Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration

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. GSDME plays a role in mitochondrial damage and axon loss. Mitochondrial neurotoxins induced caspase-dependent GSDME cleavage and rapid localization to mitochondria in axons, where GSDME promoted mitochondrial depolarization, trafficking defects, and neurite retraction. Frontotem-poral dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 induced GSDME-mediated damage to mitochondria and neurite loss. GSDME knockdown protected against neurite loss in ALS patient iPSC-derived motor neurons. Knockout of GSDME in SOD1G93A ALS mice prolonged survival, ameliorated motor dysfunction, rescued motor neuron loss, and reduced neuroinflammation. We identify GSDME as an executioner of neuronal mitochondrial dysfunction that may contribute to neuro-degeneration.

Automated summary

Mitochondrial dysfunction and axon loss are key features of neurologic diseases, and Gasdermin (GSDM) proteins, including GSDME, play a role in these processes. Proteins associated with FTD/ALS, such as TDP-43 and PR-50, induce GSDME-mediated damage to mitochondria and neurite loss. Knockdown of GSDME protects against neurite loss in ALS patient iPSC-derived motor neurons, and knockout of GSDME in SOD1G93A ALS mice improves survival, motor function, and reduces neuroinflammation, highlighting the importance of GSDME in neuro-degeneration.