Mutant superoxide dismutase 1-induced IL-1β accelerates ALS pathogenesis

ALS is a fatal motor neuron disease of adult onset. Neuroinflammation contributes to ALS disease progression; however, the inflammatory trigger remains unclear. We report that ALS-linked mutant superoxide dismutase 1 (SOD1) activates caspase-1 and IL-1 beta in microglia. Cytoplasmic accumulation of mutant SOD1 was sensed by an ASC containing inflammasome and antagonized by autophagy, limiting caspase-1-mediated inflammation. Notably, mutant SOD1 induced IL-1 beta correlated with amyloid-like misfolding and was independent of dismutase activity. Deficiency in caspase-1 or IL-1 beta or treatment with recombinant IL-1 receptor antagonist (IL-1RA) extended the lifespan of G93A-SOD1 transgenic mice and attenuated inflammatory pathology. These findings identify microglial IL-1 beta as a causative event of neuroinflammation and suggest IL-1 as a potential therapeutic target in ALS.