Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration

Neel, D. V.; Basu, H.; Gunner, G.; Bergstresser, M. D.; Giadone, R. M.; Chung, H.; Miao, R.; Chou, V.; Brody, E. M.; Jiang, X.; Lee, E. B.; Marques, C.; Held, A.; Wainger, B.; Lagier-Tourenne, C.; Zhang, Y.-J.; Petrucelli, L.; Young-Pearse, T.; Chen-Plotkin, A.; Rubin, L. L.; Lieberman, J.; Chiu, I.

doi:10.1101/2022.11.01.513927

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bioRxiv · 10.1101/2022.11.01.513927

Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration

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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. The frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS)-associated proteins TDP-43 and PR-50 induced GSDME-mediated damage to mitochondria and neurite loss. GSDME deficiency prolonged survival, ameliorated motor dysfunction, and rescued motor neuron loss in the SOD1G93A mouse model of ALS. GSDME knockdown also protected against neurite loss in ALS patient iPSC-derived motor neurons. Thus, we identify GSDME as an executioner of neuronal mitochondrial dysfunction that contributes to neurodegeneration. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/513927v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@113c13dorg.highwire.dtl.DTLVardef@1f3c5caorg.highwire.dtl.DTLVardef@13e75adorg.highwire.dtl.DTLVardef@19fdc93_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIGSDME is expressed by neurons and activated by mitochondrial neurotoxins C_LIO_LIActivated GSDME drives axonal mitochondrial damage and neurite loss prior to cell death C_LIO_LIALS/FTD associated TDP-43 and PR-50 induces GSDME-driven neurite loss in mouse and human iPSC-derived neurons. C_LIO_LISOD1G93A mice show ameliorated disease progression and motor neuron loss in absence of GSDME C_LI

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Neel, D. V., Basu, H., Gunner, G., Bergstresser, M. D., Giadone, R. M., Chung, H., Miao, R., Chou, V., Brody, E. M., Jiang, X., Lee, E. B., Marques, C., Held, A., Wainger, B., Lagier-Tourenne, C., Zhang, Y.-J., Petrucelli, L., Young-Pearse, T., Chen-Plotkin, A., Rubin, L. L., Lieberman, J., Chiu, I.. 2022-11-01. Gasdermin-E mediates mitochondrial damage in axons and neurodegeneration. https://doi.org/10.1101/2022.11.01.513927

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