2. Academic Validation
  3. 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 Oct 29;183(3):636-649.e18. doi: 10.1016/j.cell.2020.09.020.
Chien-Hsiung Yu 1,  Sophia Davidson 1,  Cassandra R Harapas 1,  James B Hilton 2,  Michael J Mlodzianoski 3,  Pawat Laohamonthonkul 1,  Cynthia Louis 1,  Ronnie Ren Jie Low 4,  Jonas Moecking 5,  Dominic De Nardo 6,  Katherine R Balka 6,  Dale J Calleja 1,  Fiona Moghaddas 7,  Erya Ni 8,  Catriona A McLean 9,  Andre L Samson 1,  Shiraz Tyebji 8,  Christopher J Tonkin 8,  Christopher R Bye 10,  Bradley J Turner 10,  Genevieve Pepin 11,  Michael P Gantier 11,  Kelly L Rogers 3,  Kate McArthur 12,  Peter J Crouch 2,  Seth L Masters 13
Affiliations

Affiliations

  • 1 Inflammation 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.
  • 2 Department of Pharmacology and Therapeutics, University of Melbourne, Parkville, VIC 3010, Australia; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia.
  • 3 Centre 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, Australia.
  • 4 Personalised 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, Australia.
  • 5 Inflammation 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, Germany.
  • 6 Inflammation 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, Australia.
  • 7 Inflammation 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, Australia.
  • 8 Infection 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, Australia.
  • 9 Anatomical Pathology, The Alfred Hospital, Melbourne, VIC 3004, Australia.
  • 10 Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3010, Australia.
  • 11 Centre 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, Australia.
  • 12 Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, VIC 3168, Australia.
  • 13 Inflammation 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: masters@wehi.edu.au.
PMID: 33031745 DOI: 10.1016/j.cell.2020.09.020
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.

Keywords

ALS; IFN; NF-κB; STING; TDP-43; cGAMP; cGAS; mPTP; mitochondria; neurodegeneration.

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