TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS
Chien‐Hsiung YuInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, AustraliaSophia DavidsonInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, AustraliaCassandra R. HarapasInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, AustraliaJames B. HiltonDepartment of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC 3010, Australia; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, AustraliaMichael J. MlodzianoskiCentre for Dynamic Imaging, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, AustraliaPawat LaohamonthonkulInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, AustraliaCynthia LouisInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, AustraliaRonnie Ren Jie LowPersonalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, AustraliaJonas MoeckingInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Institute of Structural Biology, University of Bonn, 53127 Bonn, GermanyDominic De NardoDepartment of Medical Biology, University of Melbourne, Parkville, VIC 3010, AustraliaKatherine R. BalkaInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3168, AustraliaDale J. CallejaInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, AustraliaFiona MoghaddasInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Immunology and Allergy, The Royal Melbourne Hospital, Parkville, VIC 3052, AustraliaErya NiInfection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, AustraliaCatriona McLeanAnatomical Pathology, The Alfred Hospital, Melbourne, VIC 3004, AustraliaAndré L. SamsonInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, AustraliaShiraz TyebjiInfection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, AustraliaChristopher J. TonkinInfection and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, AustraliaChristopher R. ByeFlorey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, AustraliaBradley J. TurnerFlorey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, AustraliaGeneviève PépinCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC 3168, AustraliaMichael P. GantierCentre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia; Department of Molecular and Translational Science, Monash University, Clayton, VIC 3168, AustraliaKelly L. RogersCentre for Dynamic Imaging, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, AustraliaKate McArthurDepartment of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3168, AustraliaPeter J. CrouchDepartment of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC 3010, Australia; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, AustraliaSeth L. MastersInflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3010, Australia; Immunology Laboratory, Guangzhou Institute of Paediatrics, Guangzhou Women and Children's Medical Centre, Guangzhou, Guangdong 510623, China. Electronic address: [email protected]
2020nl
ABI
Annotatsiya
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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