Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration

Abstract

Mitochondrial dysfunction and axon loss are hallmarks of neurologic diseases. Gasdermin (GSDM) proteins are executioner pore-forming molecules that mediate cell death, yet their roles in the central nervous system (CNS) are not well understood. Here, we find that one GSDM family member, GSDME, is expressed by both mouse and human neurons, and that GSDME plays a critical role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase dependent GSDME cleavage and rapid localization to mitochondria in axonal processes, where GSDME promoted mitochondrial depolarization, trafficking defects along axons, and neurite retraction. Expression of activated N-GSDME in primary neurons was sufficient to drive mitochondrial dysfunction, neurite loss and cell death. Frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 also induced GSDME activation and mediated damage to mitochondria and neurite loss; knockout of GSDME in primary mouse neurons was protective. GSDME knockdown protected against neurite loss in ALS patient iPSC-derived motor neurons. Lastly, knockout of GSDME in the mutant SOD1G93A mouse model of ALS prolonged survival, ameliorated motor dysfunction, rescued motor neuron loss, and reduced neuroinflammatory markers. We identify GSDME as an executioner of neuronal mitochondrial dysfunction that contributes to neurodegeneration.