Modifiers of polyglutamine disease pathogenesis

Huntington?s disease (HD) is an incurable, disease affecting the brain. It results in abnormal movements, psychiatric disturbances (like depression) and memory problems. HD is a genetic disease and about half of the children of affected individuals are at-risk of developing the disease. A number of studies suggests that there are genetic factors distinct from the primary HD mutation that can modulate the severity of the disease or its age-at-onset. This proposal aims to characterise genetic pathways that reduce the severity of HD in animal models. These genes and pathways will be used to prioritise and eventually select druggable targets for further investigation, e.g. with the aim of developing possible therapies. We will identify such modifiers using mouse and fly models of HD and two complementary genetic approaches that allow us to screen for such modifier genes. The logistics and screening systems for these screens have been established in current MRC grants held by the applicants. We have accumulated a large amount of pilot data that show the likely success of this program. The research will be performed by Prof David Rubinsztein and Dr Cahir O?Kane (University of Cambridge) and Prof Steve Brown (MRC Mammalian Genetics Unit, Harwell).