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Malonate and 3‐Nitropropionic Acid Neurotoxicity Are Reduced in Transgenic Mice Expressing a Caspase‐1 Dominant‐Negative Mutant
Author(s) -
Andreassen Ole A,
Ferrante Robert J,
Hughes Duncan B,
Klivenyi Peter,
Dedeoglu Alpaslan,
Ona Victor O,
Friedlander Robert M,
Beal M Flint
Publication year - 2000
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2000.0750847.x
Subject(s) - malonate , neurotoxin , neurotoxicity , genetically modified mouse , transgene , mutant , caspase , biology , apoptosis , caspase 3 , toxicity , programmed cell death , pharmacology , chemistry , microbiology and biotechnology , medicine , biochemistry , gene
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.