Gasdermin E Orchestrates Pyroptosis and Mitochondrial Dysfunction to Drive Neurodegeneration in Parkinson Disease

PD is characterized by degeneration of midbrain dopamine neurons, yet how mitochondrial injury engages programmed cell death in these neurons remains unclear. Here, we identify gasdermin E (GSDME), the caspase-3-activated executor of pyroptosis, as a critical mediator of neurodegeneration in PD mouse models. In primary cortical neurons and SH-SY5Y cells, the mitochondrial toxin MPTP induces caspase-3 activation, GSDME cleavage, and pyroptotic membrane rupture. Genetic silencing of GSDME or its transcriptional regulator Sp1 markedly limits MPTP-triggered neuronal death. In vivo, Gsdme deficiency preserves nigrostriatal dopaminergic neurons, improves motor performance, and attenuates anxiety- and depression-like behaviors in MPTP-treated mice. Gsdme loss further dampens microglial and astrocytic activation and reduces pro-inflammatory cytokines in the striatum and substantia nigra. Mechanistically, cleaved GSDME localizes to mitochondria, where it disrupts membrane potential, elevates reactive oxygen species, and precipitates organelle damage, thereby coupling mitochondrial dysfunction to pyroptotic cell death. These findings identify GSDME-mediated pyroptosis as a mechanistic link between mitochondrial toxicity and neuroinflammation in PD and highlight the GSDME as a therapeutic entry point to slow disease progression.