title: Activation of the IkappaB kinase complex and nuclear factor-kappaB contributes to mutant huntingtin neurotoxicity.
abstract: Transcriptional dysregulation by mutant huntingtin (Htt) protein has been implicated in the pathogenesis of Huntington's disease (HD). We find that cultured cells expressing mutant Htt and striatal cells from HD transgenic mice have elevated nuclear factor-kappaB (NF-kappaB) activity. Furthermore, NF-kappaB is concentrated in the nucleus of neurons in the brains of HD transgenic mice. In inducible PC12 cells and in HD transgenic mice, mutant Htt activates the IkappaB kinase complex (IKK), a key regulator of NF-kappaB. Activation of IKK is likely mediated by direct interaction with mutant Htt, because the expanded polyglutamine stretch and adjacent proline-rich motifs in mutant Htt interact with IKKgamma, a regulatory subunit of IKK. Activation of IKK may also influence the toxicity of mutant Htt, because expression of IKKgamma promotes aggregation and nuclear localization of mutant Htt exon-1. Moreover, in acute striatal slice cultures, inhibition of IKK activity with an N-terminally truncated form of IKKgamma blocks mutant Htt-induced toxicity in medium-sized spiny neurons (MSNs). In addition, blocking degradation of NF-kappaB inhibitors with a dominant-negative ubiquitin ligase beta-transducin repeat-containing protein also reduces the toxicity of mutant Htt in MSNs. Therefore, aberrant NF-kappaB activation may contribute to the neurodegeneration induced by mutant Htt.
authors.affiliation: Biology Division, California Institute of Technology, Pasadena, California 91125, USA. khoshnan@caltech.edu
authors.forename: Ali
authors.initials: A
authors.lastname: Khoshnan
authors.forename: Jan
authors.initials: J
authors.lastname: Ko
authors.forename: Erin E
authors.initials: EE
authors.lastname: Watkin
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Paige
authors.forename: Peter H
authors.initials: PH
authors.lastname: Reinhart
authors.forename: Paul H
authors.initials: PH
authors.lastname: Patterson
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D019470:Biolistics; D002460:Cell Line; D002461:Cell Line, Transformed; D003342:Corpus Striatum / Q000166:cytology; D004789:Enzyme Activation; D005091:Exons / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D017930:Genes, Reporter; D006801:Humans; D000071058:Huntingtin Protein; D051550:I-kappa B Kinase; D007375:Interleukin-1 / Q000494:pharmacology; D007668:Kidney; D051379:Mice; D008822:Mice, Transgenic; D018598:Minisatellite Repeats; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D016716:PC12 Cells; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000502:physiology
chemical_list: C086055:HTT protein, human; C506812:Htt protein, mouse; C499524:Htt protein, rat; D000071058:Huntingtin Protein; D007375:Interleukin-1; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse