Journal article

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, Shiraz Tyebji, Christopher J Tonkin, Christopher R Bye, Bradley J Turner Show all

Cell | CELL PRESS | Published : 2020

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 a..

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Grants

Awarded by Australian National Health and Medical Research Council (NHMRC)


Awarded by Independent Research Institutes Infrastructure Support Scheme grant


Awarded by Australian Research Council


Awarded by National Health and Medical Research Council


Awarded by Fonds de Recherche du Quebec -Sante


Funding Acknowledgements

We thank R. Crawley and S. Russo for outstanding animal husbandry. We thank J. Brouwer, G. Dewson, P. Czabotar (WEHI), T. Sadler (Hudson Institute), and B. Kile (Monash University) for intellectual contributions and experimental assistance. Human tissue samples were obtained from the Victorian Brain Bank with assistance from Fairlie Hinton and Geoff Pavey. This work was supported by Australian National Health and Medical Research Council (NHMRC) project grants 1057815 and 1099262, fellowships to S.L.M. and P.J.C., an Independent Research Institutes Infrastructure Support Scheme grant (361646), a research gift (Brain Foundation), and a FightMND Drug Screening Program grant (to B.J.T.). This work was also supported by fellowships from the Victorian Endowment for Science Knowledge and Innovation (to S.L.M.), an HHMIWellcome International Research Scholarship (to S.L.M.), the Sylvia and Charles Viertel Foundation (to S.L.M.), the Australian Research Council (140100594 Future Fellowship to M.P.G.), a National Health and Medical Research Council Early Career Fellowship (SD GNT1143412), fellowship Fonds de Recherche du Quebec -Sante (GP FRSQ 35071), a WEHI Centenary Fellowship (to C.-H.Y.), an Ormond College Thwaites Gutch Fellowship in Physiology (to C.-H.Y.), the Motor Neurone Disease Research Institute of Australia (Betty Laidlaw and Superball XI MND research grants), the Australian Phenomics Network, the Ian Potter Centre for Genomics and Personalized Medicine, and a Victorian State Government operational infrastructure support grant. S.L.M. receives funding from GlaxoSmithKline.