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

Nature. 1999 May 20;399(6733):263-7. doi: 10.1038/20446.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Brain / enzymology
  • Caspase 1 / genetics
  • Caspase Inhibitors*
  • Disease Progression
  • Enzyme Activation
  • Enzyme Inhibitors / therapeutic use*
  • Female
  • Huntingtin Protein
  • Huntington Disease / drug therapy
  • Huntington Disease / enzymology*
  • Huntington Disease / genetics
  • Huntington Disease / pathology
  • Injections, Intraventricular
  • Interleukin-1 / metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins / metabolism
  • Weight Loss


  • Caspase Inhibitors
  • Enzyme Inhibitors
  • Htt protein, mouse
  • Huntingtin Protein
  • Interleukin-1
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Caspase 1