Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease.
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.
Ona
V O
VO
Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Li
M
M
Vonsattel
J P
JP
Andrews
L J
LJ
Khan
S Q
SQ
Chung
W M
WM
Frey
A S
AS
Menon
A S
AS
Li
X J
XJ
Stieg
P E
PE
Yuan
J
J
Penney
J B
JB
Young
A B
AB
Cha
J H
JH
Friedlander
R M
RM
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
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