Investigation of genetic variation in MSH3, a DNA repair protein that modifies the course of Huntington's disease

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Huntington's disease (HD) is a fatal neurodegenerative condition caused by a CAG repeat mutation in the huntingtin gene (Htt). A recent Genome Wide Association Study (GWAS) performed in HD patients identified MSH3, a mismatch repair gene, as a key genetic modifier associated with the rate of disease progression[1]. This signal is driven by a three-repeat allele in MSH3 exon 1, associated with a reduced rate of somatic expansion, delayed disease onset and slower disease progression [2].This PhD project is aimed at understanding the mechanisms by which the three-repeat allele results in slower disease progression in HD. Its effects on the normal DNA repair function of MSH3, its interaction with binding partners in the MMR pathway, and the effects on somatic expansion will be examined in multiple cell systems - including U20S cells, as well as patient-derived lymphoblastoids and iPSC's, which can be differentiated into medium spiny neurons, the cell-type most significantly affected in HD. The therapeutic potential of MSH3 modulation will also be explored using MSH3 ASOs (Anti-Sense Oligonucleotides) and small molecules affecting binding interactions. If time permits, the relevance to other trinucleotide repeat diseases will also be explored.