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

亨廷顿病(HD)是一种致命的神经退行性疾病，由亨廷顿蛋白基因(Htt)的CAG重复突变引起。最近在HD患者中进行的一项基因组广泛关联研究发现，错配修复基因MSH3是与疾病进展速度相关的关键遗传修饰因子[1]。这一信号是由MSH3外显子1中的三重复等位基因驱动的，与躯体扩张速度减慢、疾病发生延迟和疾病进展缓慢相关[2]。该博士项目旨在了解三重复等位基因导致HD疾病进展缓慢的机制。它对MSH3正常DNA修复功能的影响，它与MMR途径中结合伙伴的相互作用，以及对躯体扩张的影响将在多个细胞系统中进行检测-包括U20S细胞，以及患者来源的淋巴母细胞和IPSC，这些细胞可以分化为中等刺状神经元，这是HD受影响最严重的细胞类型。MSH3调节的治疗潜力也将利用MSH3 ASO(反义寡核苷酸)和影响结合相互作用的小分子来探索。如果时间允许，还将探讨与其他三核苷酸重复疾病的相关性。

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.