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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.

Pubmed ID: 20616033 RIS Download

Mesh terms: Amino Acid Substitution | Amyloid | Amyotrophic Lateral Sclerosis | Animals | Autophagy | Caspase 1 | Cytoplasm | Disease Progression | Enzyme Activation | Humans | Interleukin 1 Receptor Antagonist Protein | Interleukin-1beta | Mice | Microglia | Mutant Proteins | Protein Conformation | Protein Folding | Superoxide Dismutase | Superoxide Dismutase-1

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