Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model |
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| Authors: | Li M Ona V O Guégan C Chen M Jackson-Lewis V Andrews L J Olszewski A J Stieg P E Lee J P Przedborski S Friedlander R M |
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| Institution: | Neuroapoptosis Laboratory and Neurosurgical Service, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. |
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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 (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. |
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