Microglial GSDMD-Mediated Pyroptosis Drives Neuroinflammation in Parkinson's Disease

RationaleParkinsons disease (PD), a globally prevalent neurodegenerative disorder, is characterized by substantia nigra dopaminergic neuron degeneration and striatal dopamine depletion. While microglial pyroptosis is implicated in neuroinflammation and neural injury via inflammatory cytokine release, the role of the CASPASE-1/GSDMD pathway in PD pathogenesis remains incompletely defined. Methods1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to construct PD model in vivo, GSDMD-knockout mice was employed to assess pyroptotic mechanisms. MPP-stimulated BV2 microglia were treated with a CASPASE-1 inhibitor in vitro. Microglia-specific GSDMD conditional knockout mice were generated to evaluate cell-type contributions to neuroinflammation and motor deficits. ResultsGSDMD deficiency attenuated MPTP-induced neuroinflammation, dopaminergic neuron loss, and motor dysfunction in vivo. MPP exposure triggered NLRP3 inflammasome activation and pyroptosis in BV2 microglia, which was suppressed by CASPASE-1 inhibition. Critically, microglia-specific GSDMD ablation mitigated nigrostriatal degeneration and dyskinesia in PD mice, confirming the centrality of microglial pyroptosis. ConclusionOur findings demonstrate that microglia drive neuroinflammation in PD via CASPASE-1/GSDMD-mediated pyroptosis, directly linking this pathway to dopaminergic neurodegeneration and motor impairment. Targeting GSDMD-dependent pyroptosis represents a promising therapeutic strategy.