title: Malonate and 3-nitropropionic acid neurotoxicity are reduced in transgenic mice expressing a caspase-1 dominant-negative mutant.
abstract: 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.
authors.affiliation: Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, USA.
authors.forename: O A
authors.initials: OA
authors.lastname: Andreassen
authors.forename: R J
authors.initials: RJ
authors.lastname: Ferrante
authors.forename: D B
authors.initials: DB
authors.lastname: Hughes
authors.forename: P
authors.initials: P
authors.lastname: Klivenyi
authors.forename: A
authors.initials: A
authors.lastname: Dedeoglu
authors.forename: V O
authors.initials: VO
authors.lastname: Ona
authors.forename: R M
authors.initials: RM
authors.lastname: Friedlander
authors.forename: M F
authors.initials: MF
authors.lastname: Beal
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D020170:Caspase 1 / Q000235:genetics* / Q000378:metabolism*; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D006816:Huntington Disease / Q000378:metabolism; D008297:Male; D008314:Malonates / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017072:Neostriatum / Q000187:drug effects / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D009574:Nitro Compounds; D017354:Point Mutation; D011422:Propionates / Q000633:toxicity*
chemical_list: D008314:Malonates; D009498:Neurotoxins; D009574:Nitro Compounds; D011422:Propionates; C030290:malonic acid; D020170:Caspase 1; C015392:3-nitropropionic acid