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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 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.

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Figure 1: Progression of disease in R6/2 mice is mediated by a caspase-1-dominant-negative-sensitive pathway.
Figure 2: zVAD-fmk delays progression and mortality in R6/2 mice.
Figure 3: NII and astrogliosis are inhibited in R6/2-NSE M17Z mice.
Figure 4: NSE M17Z inhibits neurotransmitter-receptor loss and cleavage of endogenous huntingtin in R6/2 mice.

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Acknowledgements

We thank E. Signer for advice and support; C. Swap, A. Dunah and W. Hobbs for expert technical assistance; M.MacDonald for providing Huntingtin antibodies; and E. Balodimas for editorial assistance. This work was supported by a grant from the Hereditary Disease Foundation (to R.M.F. and J.H.J.C.), the Huntington's Disease Society of America (to J.-H.J.C.), the Glendorn Foundation (to A.B.Y.) and by grants from the NIH (to J.-H.J.C., A.B.Y. and J.Y.). This paper is dedicated to J.B.P., who died during the review of this manuscript.

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Correspondence to Robert M. Friedlander.

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Ona, V., Li, M., Vonsattel, J. et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 399, 263–267 (1999). https://doi.org/10.1038/20446

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