title: Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease.
abstract: Huntington's disease is an autosomal-dominant progressive neurodegenerative disorder resulting in specific neuronal loss and dysfunction in the striatum and cortex. The disease is universally fatal, with a mean survival following onset of 15-20 years and, at present, there is no effective treatment. The mutation in patients with Huntington's disease is an expanded CAG/polyglutamine repeat in huntingtin, a protein of unknown function with a relative molecular mass of 350,000 (M(r) 350K). The length of the CAG/polyglutamine repeat is inversely correlated with the age of disease onset. The molecular pathways mediating the neuropathology of Huntington's disease are poorly understood. Transgenic mice expressing exon 1 of the human huntingtin gene with an expanded CAG/polyglutamine repeat develop a progressive syndrome with many of the characteristics of human Huntington's disease. Here we demonstrate evidence of caspase-1 activation in the brains of mice and humans with the disease. In this transgenic mouse model of Huntington's disease, expression of a dominant-negative caspase-1 mutant extends survival and delays the appearance of neuronal inclusions, neurotransmitter receptor alterations and onset of symptoms, indicating that caspase-1 is important in the pathogenesis of the disease. In addition, we demonstrate that intracerebroventricular administration of a caspase inhibitor delays disease progression and mortality in the mouse model of Huntington's disease.
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: V O
authors.initials: VO
authors.lastname: Ona
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.forename: J P
authors.initials: JP
authors.lastname: Vonsattel
authors.forename: L J
authors.initials: LJ
authors.lastname: Andrews
authors.forename: S Q
authors.initials: SQ
authors.lastname: Khan
authors.forename: W M
authors.initials: WM
authors.lastname: Chung
authors.forename: A S
authors.initials: AS
authors.lastname: Frey
authors.forename: A S
authors.initials: AS
authors.lastname: Menon
authors.forename: X J
authors.initials: XJ
authors.lastname: Li
authors.forename: P E
authors.initials: PE
authors.lastname: Stieg
authors.forename: J
authors.initials: J
authors.lastname: Yuan
authors.forename: J B
authors.initials: JB
authors.lastname: Penney
authors.forename: A B
authors.initials: AB
authors.lastname: Young
authors.forename: J H
authors.initials: JH
authors.lastname: Cha
authors.forename: R M
authors.initials: RM
authors.lastname: Friedlander
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D020170:Caspase 1 / Q000235:genetics; D061945:Caspase Inhibitors; D018450:Disease Progression; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D007276:Injections, Intraventricular; D007375:Interleukin-1 / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D015431:Weight Loss
chemical_list: D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D007375:Interleukin-1; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020170:Caspase 1