論文 - 詳細
| RRC ID | 63110 |
|---|---|
| 著者 | Yu CH, Davidson S, Harapas CR, Hilton JB, Mlodzianoski MJ, Laohamonthonkul P, Louis C, Low RRJ, Moecking J, De Nardo D, Balka KR, Calleja DJ, Moghaddas F, Ni E, McLean CA, Samson AL, Tyebji S, Tonkin CJ, Bye CR, Turner BJ, Pepin G, Gantier MP, Rogers KL, McArthur K, Crouch PJ, Masters SL. |
| タイトル | TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS. |
| ジャーナル | Cell |
| 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. |
| 巻・号 | 183(3) |
| ページ | 636-649.e18 |
| 公開日 | 2020-10-29 |
| DOI | 10.1016/j.cell.2020.09.020 |
| PII | S0092-8674(20)31161-2 |
| PMID | 33031745 |
| PMC | PMC7599077 |
| MeSH | Alarmins / metabolism Amyotrophic Lateral Sclerosis / metabolism* Amyotrophic Lateral Sclerosis / pathology Animals Cytoplasm / metabolism DNA, Mitochondrial / metabolism* DNA-Binding Proteins / metabolism* Disease Models, Animal Disease Progression HEK293 Cells Humans Induced Pluripotent Stem Cells / metabolism Inflammation / metabolism Interferon Type I / metabolism Membrane Proteins / metabolism* Mice Mice, Inbred C57BL Mitochondria / metabolism Mitochondrial Permeability Transition Pore / metabolism* NF-kappa B / metabolism Nerve Degeneration / pathology Nucleotidyltransferases / metabolism* Phosphotransferases (Alcohol Group Acceptor) Protein Subunits / metabolism Signal Transduction |
| IF | 38.637 |
| リソース情報 | |
| ヒト・動物細胞 | CiRA00026(HPS0294) |