TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS

Chien-Hsiung Yu, Sophia Davidson, Cassandra R. Harapas, James B. Hilton, Michael J. Mlodzianoski, Pawat Laohamonthonkul, Cynthia Louis, Ronnie Ren Jie Low, Jonas Moecking, Dominic De Nardo, Katherine R. Balka, Dale J. Calleja, Fiona Moghaddas, Erya Ni, Catriona A. McLean, Andre L. Samson, Michael Gantier, Kelly L. Rogers, Kate McArthur, Peter J. CrouchSeth L. Masters

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)636-649.e18
Number of pages33
JournalCell
Volume183
Issue number3
DOIs
Publication statusPublished - 29 Oct 2020

Keywords

  • ALS
  • IFN
  • NF-kappaB
  • STING
  • TDP-43
  • cGAMP
  • cGAS
  • mPTP
  • mitochondria
  • neurodegeneration

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