期刊
CELL
卷 183, 期 3, 页码 636-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2020.09.020
关键词
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资金
- Australian National Health and Medical Research Council (NHMRC) [1057815, 1099262]
- Independent Research Institutes Infrastructure Support Scheme grant [361646]
- FightMND Drug Screening Program grant
- Victorian Endowment for Science Knowledge and Innovation
- HHMIWellcome International Research Scholarship
- Sylvia and Charles Viertel Foundation
- Australian Research Council [140100594]
- National Health and Medical Research Council [SD GNT1143412]
- Fonds de Recherche du Quebec -Sante [GP FRSQ 35071]
- WEHI Centenary Fellowship
- Ormond College Thwaites Gutch Fellowship in Physiology
- Motor Neurone Disease Research Institute of Australia (Betty Laidlaw MND research grant)
- Australian Phenomics Network
- Ian Potter Centre for Genomics and Personalized Medicine
- Victorian State Government operational infrastructure support grant
- GlaxoSmithKline
- Motor Neurone Disease Research Institute of Australia (Superball XI MND research grant)
- National Health and Medical Research Council of Australia [1057815] Funding Source: NHMRC
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 kappa B (NF-kappa B) 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-kappa B 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.
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