Functional Role of Caspase-1 and Caspase-3 in an ALS Transgenic Mouse Model

TLDR

Mutations in the copper/zinc superoxide dismutase (SOD1) gene generate a transgenic mouse model of familial ALS, and caspases are implicated in neurodegeneration in these mSOD1 G93A mice, suggesting a potential protective role. The study aimed to evaluate whether caspase inhibition could serve as a therapeutic strategy in mSOD1 G93A transgenic mice. The authors administered the broad caspase inhibitor zVAD‑fmk intracerebroventricularly to mSOD1 G93A mice to assess its effects. Intracerebroventricular zVAD‑fmk delayed disease onset and mortality and inhibited caspase‑1 activity and the up‑regulation of caspase‑1 and caspase‑3 mRNA, indicating a non‑cell‑autonomous pathway regulating caspase expression.

Abstract

Mutations in the copper/zinc superoxide dismutase (SOD1) gene produce an animal model of familial amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. To test a new therapeutic strategy for ALS, we examined the effect of caspase inhibition in transgenic mice expressing mutant human SOD1 with a substitution of glycine to alanine in position 93 (mSOD1 G93A ). Intracerebroventricular administration of zVAD-fmk, a broad caspase inhibitor, delays disease onset and mortality. Moreover, zVAD-fmk inhibits caspase-1 activity as well as caspase-1 and caspase-3 mRNA up-regulation, providing evidence for a non–cell-autonomous pathway regulating caspase expression. Caspases play an instrumental role in neurodegeneration in transgenic mSOD1 G93A mice, which suggests that caspase inhibition may have a protective role in ALS.