@article{b74618bc99c643caa8a6d094ed9e423e,
title = "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. 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.",
keywords = "ALS, FTD, axon degeneration, cell death, gasdermins, innate immunity, mitochondria, neurodegeneration, neuroimmunology, pyroptosis",
author = "Neel, {Dylan V.} and Himanish Basu and Georgia Gunner and Bergstresser, {Matthew D.} and Giadone, {Richard M.} and Haeji Chung and Rui Miao and Vicky Chou and Eliza Brody and Xin Jiang and Edward Lee and Watts, {Michelle E.} and Christine Marques and Aaron Held and Brian Wainger and Clotilde Lagier-Tourenne and Zhang, {Yong Jie} and Leonard Petrucelli and Young-Pearse, {Tracy L.} and Chen-Plotkin, {Alice S.} and Rubin, {Lee L.} and Judy Lieberman and Chiu, {Isaac M.}",
note = "Funding Information: We thank Aaron Gitler for plasmids; Laura Volpicelli-Daley, Ulf Dettmer, Thomas Schwarz, Beth Stevens, and Francisco Quintana for their feedback and advice; and Alex Yueting-Lu, Victoria Tong, Zane Russom, and Samantha Choi for their technical support. This work was supported by R01DK127257 (to I.M.C.); CZI Neurodegeneration Challenge Network (to I.M.C. and A.S.C.-P.); R01CA240955 (to J.L.); Cancer Research Institute fellowship (R.M.); R01AG055909 (T.L.Y.-P.); R01NS115139 (A.S.C.-P.); and U19 AG062418, P50 NS053488 (UPenn Brain Bank, E.L.) and F31NS122292 (to D.V.N.). A.S.C.-P. is supported by the Parker Family Chair/AHA/Allen Brain Health Initiative. Conceptualization, D.V.N. H.B. and I.M.C.; experimental data collection/analysis, D.V.N. H.B. G.G. M.D.B. H.C. R.M. E.B. A.S.C.-P. V.C. and M.E.W.; securing key reagents, L.P. Y.-J.Z. T.L.Y.-P. C.L.-T. and J.L.; original draft, D.V.N. H.B. and I.M.C.; reviewing and editing the manuscript, D.V.N. H.B. I.M.C. G.G. A.S.C.-P. J.L. T.L.Y.-P. and C.L.-T.; funding acquisition, I.M.C. I.M.C. receives sponsored research support from Abbvie/Allergan Pharmaceuticals and is on the SAB for GSK and LIMM therapeutics. J.L. is a cofounder and SAB member of Ventus Therapeutics. Funding Information: We thank Aaron Gitler for plasmids; Laura Volpicelli-Daley, Ulf Dettmer, Thomas Schwarz, Beth Stevens, and Francisco Quintana for their feedback and advice; and Alex Yueting-Lu, Victoria Tong, Zane Russom, and Samantha Choi for their technical support. This work was supported by R01DK127257 (to I.M.C.); CZI Neurodegeneration Challenge Network (to I.M.C. and A.S.C.-P.); R01CA240955 (to J.L.); Cancer Research Institute fellowship (R.M.); R01AG055909 (T.L.Y.-P.); R01NS115139 (A.S.C.-P.); and U19 AG062418, P50 NS053488 (UPenn Brain Bank, E.L.) and F31NS122292 (to D.V.N.). A.S.C.-P. is supported by the Parker Family Chair/AHA/Allen Brain Health Initiative . Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",
year = "2023",
month = apr,
day = "19",
doi = "10.1016/j.neuron.2023.02.019",
language = "English (US)",
volume = "111",
pages = "1222--1240.e9",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "8",
}