TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS.
1. Cell. 2020 Oct 29;183(3):636-649.e18. doi: 10.1016/j.cell.2020.09.020. Epub 2020 Oct 7. TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS. Yu CH(1), Davidson S(1), Harapas CR(1), Hilton JB(2), Mlodzianoski MJ(3), Laohamonthonkul P(1), Louis C(1), Low RRJ(4), Moecking J(5), De Nardo D(6), Balka KR(6), Calleja DJ(1), Moghaddas F(7), Ni E(8), McLean CA(9), Samson AL(1), Tyebji S(8), Tonkin CJ(8), Bye CR(10), Turner BJ(10), Pepin G(11), Gantier MP(11), Rogers KL(3), McArthur K(12), Crouch PJ(2), Masters SL(13). Author information: (1)Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. (2)Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC 3010, Australia; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia. (3)Centre for Dynamic Imaging, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. (4)Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. (5)Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Institute of Structural Biology, University of Bonn, 53127 Bonn, Germany. (6)Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3168, Australia. (7)Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Immunology and Allergy, The Royal Melbourne Hospital, Parkville, VIC 3052, Australia. (8)Infection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia. (9)Anatomical Pathology, The Alfred Hospital, Melbourne, VIC 3004, Australia. (10)Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia. (11)Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC 3168, Australia. (12)Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3168, Australia. (13)Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Immunology Laboratory, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou, Guangdong 510623, China. Electronic address: masters@wehi.edu.au. Comment in Trends Neurosci. 2021 Feb;44(2):81-82. doi: 10.1016/j.tins.2020.12.001. Cell Res. 2021 Apr;31(4):379-380. doi: 10.1038/s41422-020-00461-x. Liver Int. 2021 Aug;41(8):1969-1971. doi: 10.1111/liv.14895. Cytoplasmic accumulation of TDP-43 is a disease hallmark for many cases of amyotrophic lateral sclerosis (ALS), associated with a neuroinflammatory cytokine profile related to upregulation of nuclear factor κB (NF-κB) and type I interferon (IFN) pathways. Here we show that this inflammation is driven by the cytoplasmic DNA sensor cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS) when TDP-43 invades mitochondria and releases DNA via the permeability transition pore. Pharmacologic inhibition or genetic deletion of cGAS and its downstream signaling partner STING prevents upregulation of NF-κB and type I IFN induced by TDP-43 in induced pluripotent stem cell (iPSC)-derived motor neurons and in TDP-43 mutant mice. Finally, we document elevated levels of the specific cGAS signaling metabolite cGAMP in spinal cord samples from patients, which may be a biomarker of mtDNA release and cGAS/STING activation in ALS. Our results identify mtDNA release and cGAS/STING activation as critical determinants of TDP-43-associated pathology and demonstrate the potential for targeting this pathway in ALS. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved. DOI: 10.1016/j.cell.2020.09.020 PMCID: PMC7599077 PMID: