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The CAG trinucleotide repeat mutation in the Huntington’s disease gene ( HTT ) exhibits age-dependent tissue-specific expansion that correlates with disease onset in patients, implicating somatic expansion as a disease modifier and potential therapeutic target. Somatic  HTT  CAG expansion is critically dependent on proteins in the mismatch repair (MMR) pathway. To gain further insight into mechanisms of somatic expansion and the relationship of somatic expansion to the disease process in selectively vulnerable MSNs we have crossed  HTT  CAG knock-in mice ( HdhQ111 ) with mice carrying a conditional ( floxed )  Msh2  allele and  D9-Cre  transgenic mice, in which Cre recombinase is expressed specifically in MSNs within the striatum. Deletion of  Msh2  in MSNs eliminated Msh2 protein in those neurons. We demonstrate that MSN-specific deletion of  Msh2  was sufficient to eliminate the vast majority of striatal  HTT  CAG expansions in  HdhQ111  mice. Furthermore, MSN-specific deletion of  Msh2  modified two mutant huntingtin phenotypes: the early nuclear localization of diffusely immunostaining mutant huntingtin was slowed; and the later development of intranuclear huntingtin inclusions was dramatically inhibited. Therefore,  Msh2  acts within MSNs as a genetic enhancer both of somatic  HTT  CAG expansions and of  HTT  CAG-dependent phenotypes in mice. These data suggest that the selective vulnerability of MSNs may be at least in part contributed by the propensity for somatic expansion in these neurons, and imply that intervening in the expansion process is likely to have therapeutic benefit.

Msh2 Acts in Medium-Spiny Striatal Neurons as an Enhancer of CAG Instability and Mutant Huntingtin Phenotypes in Huntington’s Disease Knock-In Mice