title: Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis.
abstract: 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.
authors.affiliation: Department of Genetics, Emory University School of Medicine, 1462 Clifton Road NE, Atlanta, GA 30322, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Lam
authors.forename: A L
authors.initials: AL
authors.lastname: Cheng
authors.forename: X J
authors.initials: XJ
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D020170:Caspase 1 / Q000235:genetics* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism; D053938:DNA Fragmentation; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000201:enzymology / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D016716:PC12 Cells; D010455:Peptides / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D014162:Transfection; D019680:Trinucleotide Repeat Expansion / Q000235:genetics; D015854:Up-Regulation
chemical_list: D003574:Cytochrome c Group; C086055:HTT protein, human; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D012333:RNA, Messenger; C097188:polyglutamine; D020169:Caspases; D020170:Caspase 1