HD research news - medical research into treatment & prevention

Dramatic mutation Instability in Huntington's disease

This is a summary of a manuscript accepted for publication in the October issue of Human Molecular Genetics

Kennedy L. and Shelbourne P. F. (2000)

Huntington’s disease (HD) is caused by the increase of CAG repeats in a gene that encodes a protein called huntingtin. The discovery of this faulty gene has allowed scientists to start investigating the chain of events that leads to the symptoms and pathology associated with the disease.

The number of CAG repeats carried by an individual affected by HD appears to influence certain characteristics of their clinical picture including the age at which symptoms first occur. Larger numbers of CAG repeats are typically associated with earlier symptoms, suggesting that the detrimental effects of the faulty gene are somehow enhanced by increasing CAG repeat numbers.

One puzzling feature of HD is that whilst the faulty huntingtin protein is present in every cell of the body, only a relatively small number of nerve cells in the brain are vulnerable to the disease process and die. Because the CAG repeat size can vary between individuals with the disease, we wondered whether the CAG number can also vary within the cells of someone affected by the disease. If nerve cells that die in the disease have more CAG repeats than the other cells in the body, this may help explain the selective nature of HD pathology.

In order to test this hypothesis, we have turned to a mouse model of HD. These mice have been genetically engineered to carry a faulty HD gene containing an extended stretch of 70-80 CAG repeats and show changes that are reminiscent of early symptoms of the human disease. A technique called small-pool PCR was used to measure the number of CAG repeats in cells from different tissues of these mice and we have found some intriguing results.

In old mice the CAG repeat numbers do appear to vary from tissue to tissue, with the largest size increases occurring in the region of the brain that contains the vulnerable nerve cells. However, similar studies of young animals show that all cells in the body start off with the same number of CAG repeats, indicating that the faulty gene in these vulnerable nerve cells progressively accumulates CAG repeats with age. Our future work will be aimed at determining what actually causes the CAG repeats to increase with age as well as more precisely defining the cellular consequences of such expansions.

Hopefully a better understanding of these processes in the future might permit the development of therapeutic strategies that slow down or prevent the molecular changes responsible for HD symptoms.