IKKβ Linked to Huntington’s Disease

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George HuntingtonThe neurodegenerative disorder, Huntington’s Disease (HD, Huntington’s Chorea), is caused by mutations in the gene for the protein Huntingtin (Htt). Mutant Htt (mHtt) results when the number of trinucleotide repeats, in this case the CAG sequence encoding glutamine, exceeds a threshold value. Typically, HD affects patients when the number of repeats is greater than 35.

Although the mechanisms by which mHtt causes the disease are poorly understood, proteolysis of the mutant protein is key and neurotoxicity is attributed to the cleaved N-terminal fragments of mHtt. Scientists at the California Institute of Technology and the Wallenberg Neuroscience Center, Lund, Sweden have now reported that the pro-inflammatory kinase, IKKβ , can regulate mHtt proteolysis in response to neuronal DNA damage.

The team demonstrated that DNA damage in neurons induced by etoposide or γ-irradiation results in cleavage of both wild-type and mutant Htt and that the proteolysis requires IKKβ. Elevation of IKKα, inhibition of IKKβ expression or inhibition of IKKβ catalytic activity all suppressed proteolysis and increased neuronal resistance to DNA damage.

Since elevated neuronal DNA damage is observed in HD patients and animal models of HD, inhibition of IKKβ activity may represent a treatment option for the disease. The study is published in the journal PLoS one.

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