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

• Author: 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.
• Subjects: Alarmins - metabolism ; ALS ; Amyotrophic Lateral Sclerosis - metabolism ; Amyotrophic Lateral Sclerosis - pathology ; Animals ; cGAMP ; cGAS ; Cytoplasm - metabolism ; Disease Models, Animal ; Disease Progression ; DNA, Mitochondrial - metabolism ; DNA-Binding Proteins - metabolism ; HEK293 Cells ; Humans ; IFN ; Induced Pluripotent Stem Cells - metabolism ; Inflammation - metabolism ; Interferon Type I - metabolism ; Membrane Proteins - metabolism ; Mice ; Mice, Inbred C57BL ; mitochondria ; Mitochondria - metabolism ; Mitochondrial Permeability Transition Pore - metabolism ; mPTP ; Nerve Degeneration - pathology ; neurodegeneration ; NF-kappa B - metabolism ; NF-κB ; Nucleotidyltransferases - metabolism ; Phosphotransferases (Alcohol Group Acceptor) ; Protein Subunits - metabolism ; Signal Transduction ; STING ; TDP-43
• Is Part Of: Cell, 2020-10, Vol.183 (3), p.636-649.e18
• Description: 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. [Display omitted] •TDP-43 enters mitochondria, triggers mtDNA release via the mPTP•TDP-43-induced cytosolic mtDNA accumulation activates the cGAS/STING pathway•Evidence of cytoplasmic mtDNA was found in ALS patient cells and disease models•Blocking STING prevents inflammation and neurodegeneration in vitro and in vivo TDP-43 causes inflammation in ALS by stimulating mitochondrial DNA release, which is subsequently sensed by the cytosolic cGAS/STING pathway, suggesting that inhibition of cGAS/STING could help alleviate inflammation-related damage in ALS.
  
• Publisher: United States: Elsevier Inc
  
• Language: English
  
• Identifier: ISSN: 0092-8674
  EISSN: 1097-4172
  DOI: 10.1016/j.cell.2020.09.020
  PMID: 33031745
  
• Source: MEDLINE
  Open Access: Cell Press Free Archives