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

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

Cell (2020-10-09)
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, Genevieve Pepin, Michael P Gantier, Kelly L Rogers, Kate McArthur, Peter J Crouch, Seth L Masters
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.

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