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Human Molecular Genetics, 2000, Vol. 9, No. 19 2859-2867
© 2000 Oxford University Press

Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis

Shi-Hua Li, Suzanne Lam, Anna L. Cheng and Xiao-Jiang Li+

Department of Genetics, Emory University School of Medicine, 1462 Clifton Road NE, Atlanta, GA 30322, USA

Expansion of a polyglutamine repeat in huntingtin causes Huntington’s disease (HD). Although full-length huntingtin is predominantly distributed in the cytoplasm, N-terminal fragments of huntingtin with expanded polyglutamine tracts are able to accumulate in the nucleus and kill neurons through apoptotic pathways. Transgenic mice expressing N-terminal mutant huntingtin show intranuclear huntingtin accumulation and develop progressive neurological symptoms. Inhibiting caspase-1 can prolong the survival of these HD mice. How intranuclear huntingtin is associated with caspase activation and apoptosis is unclear. Here we report that intranuclear huntingtin induces the activation of caspase-3 and the release of cytochrome c from mitochondria in cultured cells. As a result, cells expressing intranuclear huntingtin undergo apoptosis. We show that intranuclear huntingtin increases the expression of caspase-1, which may in turn activate caspase-3 and trigger apoptosis. We propose that the increased level of caspase-1 induced by intranuclear huntingtin contributes to HD-associated cell death.

+ To whom correspondence should be addressed. Tel: +1 404 727 3290; Fax: +1 404 727 3949; Email: xiaoli@genetics.emory.edu


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