cGAS and DDX41-STING mediated intrinsic immunity spreads intercellularly to promote neuroinflammation in SOD1 ALS model

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.

Automated summary

Neuroinflammation worsens the development of ALS caused by SOD1 mutation. The mitochondrial damage triggered by ALS leads to the release of mtDNA and RNA:DNA hybrids, activating the IRF3- and IFNAR-dependent IFN-I and interferon-stimulating genes, causing high levels of IFN-I and pro-inflammatory response. Inter-neuronal gap junctions amplify the response through cGAS/DDX41-STING signaling. This highlights the role of a common DNA sensing pathway between SOD1 and TDP-43 in ALS progression.