Caspase-1 is activated in neural cells and tissue with amyotrophic lateralsclerosis-associated mutations in copper-zinc superoxide dismutase

The mechanism by which mutations in the superoxide dismutase (SOD1) gene ca use motor neuron degeneration in familial amyotrophic lateral sclerosis (AL S) is unknown. Recent reports that neuronal death in SOD1-familial ALS is a poptotic have not documented activation of cell death genes. We present evi dence that the enzyme caspase-1 is activated in neurons expressing mutant S OD1 protein. Proteolytic processing characteristic of caspase-1 activation is seen both in spinal cords of transgenic ALS mice and neurally differenti ated neuroblastoma (line N2a) cells with SOD1 mutations. This activation of caspase-1 is enhanced by oxidative challenge (xanthine/xanthine oxidase),w hich triggers cleavage and secretion of the interleukin 1 beta converting e nzyme substrate, pro-interleukin 1 beta, and induces apoptosis. This N2a cu lture system should be an instructive irt vitro model for further investiga tion of the proapoptotic properties of mutant SOD1.