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

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 drive...

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Detalles Bibliográficos
Autores principales: Yu, Chien-Hsiung, Davidson, Sophia, Harapas, Cassandra R., Hilton, James B., Mlodzianoski, Michael J., Laohamonthonkul, Pawat, Louis, Cynthia, Low, Ronnie Ren Jie, Moecking, Jonas, De Nardo, Dominic, Balka, Katherine R., Calleja, Dale J., Moghaddas, Fiona, Ni, Erya, McLean, Catriona A., Samson, Andre L., Tyebji, Shiraz, Tonkin, Christopher J., Bye, Christopher R., Turner, Bradley J., Pepin, Genevieve, Gantier, Michael P., Rogers, Kelly L., McArthur, Kate, Crouch, Peter J., Masters, Seth L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599077/
https://www.ncbi.nlm.nih.gov/pubmed/33031745
http://dx.doi.org/10.1016/j.cell.2020.09.020
Descripción
Sumario: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.