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

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 mic...

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Bibliographic Details
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
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Summary: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.
ISSN:0022-3042
1471-4159
DOI:10.1046/j.1471-4159.2000.0750847.x