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 striat um and cortex(1). The disease is universally fatal, with a mean survival fo llowing onset of 15-20 years and, at present, there is no effective treatme nt. The mutation in patients with Huntington's disease is an expanded CAG/p olyglutamine repeat in huntingtin, a protein of unknown function with a rel ative molecular mass of 350,000 (M-r 350K)(2). The length of the CAG/polygl utamine repeat is inversely correlated with the age of disease onset. The m olecular pathways mediating the neuropathology of Huntington's disease are poorly understood. Transgenic mice expressing exon 1 of the human huntingti n gene with an expanded CAG/polyglutamine repeat develop a progressive synd rome with many of the characteristics of human Huntington's disease(3). Her e 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 di sease, 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 intrac erebroventricular administration of a caspase inhibitor delays disease prog ression and mortality in the mouse model of Huntington's disease.