Functional Role of Caspase-1 and Caspase-3 in an ALS Transgenic Mouse Model
2000; American Association for the Advancement of Science; Volume: 288; Issue: 5464 Linguagem: Inglês
10.1126/science.288.5464.335
ISSN1095-9203
AutoresMingwei Li, Victor Ona, Christelle Guégan, Minghua Chen, Vernice Jackson‐Lewis, L. John Andrews, Adam J. Olszewski, Philip E. Stieg, Jean-Pyo. Lee, Serge Przedborski, Robert M. Friedlander,
Tópico(s)Prion Diseases and Protein Misfolding
ResumoMutations 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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