Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model
M Li, VO Ona, C Guegan, M Chen, V Jackson-Lewis… - Science, 2000 - science.org
M Li, VO Ona, C Guegan, M Chen, V Jackson-Lewis, LJ Andrews, AJ Olszewski, PE Stieg…
Science, 2000•science.orgMutations 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 …
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 …
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.
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