Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model

Mutations in the copper/zinc superoxide dismutase (SOD1) gene produce an an imal model of familiar amyotrophic Lateral sclerosis (ALS), a fatal neurode generative disorder., To test a new therapeutic strategy for ALS, we examin ed the effect of caspase inhibition in transgenic mice expressing mutant hu man SOD1 with a substitution of glycine to alanine in position 93 (mSOD1(G9 3A)). Intracerebroventricular administration of zVAD-fmk, a broad caspase i nhibitor. delays disease onset and mortality. Moreover, zVAD-fmk inhibits c aspase-1 activity as well as caspase-1 and caspase-3 mRNA up-regulation, pr oviding evidence for a non-cell-autonomous pathway regulating caspase expre ssion. Caspases play an instrumental role in neurodegeneration in transgeni c mSOD1(G93A) mice, which suggests that caspase inhibition may have a prote ctive role in ALS.