-induced ALP impairment: the LC3-II and cathepsin D levels decreased, p62 and α-syn aggregates accumulated, the colocalization of α-syn with Lamp1 declined, lysosomal acidification decreased, and TFEB nuclear translocation was blocked. The TFEB-activating autophagy agonist rapamycin restored TFEB nuclear translocation, reactivated the ALP, accelerated α-syn clearance, and abolished the increased toxicity of Irgm1-deficient microglia toward cocultured SH-SY5Y neurons after PFFs preexposure. Thus, Irgm1 promotes microglial α-syn clearance via the TFEB-ALP axis, and targeting this pathway could be a potential therapeutic strategy for PD.