Huntingtin Protein and Protein Aggregation
Part 5

What Causes the Onset of HD?

Altered Huntingtin and CREB-binding Protein

Recent studies have shown that altered huntingtin can “kidnap” smaller proteins from their usual locations, preventing them from functioning normally within nerve cells. A recent Johns Hopkins University study showed that Htt entangles and inhibits CREB-binding protein (also known as CBP), a smaller regulatory protein that is key for cell survival. CBP has its own tract of 18 glutamines, and these glutamines interact directly with the expanded Htt glutamine chain. Huntingtin aggregates pull CBP away from its normal position alongside the DNA in the nucleus. Live mouse models with altered huntingtin and autopsied brains of patients who have died of HD show very reduced amounts of CBP, suggesting that it has been pulled away from the DNA and sequestered by the altered huntingtin.

Once seized, CBP is out of service. It can no longer accomplish its normal function of activating transcription or “turning on” genes for survival pathways. Fewer proteins are produced, ultimately leading to nerve cell death. However, researchers were able to fully halt and reverse this degenerative process in the laboratory. This reversal was accomplished by inserting an engineered form of CBP that did not have glutamine repeats. Since Htt interacts directly with the CBP’s glutamines, the modified CBP was not recognized by Htt. The modified CBP was not sequestered in huntingtin inclusion bodies, and the nerve cells survived.

In addition, other compounds known as histone-deacetylase inhibitors (HDAC inhibitors) have been shown to compensate for the negative effects of CBP. It has been shown in fruit flies that HDAC inhibitors reduce the lethal effects of the altered huntingtin. These developments indicate potential targets for new drug treatments, but further research is still needed.

Last Modified: 9-13-02

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