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Activation of the IκB Kinase Complex and Nuclear Factor-κB Contributes to Mutant Huntingtin Neurotoxicity

Khoshnan, Ali and Ko, Jan and Watkin, Erin E. and Paige, Lisa A. and Reinhart, Peter-H. and Patterson, Paul H. (2004) Activation of the IκB Kinase Complex and Nuclear Factor-κB Contributes to Mutant Huntingtin Neurotoxicity. Journal of Neuroscience, 24 (37). pp. 7999-8008. ISSN 0270-6474. PMCID PMC6729796. https://resolver.caltech.edu/CaltechAUTHORS:20160212-085217983

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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-κB (NF-κB) activity. Furthermore, NF-κB 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 IκB kinase complex (IKK), a key regulator of NF-κB. 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 IKKγ, a regulatory subunit of IKK. Activation of IKK may also influence the toxicity of mutant Htt, because expression of IKKγ 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 IKKγ blocks mutant Htt-induced toxicity in medium-sized spiny neurons (MSNs). In addition, blocking degradation of NF-κB inhibitors with a dominant-negative ubiquitin ligase β-transducin repeat-containing protein also reduces the toxicity of mutant Htt in MSNs. Therefore, aberrant NF-κB activation may contribute to the neurodegeneration induced by mutant Htt.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1523/JNEUROSCI.2675-04.2004DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6729796/PubMed CentralArticle
Additional Information:© 2004 Society for Neuroscience. For the first six months after publication SfN’s license will be exclusive. Beginning six months after publication the Work will be made freely available to the public on SfN’s website to copy, distribute, or display under a Creative Commons Attribution 4.0 International (CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/). Received March 25, 2004; revised July 30, 2004; accepted July 31, 2004. Support for this project was provided by the Hereditary Disease Foundation and by a grant (NS045165-01A1) from the National Institute of Neurological Disorders and Stroke awarded to P.H.P and A. K. We thank E. Schweitzer for providing ecdysone inducible PC12 cells, M. McDonald and S. Gines for mouse striatal cells, W. Greene for the GST-IkBɑ construct, E. Zandi for IKKy plasmids, R. Deshaies for ΔF-βTrCP, E. Wanker for GST-HDx1, D. Housman and A. Kazantsev for HDx1–103Q-EGFP, B. Kerr for dissection of brain tissue from HD mice, M. Henson, D. Dunn, and D. Lo for helpful discussions and work with the brain slice experiments, and D. McDowell for administrative assistance.
Funders:
Funding AgencyGrant Number
Hereditary Disease FoundationUNSPECIFIED
NIHNS045165-01A1
Subject Keywords:Huntington’s disease; IKK; polyproline; striatum; polyQ; intrabody
Issue or Number:37
PubMed Central ID:PMC6729796
Record Number:CaltechAUTHORS:20160212-085217983
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160212-085217983
Official Citation:Activation of the IκB Kinase Complex and Nuclear Factor-κB Contributes to Mutant Huntingtin Neurotoxicity Ali Khoshnan, Jan Ko, Erin E. Watkin, Lisa A. Paige, Peter H. Reinhart, and Paul H. Patterson The Journal of Neuroscience, 15 September 2004, 24(37):7999-8008; doi:10.1523/JNEUROSCI.2675-04.2004
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:64455
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:19 Feb 2016 20:59
Last Modified:02 Jul 2020 18:52

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