The role of IκB kinase complex in the neurobiology of Huntington's disease

The I kappa B kinase beta (IKK beta) 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. IKK beta may also directly regulate the neurotoxicity of huntingtin (Htt). Activation of IKK beta by DNA damage triggers caspase-dependent cleavage of WT and mutant Hit and enhances the accumulation of oligomeric fragments. Moreover, the N-terminal fragments of mutant Htt (HDx1) directly bind to and activate IKK beta. Thus, the IKK beta-dependent cleavage of full-length mutant Htt and the buildup of HDx1 could form a deleterious feed-forward loop. Elevated IKK beta 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. IKK beta could also influence the phosphorylation of Htt at Ser13 and Ser16, which is linked to HD pathology. IKK beta inhibitors ameliorate the toxicity of mutant Htt in striatal neurons and prevent DNA damage-induced Htt cleavage. Inhibition of IKK beta in the CNS also reduces neuroinflammation and imparts neuroprotection in a chemical model of HD. These findings support an active role for IKK beta 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 IKK beta for HD. Published by Elsevier Inc.