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The Journal of Neuroscience, September 15, 2004, 24(37):7999-8008; doi:10.1523/JNEUROSCI.2675-04.2004

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Neurobiology of Disease
Activation of the IB Kinase Complex and Nuclear Factor-B Contributes to Mutant Huntingtin Neurotoxicity

Ali Khoshnan,¹ Jan Ko,¹ Erin E. Watkin,¹ Lisa A. Paige,² Peter H. Reinhart,² and Paul H. Patterson¹

¹Biology Division, California Institute of Technology, Pasadena, California 91125, and ²Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27710

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

Key words: Huntington's disease; IKK; polyproline; striatum; polyQ; intrabody

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Received March 25, 2004; revised July 30, 2004; accepted July 31, 2004.

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