title: The role of IκB kinase complex in the neurobiology of Huntington's disease.
abstract: The IκB kinase β (IKKβ) is a prominent regulator of neuroinflammation, which is implicated in the pathogenesis of Huntington's disease (HD). Inflammatory mediators accumulate in the serum and CNS of premanifest and manifest HD patients, and cytokine levels correlate with disease progression. IKKβ may also directly regulate the neurotoxicity of huntingtin (Htt). Activation of IKKβ by DNA damage triggers caspase-dependent cleavage of WT and mutant Htt and enhances the accumulation of oligomeric fragments. Moreover, the N-terminal fragments of mutant Htt (HDx1) directly bind to and activate IKKβ. Thus, the IKKβ-dependent cleavage of full-length mutant Htt and the buildup of HDx1 could form a deleterious feed-forward loop. Elevated IKKβ activity is present throughout the CNS in a symptomatic mouse model of HD expressing HDx1, whereas in asymptomatic mice with full-length mutant Htt, it is confined to the striatum. IKKβ could also influence the phosphorylation of Htt at Ser13 and Ser16, which is linked to HD pathology. IKKβ inhibitors ameliorate the toxicity of mutant Htt in striatal neurons and prevent DNA damage-induced Htt cleavage. Inhibition of IKKβ in the CNS also reduces neuroinflammation and imparts neuroprotection in a chemical model of HD. These findings support an active role for IKKβ in HD pathogenesis and represent an example of how gene-environment (exemplified by DNA damage and inflammation) interactions can influence Htt neurotoxicity. We will summarize these findings and describe the therapeutic potentials of IKKβ for HD.
authors.affiliation: Biology Division, 216-76, California Institute of Technology, Pasadena CA 91125, USA. Khoshnan@caltech.edu
authors.forename: Ali
authors.initials: A
authors.lastname: Khoshnan
authors.forename: Paul H
authors.initials: PH
authors.lastname: Patterson
mesh_terms: D000818:Animals; D018450:Disease Progression; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051550:I-kappa B Kinase / Q000502:physiology*; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology
chemical_list: D018836:Inflammation Mediators; D051550:I-kappa B Kinase