Letters to Nature
Nature 399, 263-267 (20 May 1999) | doi:10.1038/20446; Received 22 February 1999; Accepted 14 April 1999
Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease
Victor O. Ona1, Mingwei Li1, Jean Paul G. Vonsattel2, L. John Andrews1, Sohail Q. Khan1, Woosik M. Chung3, Ariel S. Frey3, Anil S. Menon3, Xiao-Jiang Li4, Philip E. Stieg1, Junying Yuan5, John B. Penney3, Anne B. Young3, Jang-Ho J. Cha3 & Robert M. Friedlander1
- Neurosurgical Service, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
- Department of Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
- Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA
- Department of Genetics, Emory University School of Medicine, Atlanta, Georgia 30322 , USA
- Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115 , USA
Correspondence to: Robert M. Friedlander1 Correspondence and requests for materials should be addressed to R.M.F. (e-mail: Email: rfriedlander@rics.bwh.harvard.edu).
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.
