| First Author | Tan HY | Year | 2022 |
| Journal | iScience | Volume | 25 |
| Issue | 6 | Pages | 104404 |
| PubMed ID | 35712074 | Mgi Jnum | J:327508 |
| Mgi Id | MGI:7293902 | Doi | 10.1016/j.isci.2022.104404 |
| Citation | Tan HY, et al. (2022) cGAS and DDX41-STING mediated intrinsic immunity spreads intercellularly to promote neuroinflammation in SOD1 ALS model. iScience 25(6):104404 |
| abstractText | Neuroinflammation exacerbates the progression of SOD1-driven amyotrophic lateral sclerosis (ALS), although the underlying mechanisms remain largely unknown. Herein, we demonstrate that misfolded SOD1 (SOD1(Mut))-causing ALS results in mitochondrial damage, thus triggering the release of mtDNA and an RNA:DNA hybrid into the cytosol in an mPTP-independent manner to activate IRF3- and IFNAR-dependent type I interferon (IFN-I) and interferon-stimulating genes. The neuronal hyper-IFN-I and pro-inflammatory responses triggered in ALS-SOD1(Mut) were sufficiently robust to cause a strong physiological outcome in vitro and in vivo. cGAS/DDX41-STING-signaling is amplified in bystander cells through inter-neuronal gap junctions. Our results highlight the importance of a common DNA-sensing pathway between SOD1 and TDP-43 in influencing the progression of ALS. |
