IKK may act as both inhibitor and promoter of Huntington's disease

Dec 21, 2009

The kinase IKK phosphorylates the protein mutated in Huntington's disease to promote its removal and neuron survival, but IKK may be a double-edged sword that increases neurotoxicity in later stages of the disease. The study, led by researchers from the University of California, Irvine, will be published online December 21 in the Journal of Cell Biology.

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 on neighboring lysine residues. The net result was to promote Htt's degradation by both the proteasome and . 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 —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 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.

Explore further: Fighting bacteria—with viruses

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

add to favorites email to friend print save as pdf

Related Stories

Study suggests new treatments for Huntington's disease

Jan 09, 2008

Working with fruit flies, researchers have discovered a new mechanism by which the abnormal protein in Huntington’s disease causes neurodegeneration. They have also manipulated the flies to successfully suppress that neurodegeneration, ...

Inflammation May Play Role in Metastasis of Prostate Cancer

Mar 20, 2007

Many would assume that “mounting an immune response” or “having your body fight the cancer” is a good thing. Now, research at the University of California, San Diego (UCSD) School of Medicine strongly suggests that ...

Metabolic disorder underlies Huntington's disease

Oct 19, 2006

A metabolic disorder underlies the brain effects found in those with Huntington's disease, researchers report in an advance article publishing online October 19, 2006. The article will appear in the November 2006 issue of ...

Recommended for you

Fighting bacteria—with viruses

19 hours ago

Research published today in PLOS Pathogens reveals how viruses called bacteriophages destroy the bacterium Clostridium difficile (C. diff), which is becoming a serious problem in hospitals and healthcare institutes, due to its re ...

Atomic structure of key muscle component revealed

19 hours ago

Actin is the most abundant protein in the body, and when you look more closely at its fundamental role in life, it's easy to see why. It is the basis of most movement in the body, and all cells and components ...

Brand new technology detects probiotic organisms in food

Jul 23, 2014

In the food industr, ity is very important to ensure the quality and safety of products consumed by the population to improve their properties and reduce foodborne illness. Therefore, a team of Mexican researchers ...

Protein evolution follows a modular principle

Jul 23, 2014

Proteins impart shape and stability to cells, drive metabolic processes and transmit signals. To perform these manifold tasks, they fold into complex three-dimensional shapes. Scientists at the Max Planck ...

Report on viruses looks beyond disease

Jul 22, 2014

In contrast to their negative reputation as disease causing agents, some viruses can perform crucial biological and evolutionary functions that help to shape the world we live in today, according to a new report by the American ...

User comments : 0