HD research news - medical research into treatment & prevention

Progress report from Dr. Peggy Shelbourne

January 2005

The Glasgow lab is currently investigating the pathological processes responsible for the symptoms of Huntington's disease, with a view to identifying new opportunities for developing effective treatments for the disorder. They are concentrating their efforts on identifying molecular changes that occur early in the disease process, and in particular, trying to understand how the genetic fault triggers the chain of events that results in nerve cell loss and why this pathological cascade occurs in certain cell types and not others.

HD is caused by an increase of CAG repeats in the gene that produces a protein called huntingtin. (Editors note: CAG codes for a part of the gene which is translated into the chemical glutamine in the protein. The scientific shorthand for glutamine is Q. This term was used in the article above. It is confusing but extra CAG refers to the gene and extra Q refers to the protein.) The number of CAG repeats carried by an individual with HD influences 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 get worse as the CAG repeat number gets bigger.

One puzzling feature of HD is that faulty huntingtin protein is present in every cell of the body, yet 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 HD, the scientists wondered whether the CAG number also varies within the cells of someone affected by the disease. Using a mouse model of HD, the researchers found that the CAG repeat numbers do tend to get bigger over time in a variety of tissues and that the largest size increases occurred in regions of the brain containing the vulnerable nerve cells. Very similar patterns of CAG repeat number variability are observed in autopsy brain material from human HD cases and further studies have indicated that CAG repeat numbers probably start getting bigger quite early in the disease course.

If nerve cells that die in the disease have more CAG repeats than the other cells, an accelerated activation of pathological events may help explain why they are selectively vulnerable to the disease. For this reason scientists are interested in understanding the process by which CAG repeat numbers in nerve cells can get bigger over time.

One possibility being tested by the Glasgow lab is that very reactive molecules called free radicals may be involved. HD mice are being used to see whether reducing levels of free radicals in the brain by administering high doses of anti-oxidants, such as vitamin E in the diet, will slow down the rate at which CAG repeats in nerve cells get bigger. If this is the case and there is a corresponding delay in the symptoms shown by the mice, the findings will represent a very important step towards the ultimate goal of developing an effective treatment that slows down or prevents the molecular changes responsible for HD symptoms.