2021 PDC Thomas Massey

Dr Thomas Massey

2021 Post-doctoral Clinical Fellowship

Using genetic modifiers to investigate the molecular mechanisms of repeat expansion in Huntington’s disease

Huntington’s disease (HD) is a degenerative disorder of the brain characterised by progressive involuntary movements, psychiatric problems, and eventually dementia. It affects about 1 in 8,000 people in the UK and is untreatable, leading to premature death after 10-20 years of debilitating decline. HD is an inherited condition caused by an abnormally long stretch of consecutive ‘CAG’ repeats in the DNA. The more repeats you have, the earlier in life the disease starts- but there is considerable variation. Repeats also expand further in the brains of people with HD, and this process probably causes earlier onset of disease symptoms. It is driven by factors like DNA repair proteins MSH3 and MLH1 but is not well understood. If we could understand the biochemical reactions that cause CAG repeats to expand, we could develop new drugs to target this process and potentially slow onset and progression of HD. My Fellowship project takes two approaches to understanding repeat biology. First, we will use induced pluripotent stem cells from a patient with 109 CAG repeats as a model system of repeat expansion. When we grow these cells in the laboratory the repeats expand, allowing us to discover the critical factors that drive this pathogenic process. We will use specific antibodies to pull out MLH1 and MSH3 proteins from these cells before identifying attached proteins that might be novel factors, and potential drug targets, in repeat expansions. Secondly, we will use extracts from these cells on artificial DNA substrates with CAG repeats to develop a rapid laboratory test of expansions that we hope will speed up research and aid therapeutic development.