title: Msh2 acts in medium-spiny striatal neurons as an enhancer of CAG instability and mutant huntingtin phenotypes in Huntington's disease knock-in mice.
abstract: 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.
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Marina
authors.initials: M
authors.lastname: Kovalenko
authors.forename: Ella
authors.initials: E
authors.lastname: Dragileva
authors.forename: Jason
authors.initials: J
authors.lastname: St Claire
authors.forename: Tammy
authors.initials: T
authors.lastname: Gillis
authors.forename: Jolene R
authors.initials: JR
authors.lastname: Guide
authors.forename: Jaclyn
authors.initials: J
authors.lastname: New
authors.forename: Hualing
authors.initials: H
authors.lastname: Dong
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
authors.forename: Melanie H
authors.initials: MH
authors.lastname: Kucherlapati
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Ehrlich
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Lee
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Wheeler
mesh_terms: D000483:Alleles; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D055879:Gene Knock-In Techniques; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051718:MutS Homolog 2 Protein / Q000378:metabolism*; D050505:Mutant Proteins / Q000378:metabolism*; D017072:Neostriatum / Q000378:metabolism* / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein