Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease

Victor O. Ona, Mingwei Li, Jean Paul G. Vonsattel, L. John Andrews, Sohail Q. Khan, Woosik M. Chung, Ariel S. Frey, Anil S. Menon, Xiao-Jiang Li, Philip E. Stieg, Junying Yuan, John B. Penney, Anne B. Young, Jang-Ho J. Cha and Robert M. Friedlander ()
Additional contact information
Victor O. Ona: Neurosurgical Service, Brigham and Women's Hospital, Harvard Medical School
Mingwei Li: Neurosurgical Service, Brigham and Women's Hospital, Harvard Medical School
Jean Paul G. Vonsattel: Massachusetts General Hospital, Harvard Medical School
L. John Andrews: Neurosurgical Service, Brigham and Women's Hospital, Harvard Medical School
Sohail Q. Khan: Neurosurgical Service, Brigham and Women's Hospital, Harvard Medical School
Woosik M. Chung: Massachusetts General Hospital, Harvard Medical School
Ariel S. Frey: Massachusetts General Hospital, Harvard Medical School
Anil S. Menon: Massachusetts General Hospital, Harvard Medical School
Xiao-Jiang Li: Emory University School of Medicine
Philip E. Stieg: Neurosurgical Service, Brigham and Women's Hospital, Harvard Medical School
Junying Yuan: Harvard Medical School
John B. Penney: Massachusetts General Hospital, Harvard Medical School
Anne B. Young: Massachusetts General Hospital, Harvard Medical School
Jang-Ho J. Cha: Massachusetts General Hospital, Harvard Medical School
Robert M. Friedlander: Neurosurgical Service, Brigham and Women's Hospital, Harvard Medical School

Nature, 1999, vol. 399, issue 6733, 263-267

Abstract: Abstract Huntington's disease is an autosomal-dominant progressive neurodegenerative disorder resulting in specific neuronal loss and dysfunction in the striatum and cortex1. 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)2. 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 disease3. 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.

Date: 1999
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DOI: 10.1038/20446

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