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
  • 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: [email protected].
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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