22 Mar 2001

The abnormal form of the protein huntingtin may exert its toxic effects on neurons in Huntington's disease by interfering with a protein essential for gene transcription, according to a study published in this week's issue of Science. Researchers at Johns Hopkins University and their collaborators at Niigata University in Japan were intrigued by evidence that CREB binding protein (CBP) was found inside the aggregates of mutant huntingtin that collect in the neurons of Huntington's disease patients. CREB-mediated transcripton-and CBP in particular-promote the survival of mature cells. In the present study, they found that the sequestering of CBP by the abnormal huntingtin depletes the protein from its usual location in the nucleus. This was the case in an HD cell culture model, in HD transgenic mice, and in human HD postmortem brain. The researchers further showed that it is specifically the polyglutamine repeats in abnormal huntingtin that interfere with CBP-activated gene transcription and that the resultant cell toxicity can be reversed if CBP is overexpressed in the cells. (Overexpression of CBP also rescued cells from atrophin-1 toxicity. Similar to huntingtin, polyglutamine repeats in this protein lead to a rare neurodegenerative disorder.)

In the model that these results suggest, write the authors, "it is not the [huntingtin] inclusions or aggregations that are directly toxic, but rather the indirect effect on other proteins such as CBP." Obviously, this interaction between abnormal huntingtin and other proteins represents a potential therapeutic target.—Hakon Heimer