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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by the progressive loss of motor neurons, leading to paralysis and death from respiratory failure. The most common inherited cause of ALS involves dominant gain-of-function mutations in superoxide dismutase 1 (SOD1). Neurodegeneration in ALS is associated with significant inflammation in the spinal cord and cortex, although the cause of this neuroinflammation remains unclear. This study reveals that mutant SOD1 activates caspase-1 in microglia, leading to the maturation of interleukin (IL)-1ß. The level of mature IL-1ß produced correlates with the amyloid-forming propensity of various SOD1 mutants, independent of their enzymatic activity. Misfolded SOD1 is recognized by an ASC-containing inflammasome after being phagocytosed. The activation of caspase-1 by mutant SOD1 requires cathepsin B, while autophagy helps limit the accumulation of cytoplasmic SOD1, thereby reducing IL-1ß release. In vivo studies using G93A SOD1 transgenic mice showed that deficiencies in caspase-1 or IL-1ß extended lifespan and reduced inflammatory pathology. Additionally, treatment with recombinant IL-1 receptor antagonist (IL-1RA) prolonged survival. These findings suggest that microglial caspase-1-dependent IL-1ß maturation, induced by mutant SOD1, is a key factor in ALS-related neuroinflammation, positioning IL-1 as a potential therapeutic target.
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The role of caspase-1 and interleukin-1 ß [beta] in amyotrophic lateral sclerosis, Kaaweh Molawi
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- 2009
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