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

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Science  14 Apr 2000:
Vol. 288, Issue 5464, pp. 335-339
DOI: 10.1126/science.288.5464.335

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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 (mSOD1G93A). 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 mSOD1G93A mice, which suggests that caspase inhibition may have a protective role in ALS.

  • * To whom correspondence should be addressed. E-mail: rfriedlander{at}rics.bwh.harvard.edu

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