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

• DOI: 10.1523/jneurosci.2675-04.2004
• Publication Date: 2004-09-15T19:22:48Z
• Authors: Ali Khoshnan; Jan Ko; Erin E. Watkin; Lisa A. Paige; Peter H. Reinhart; Paul H. Patterson
• Keywords: IκB kinase

Transcriptional dysregulation by mutant huntingtin (Htt) protein has been implicated in the pathogenesis of Huntington's disease (HD). We find that cultured cells expressing Htt and striatal from HD transgenic mice have elevated nuclear factor-κB (NF-κB) activity. Furthermore, NF-κB is concentrated nucleus neurons brains mice. In inducible PC12 mice, activates IκB kinase complex (IKK), a key regulator NF-κB. Activation IKK likely mediated direct interaction with Htt, because expanded polyglutamine stretch adjacent proline-rich motifs interact IKKγ, regulatory subunit IKK. may also influence toxicity expression IKKγ promotes aggregation localization exon-1. Moreover, acute slice cultures, inhibition activity an N-terminally truncated form blocks Htt-induced medium-sized spiny (MSNs). addition, blocking degradation inhibitors dominant-negative ubiquitin ligase β-transducin repeat-containing reduces MSNs. Therefore, aberrant activation contribute to neurodegeneration induced Htt.