Sleep deprivation exacerbates Parkinson’s disease via PPARγ–PLIN4-mediated microglial lipid droplet accumulation and neuroinflammation

Sleep disturbances are common early non-motor features of Parkinson’s disease (PD), yet how chronic sleep loss accelerates PD progression remains poorly understood. Here, we demonstrate in an MPTP-induced mouse model that sleep deprivation (SD) triggers robust neuroinflammation and metabolic reprogramming in the Substantia Nigra Pars Compacta (SNpc), accompanied by marked accumulation of lipid droplets (LDs) within microglia. Transcriptomic and histological analyses identified Perilipin 4 (PLIN4) as a sleep deprivation-responsive LD-associated gene in microglia. PLIN4 overexpression promoted LD accumulation, mitochondrial stress, and inflammatory activation, whereas PLIN4 knockdown attenuated these phenotypes and reduced SD/MPTP-induced microglial LD burden and behavioral impairment in vivo. Mechanistically, SD/PD conditions were associated with reduced PPARγ expression and increased PLIN4 accumulation. CUT&Tag (Cleavage Under Targets and Tagmentation) analysis revealed PPARγ occupancy at a Plin4-associated regulatory region, and motif-mutated reporter assays confirmed PPARγ responsiveness of this region, supporting a context-dependent regulatory relationship between PPARγ and PLIN4. Pharmacological activation and microglia-targeted overexpression of PPARγ reduced PLIN4 expression, microglial LD accumulation, neuroinflammatory activation, and motor deficits. Together, our findings identify a sleep-sensitive PPARγ-PLIN4 lipid-inflammatory pathway in microglia and suggest that microglial LD remodeling contributes to vulnerability to dopaminergic neurodegeneration.