Malonate and 3-nitropropionic acid neurotoxicity are reduced in transgenicmice expressing a caspase-1 dominant-negative mutant

Increasing evidence implicates caspase-1-mediated cell death as a major mec hanism of neuronal death in neurodegenerative diseases. In the present stud y we investigated the role of caspase-1 in neurotoxic experimental animal m odels of Huntington's disease (HD) by examining whether transgenic mice exp ressing a caspase-1 dominant-negative mutant are resistant to malonate and 3-nitropropionic acid (3-NP) neurotoxicity. Intrastriatal injection of malo nate resulted in significantly smaller striatal lesions in mutant caspase-1 mice than those observed in littermate control mice. Caspase-1 was signifi cantly activated following malonate intrastriatal administration in control mice but significantly attenuated in mutant caspase-1 mice. Systemic 3-NP treatment induced selective striatal lesions that were significantly smalle r within mutant caspase-1 mice than in littermate control mice. These resul ts provide further evidence of a functional role for caspase-1 in both malo nate- and 3-NP-mediated neurotoxin models of HD.