Characterizing microglial heterogeneity in autophagy impairment of Paraquat-induced Parkinson’s disease-like neurodegeneration

Parkinson's disease (PD) is a prevalent neurodegenerative condition influenced by environmental elements, notably Paraquat (PQ), which is one of the known risk factors. Impaired autophagy is a critical factor in the pathogenesis of PD, yet the cellular heterogeneity related to autophagy in PD has not been thoroughly investigated. Here, we established a PQ-induced PD-like neurodegeneration model and found that PQ impairs autophagy during experimental PD progression. Using single-cell RNA sequencing (scRNA-seq), we elucidated the autophagy-related transcriptomic landscapes in this model, identifying microglia as the central cell type associated with PQ-induced autophagy across all brain cell types. Additionally, microglial subtypes in the PQ-exposed model exhibited significant heterogeneity in gene expression characteristics, biological functions, and roles in autophagic regulation. PQ exposure induced potential genetic transformations between microglial subtypes, which may further disrupt their immune response and energy metabolism regulation functions. Subsequently, we validated the identity transformation of microglia revealed by scRNA-seq in both in vivo and in vitro PQ exposure models. Moreover, we identified a specific microglial subtype primarily responsible for the autophagy-related changes observed in the PQ-exposed model. The expression of the autophagic subtype marker gene Inpp5d may contribute to the regulation of PQ-induced autophagic impairment in BV2 cells. This study generates the first scRNA-seq atlas of autophagy in the context of PQ exposure, highlighting the heterogeneity of microglial subtypes and identifying an autophagy-specific microglial subtype as a central mechanism in the pathology of PQ-induced PD-like neurodegeneration.