VPS35 Regulates Microglial Lipid Droplet Accumulation in P arkinson's Disease via Rab 7

Microglial dysfunction and aberrant lipid metabolism are emerging as key contributors to Parkinson's disease (PD) pathogenesis. However, the specific role and regulation of lipid droplets (LDs) within microglia remain poorly defined. In this study, we employed MPTP‐ and LPS‐induced PD mouse models and an in vitro system utilizing astrocyte‐conditioned medium to model disease‐relevant lipid stress and found enhanced LD accumulation in microglia. VPS35 expression was decreased in microglia, correlating with elevated microglial LD levels in PD mouse models. We then performed genetic manipulations (knockdown and overexpression) of VPS35, including the PD‐associated D620N mutant, in primary microglia and assessed LD accumulation, phagocytic function, inflammatory responses, and integrated stress pathways. We showed that VPS35 knockdown exacerbated the accumulation of LDs in microglia. Conversely, VPS35 overexpression ameliorated LD formation, improved phagocytic function, and reduced inflammatory and integrated stress responses in microglia. The PD‐related VPS35[D620N] mutation abolished these protective effects. We further found that VPS35 interacts with Rab7 to maintain lysosomal function, and the D620N mutation disrupts this interaction, leading to defective LD clearance. Our findings reveal VPS35 dysfunction as a key pathogenic mechanism in PD, where the D620N mutation disrupts microglial lipid handling to promote disease progression, thereby nominating VPS35 restoration as a promising therapeutic strategy.