TDP-43 triggers mitochondrial DNA release via mPTP to activate cGAS/STING in ALS
Details
Publication Year 2020-10-03, Volume 183, Issue #3, Page 636-649.e18
Journal Title
Cell
Publication Type
Journal Article
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 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.
Publisher
Cell Press
WEHI Research Division(s)
Inflammation; Infectious Diseases And Immune Defence; Advanced Technology And Biology
PubMed ID
33031745
Open Access at Publisher's Site
https://doi.org/10.1016/j.cell.2020.09.020
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2020-11-02 04:55:20
Last Modified: 2020-11-03 09:39:17
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