This paper describes data supporting one of the major hypotheses for the pathogenesis of Huntington’s disease (HD). HD and other polyglutamine expansion diseases have become very active areas of research, in part because they are providing powerful biochemical, cellular, and in vivo models for neuronal degeneration. Our paper also has implications for other neurodegenrative diseases with protein aggregation and inclusion bodies, such as Parkinson’s disease and Alzheimer’s disease, suggesting that aggregates of the disease protein are not directly toxic, but can provide a downstream marker of other pathogenic events, such as redistribution of critical proteins.

It provides evidence for a plausible mechanism of how the mutant HD protein causes cell dysfunction and death, leading to HD. The paper demonstrates how aberrant polyglutamine interactions can interfere with gene transcription.

There were two recent hypotheses driving the experiments. First was the observation made in our own lab, as well as several others, that nuclear processes seemed critical for cell death caused by mutant polyglutamine proteins. Second was the proposal by Max Perutz that polygluatmine pathogenesis could be caused by aberrant beta sheet interactions between the expanded polyglumine stretch in the disease protein and short stretches of polyglutamine normally present in other proteins within cells. We were searching for candidate nuclear proteins that were involved in cellular survival and could interact with the abnormal HD protein.

Research at the time indicated that Creb binding protein (CBP), a transcriptional co-activator critical for cell survival, could undergo polyglutamine interactions with the mutant huntingtin protein. These suggestions were made by David Housman’s laboratory, Kurt Fischbeck’s laboratory, and others. Therefore, we pursued the hypothesis that an abnormal interaction between the mutant HD protein and CBP would interfere with CBP mediated transcription, leading to cell death.

Our paper demonstrates one mechanism by which the mutant HD protein can cause neuronal cell dysfunction and death, and thus lead to the symptoms of HD. We found that the mutant HD protein can have abnormal interactions with another protein, called CBP, which is normally needed for neuronal cell survival. We gathered evidence that this abnormal interaction might be toxic, using cell models, a transgenic mouse model, and postmortem brain samples from patients who had died of HD. Our result helps clarify the biology of the disease and provides a possible therapeutic target.

Frederick C. Nucifora Jr., Ph.D., M.H.S.
Division of Neurobiology, 
Department of Psychiatry and Behavioral Science
Johns Hopkins University School of Medicine,
Baltimore, MD 21205