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

• Published in: Human molecular genetics 2000-11, Vol.9 (19), p.2859-2867
• Main Authors: LI, Shi-Hua, LAM, Suzanne, CHENG, Anna L, LI, Xiao-Jiang
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biological and medical sciences; Caspase 1 - genetics; Caspase 1 - metabolism; Caspases - metabolism; Cell Line; Cell Nucleus - metabolism; Cytochrome c Group - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA Fragmentation; Enzyme Activation; Fluorescent Antibody Technique; Gene Expression Regulation, Enzymologic; Humans; Huntingtin Protein; Huntington Disease - enzymology; Huntington Disease - metabolism; Medical sciences; Mitochondria - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oxidative Stress; PC12 Cells; Peptides - genetics; Rats; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transfection; Trinucleotide Repeat Expansion - genetics; Up-Regulation
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/9.19.2859

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.