1. TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS.
- Author
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Yu CH, Davidson S, Harapas CR, Hilton JB, Mlodzianoski MJ, Laohamonthonkul P, Louis C, Low RRJ, Moecking J, De Nardo D, Balka KR, Calleja DJ, Moghaddas F, Ni E, McLean CA, Samson AL, Tyebji S, Tonkin CJ, Bye CR, Turner BJ, Pepin G, Gantier MP, Rogers KL, McArthur K, Crouch PJ, and Masters SL
- Subjects
- Alarmins metabolism, Amyotrophic Lateral Sclerosis pathology, Animals, Cytoplasm metabolism, Disease Models, Animal, Disease Progression, HEK293 Cells, Humans, Induced Pluripotent Stem Cells metabolism, Inflammation metabolism, Interferon Type I metabolism, Mice, Mice, Inbred C57BL, Mitochondria metabolism, NF-kappa B metabolism, Nerve Degeneration pathology, Phosphotransferases (Alcohol Group Acceptor), Protein Subunits metabolism, Signal Transduction, Amyotrophic Lateral Sclerosis metabolism, DNA, Mitochondrial metabolism, DNA-Binding Proteins metabolism, Membrane Proteins metabolism, Mitochondrial Permeability Transition Pore metabolism, Nucleotidyltransferases metabolism
- Abstract
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., Competing Interests: Declaration of Interests S.L.M. declares consultancy with IFM Therapeutics and Quench Bio and received funding from GlaxoSmithKline. S.L.M. and C.-H.Y. are named inventors on International Patent Application No. PCT/AU2019051201. All other authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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