TDP-43 triggers mitochondrial DNA release via mPTP to activate cGAS/STING in ALS
- 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; Masters, SL;
Publication Year 2020-10-03, Volume 183, Issue #3, Page 636-649.e18
- Journal Title
- Publication Type
- Journal Article
- 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 kappaB (NF-kappaB) 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-kappaB 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.
- Cell Press
- WEHI Research Division(s)
- Inflammation; Infectious Diseases And Immune Defence; Advanced Technology And Biology
- PubMed ID
- Publisher's Version
- Open Access at Publisher's Site
- Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2020-11-02 04:55:20Last Modified: 2020-11-03 09:39:17