| Abstract |
Background and aims: Huntington's disease (HD) is an inherited degenerative brain condition in which patients develop a mixture of symptoms including involuntary movements, changes in mood and behaviour, and dementia. The disease progresses slowly but relentlessly over 15-20 years, and is life-shortening. We have no treatments that can prevent or slow it. Patients often have complex care needs over a long period of time and these put a considerable strain on their carers and families, as well as on healthcare resources in general. Although HD is a rare condition (affecting about 1 in 8000 people), it is one of a family of over 30 diseases caused by expansion of repeating sections of DNA in genes. Together these conditions are estimated to affect over 3 million people worldwide (1 in 2000) at considerable human and economic cost. The genetic mutation causing HD was identified in 1993 but it is still unclear exactly how this leads to specific nerve damage and loss in the brain. The mutation consists of expansion of a repeating 'CAG' sequence in the DNA of the huntingtin gene. Unaffected people have between 9 and 35 CAG repeats; HD patients have at least 36, and generally the greater the number of repeats, the earlier the disease starts. The brain nerve cells that are most affected by the disease harbour more repeats than other cells in the same patient. A recent genetic study involving our group and others identified various DNA repair factors as determinants of the age at which HD symptoms start. We think that DNA repair processes might directly cause an increased number (expansion) of CAG repeats in vulnerable cells and lead to cell death and the onset of disease. The aims of this project are to characterise how this process occurs, and to try to identify ways in which it could be blocked. How the project will be carried out: It is difficult to study cellular processes in the brains of living HD patients and so we will use a variety of experimental methods to test our ideas. 1. Genetics. We will look for variants in the DNA repair genes of patients who have developed HD at an unexpectedly early or late age compared to that predicted from their CAG repeat length. We expect that this will identify new variants that will give insight into how and when HD starts. 2. Cell culture. We will develop a model system for testing CAG expansion in nerve cells grown in the laboratory. Once this system is established we will test the effects of the DNA repair variants on CAG expansion. Factors that lead to greatly enhanced repeat expansion could represent novel therapeutic targets: if we can block this process we could theoretically delay disease onset. 3. Biochemistry. To work out exactly how DNA repair proteins interact with CAG repeats in DNA and cause them to expand, we will purify the different components and analyse their reactions in the laboratory. We will be able to plug the most interesting mutations from our genetic screen into the biochemical analysis to uncover more detail about mechanism. 4. Inhibitors of repeat expansion. We will test compounds that can block DNA repair proteins in our CAG expansion system. If they can block CAG expansion then they could represent new therapeutic leads with the potential to alter disease onset. Therefore this project will add important insight as to how the HD mutation leads to disease, linking genetics with cellular and molecular biology. It could elucidate mechanisms of repeat expansion and identify new drug targets, giving a clear link from bench to bedside. These findings are likely to be beneficial in other DNA repeat diseases as well as HD given that the underlying pathogenic mechanisms are probably similar. More broadly, insights into the cellular mechanisms underlying HD may well reveal novel aspects of neuronal biology that are useful in the investigation of other types of neurological disease and dementia. |
