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-Plotkin; Lee L Rubin; Judy Lieberman; Isaac M Chiu

doi:10.1016/j.neuron.2023.02.019

Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration

Neuron. 2023 Apr 19;111(8):1222-1240.e9. doi: 10.1016/j.neuron.2023.02.019. Epub 2023 Mar 13.

Authors

Dylan V Neel¹, Himanish Basu¹, Georgia Gunner¹, Matthew D Bergstresser¹, Richard M Giadone², Haeji Chung¹, Rui Miao³, Vicky Chou⁴, Eliza Brody⁵, Xin Jiang⁶, Edward Lee⁷, Michelle E Watts², Christine Marques⁸, Aaron Held⁸, Brian Wainger⁸, Clotilde Lagier-Tourenne⁹, Yong-Jie Zhang¹⁰, Leonard Petrucelli¹⁰, Tracy L Young-Pearse⁴, Alice S Chen-Plotkin⁵, Lee L Rubin², Judy Lieberman¹¹, Isaac M Chiu¹²

Affiliations

¹ Department of Immunology, Harvard Medical School, Boston, MA 02115, USA.
² Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave, Cambridge, MA 02138, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
³ Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
⁴ Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
⁵ Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Department of Neurology, Mass General Institute for Neurodegenerative Disease (MIND), Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁷ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁸ Department of Neurology, Sean M. Healey & AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁹ Department of Neurology, Mass General Institute for Neurodegenerative Disease (MIND), Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA.
¹⁰ Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
¹¹ Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
¹² Department of Immunology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].

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 SOD1^G93A 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.

Keywords: ALS; FTD; axon degeneration; cell death; gasdermins; innate immunity; mitochondria; neurodegeneration; neuroimmunology; pyroptosis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis* / metabolism
Animals
Axons / metabolism
Frontotemporal Dementia
Gasdermins
Humans
Mice
Mice, Knockout
Motor Neurons / metabolism

Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration

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