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

Expansion of a polyglutamine repeat in huntingtin causes Huntington's disea se (HD). Although full-length huntingtin is predominantly distributed in th e cytoplasm, N-terminal fragments of huntingtin with expanded polyglutamine tracts are able to accumulate in the nucleus and kill neurons through apop totic pathways. Transgenic mice expressing N-terminal mutant huntingtin sho w 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 apopt osis is unclear. Here we report that intranuclear huntingtin induces the ac tivation of caspase-3 and the release of cytochrome c from mitochondria in cultured cells, As a result, cells expressing intranuclear huntingtin under go apoptosis. We show that intranuclear huntingtin increases the expression of caspase-1,which may in turn activate caspase-3 and trigger apoptosis. W e propose that the increased level of caspase-1 induced by intranuclear hun tingtin contributes to HD-associated cell death.