Activation of the IκB Kinase Complex and Nuclear Factor-κB Contributes to Mutant Huntingtin Neurotoxicity
| Autor: | Ali Khoshnan, Lisa A. Paige, Peter H. Reinhart, Jan Ko, Erin E. Watkin, Paul H. Patterson |
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| Rok vydání: | 2004 |
| Předmět: |
Huntingtin
Amino Acid Motifs Mutant Minisatellite Repeats IκB kinase Kidney PC12 Cells Rats Sprague-Dawley Mice Genes Reporter Protein Interaction Mapping Phosphorylation Cell Line Transformed Huntingtin Protein biology Kinase General Neuroscience Neurodegeneration NF-kappa B Nuclear Proteins Exons I-kappa B Kinase Ubiquitin ligase Protein Binding Genetically modified mouse congenital hereditary and neonatal diseases and abnormalities Recombinant Fusion Proteins Ubiquitin-Protein Ligases Mice Transgenic Nerve Tissue Proteins Protein Serine-Threonine Kinases Transfection Cell Line Neurobiology of Disease mental disorders medicine Animals Humans Biolistics medicine.disease Molecular biology Corpus Striatum Rats nervous system diseases Enzyme Activation Gene Expression Regulation nervous system Nerve Degeneration biology.protein Protein Processing Post-Translational Nuclear localization sequence Interleukin-1 |
| Zdroj: | The Journal of Neuroscience. 24:7999-8008 |
| ISSN: | 1529-2401 0270-6474 |
| DOI: | 10.1523/jneurosci.2675-04.2004 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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