DNA repair in Huntington’s disease and other repeat-associated disorders (360G-Wellcome-109088_Z_15_A)

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG repeat in the huntingtin gene, HTT. The disease has characteristic motor and cognitive symptoms resulting initially from degeneration of the medium spiny neurons (MSNs) in the striatum. There are currently no disease-modifying treatments. The length of the CAG repeat is inversely correlated with age at motor onset but other factors influence onset including genetic variation elsewhere in the genome. A recent GWAS (GeM-HD) identified genetic variation in or near DNA repair genes as modifiers of age at onset. We hypothesise that DNA repair processes trigger post-mitotic CAG repeat expansion in MSNs leading to their degeneration. The work here aims to establish a cellular model of CAG repeat expansion which we can use to assess the effects of the DNA repair genes (and their variants) implicated by the GeM-HD GWAS. CRISPR technology will be used to knock-out or introduce the relevant genetic variation into HD-iPSC lines. Functional assays will then be conducted to assess cell viability. Characterising how these genetic variants affect cells harbouring the expanded CAG repeat will better define appropriate targets in the DNA repair pathway for further exploitation in therapeutic development.