Mutant superoxide dismutase 1-induced IL-1beta 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-1beta 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-1beta correlated with amyloid-like misfolding and was independent of dismutase activity. Deficiency in caspase-1 or IL-1beta 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-1beta as a causative event of neuroinflammation and suggest IL-1 as a potential therapeutic target in ALS.
Meissner
Felix
F
Department of Cellular Microbiology, Max Planck Institute for Infection Biology, 10117 Berlin, Germany.
Molawi
Kaaweh
K
Zychlinsky
Arturo
A
D019943:Amino Acid Substitution / Q000235:genetics; D000682:Amyloid / Q000737:chemistry; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology*; D000818:Animals; D001343:Autophagy; D020170:Caspase 1 / Q000378:metabolism; D003593:Cytoplasm / Q000201:enzymology; D018450:Disease Progression; D004789:Enzyme Activation; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000201:enzymology; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D017510:Protein Folding; D013482:Superoxide Dismutase / Q000737:chemistry / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
D000682:Amyloid; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D050505:Mutant Proteins; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D020170:Caspase 1