Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration

Dylan V. Neel, Himanish Basu, Georgia Gunner, Matthew D. Bergstresser, Richard M. Giadone, Haeji Chung, Rui Miao, Vicky Chou, Eliza Brody, Xin Jiang, Edward Lee, Michelle E. Watts, Christine Marques, Aaron Held, Brian Wainger, Clotilde Lagier-Tourenne, Yong Jie Zhang, Leonard Petrucelli, Tracy L. Young-Pearse, Alice S. Chen-PlotkinLee L. Rubin, Judy Lieberman, Isaac M. Chiu

Research output: Contribution to journalArticlepeer-review

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. 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. Frontotemporal 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 neurodegeneration.

Original languageEnglish (US)
Pages (from-to)1222-1240.e9
JournalNeuron
Volume111
Issue number8
DOIs
StatePublished - Apr 19 2023

Keywords

  • ALS
  • FTD
  • axon degeneration
  • cell death
  • gasdermins
  • innate immunity
  • mitochondria
  • neurodegeneration
  • neuroimmunology
  • pyroptosis

ASJC Scopus subject areas

  • General Neuroscience

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