Malonate and 3‐Nitropropionic Acid Neurotoxicity Are Reduced in Transgenic Mice Expressing a Caspase‐1 Dominant‐Negative Mutant

• Published in: Journal of neurochemistry 2000-08, Vol.75 (2), p.847-852
• Main Authors: Andreassen, Ole A, Ferrante, Robert J, Hughes, Duncan B, Klivenyi, Peter, Dedeoglu, Alpaslan, Ona, Victor O, Friedlander, Robert M, Beal, M Flint
• Format: Article
• Language: English
• Subjects: 3-nitropropionic acid; Animals; Apoptosis; Biological and medical sciences; Brain - drug effects; Brain - enzymology; Brain - pathology; Caspase 1 - genetics; Caspase 1 - metabolism; caspase-1; Caspases; Crosses, Genetic; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Female; Huntington Disease - metabolism; Huntington's disease; Male; Malonates - toxicity; malonic acid; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Neostriatum - drug effects; Neostriatum - pathology; Neurology; Neurotoxins - toxicity; Nitro Compounds; Point Mutation; Propionates - toxicity
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2000.0750847.x

Increasing evidence implicates caspase‐1‐mediated cell death as a major mechanism of neuronal death in neurodegenerative diseases. In the present study we investigated the role of caspase‐1 in neurotoxic experimental animal models of Huntington's disease (HD) by examining whether transgenic mice expressing a caspase‐1 dominant‐negative mutant are resistant to malonate and 3‐nitropropionic acid (3‐NP) neurotoxicity. Intrastriatal injection of malonate resulted in significantly smaller striatal lesions in mutant caspase‐1 mice than those observed in littermate control mice. Caspase‐1 was significantly 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 smaller within mutant caspase‐1 mice than in littermate control mice. These results provide further evidence of a functional role for caspase‐1 in both malonate‐ and 3‐NP‐mediated neurotoxin models of HD.