PO166 Investigating how dna repair influences pathogenesis in huntington’s disease

Huntington’s Disease is a life-shortening neurodegenerative condition caused by a CAG repeat expansion in exon 1 of the HTT gene. The age at onset of involuntary motor symptoms is inversely correlated with CAG repeat length but there is considerable variation between patients. A recent genome-wide association study has identified DNA repair processes as significant modifiers of the age at which symptoms start. Our work aims to investigate this link further by using exome sequencing of a stratified HD population with particularly early or late disease onset to identify variation in DNA repair genes that influences age of onset. This variation will be introduced into cellular and mouse models of HD in order to investigate the mechanisms underlying HD pathogenesis. We hypothesise that DNA repair factors act directly on the CAG repeat in HTT, triggering its expansion in susceptible neurons of the striatum and ultimately leading to neurodegeneration. Identifying and understanding the key factors influencing this process will aid the development of disease-modifying therapies, of which there is currently none.