Huntington's disease is caused by an expanded polyglutamine repeat in the protein Huntingtin (Htt), which causes the protein to aggregate and damage neurons. Ubiquitination and SUMOylation of Htt's N-terminal domain affect the protein's stability and toxicity, but other post-translational modifications in this region of the protein might be important as well.

Thompson et al. discovered that the inflammatory kinase IKK phosphorylates Htt, altering the complex pattern of SUMOylation, ubiquitination, and acetylation on neighboring lysine residues. The net result was to promote Htt's degradation by both the proteasome and lysosomes. Lysosome-mediated degradation of Htt was blocked by knocking down the autophagy proteins LAMP-2A and Atg7. Compared to wild type, mutant Htt with an expanded polyglutamine stretch was degraded inefficiently, but a version that mimicked IKK phosphorylation with negatively charged aspartate residues was still less toxic to neuronal slice cultures.

But there may be a darker side to IKK phosphorylation -- it also targets Htt to the nucleus where, says senior author Joan Steffan, a particularly toxic fragment that enhances neurodegeneration may accumulate. IKK may thus be involved in both clearing Htt and in generating a more dangerous version of the protein. The latter pathway would predominate in older patients because proteasome and lysosome function declines with age. Therapies aimed at IKK might need to either enhance or block the kinase's function, depending on the patient's age and stage of disease.

Journal reference: Thompson, L.M., et al. 2009. J. Cell Biol. doi:10.1083/jcb.200909067.

Note: If no author is given, the source is cited instead.

• Healthy Aging
• Nervous System
• Human Biology
• Sickle Cell Anemia
• Alzheimer's Research
• Parkinson's Research

• Huntington's disease
• Protein biosynthesis
• Amyloid
• Vitamin K
• Dementia with Lewy bodies
• Protein structure