摘要：SummaryNeuroinflammation exacerbates the progression of SOD1-driven amyotrophic lateral sclerosis (ALS), although the underlying mechanisms remain largely unknown. Herein, we demonstrate that misfolded SOD1 (SOD1Mut)-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-SOD1Mutwere sufficiently robust to cause a strong physiological outcomein vitroandin 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.Graphical abstractDisplay OmittedHighlights•Constitutive basal activation of IFN-I was found in the SOD1-ALS animal model•SOD1-ALS damaged mitochondria to release mtDNA and RNA:DNA to activate the STING-pathway•Blocking cGAS and STING diminishes neurodegenerationin vivoin the SOD1-ALS model•Connexin and pannexin channels are required to propagate neuroinflammation in SOD1-ALSPathophysiology; Neuroscience; Immunology
