Msh2 Acts in Medium-Spiny Striatal Neurons as an Enhancer of CAG Instability and Mutant Huntingtin Phenotypes in Huntington’s Disease Knock-In Mice
et al. (2012) Msh2 Acts in Medium-Spiny Striatal Neurons as an Enhancer of CAG Instability and
Mutant Huntingtin Phenotypes in Huntington's Disease Knock-In Mice. PLoS ONE 7(9): e44273. doi:10.1371/journal.pone.0044273
Msh2 Acts in Medium-Spiny Striatal Neurons as an Enhancer of CAG Instability and Mutant Huntingtin Phenotypes in Huntington's Disease Knock-In Mice
Marina Kovalenko 0
Ella Dragileva 0
Jason St. Claire 0
Tammy Gillis 0
Jolene R. Guide 0
Jaclyn New 0
Hualing Dong 0
Raju Kucherlapati 0
Melanie H. Kucherlapati 0
Michelle E. Ehrlich 0
Jong-Min Lee 0
Vanessa C. Wheeler 0
Kari Hoyt, Ohio State University, United States of America
0 1 Center for Human Genetic Research, Massachusetts General Hospital , Boston , Massachusetts, United States of America, 2 Department of Medicine, Brigham and Women's Hospital , Boston , Massachusetts, United States of America, 3 Farber Institute for Neurosciences, Thomas Jefferson University College of Medicine , Philadelphia, Pennsylvania , United States of America
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, MSNspecific 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.
-
Funding: This work was supported by the National Institutes of Health [NS049206] and the CHDI Foundation. The funders had no role in study design, data
collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
. These authors contributed equally to this work.
Huntingtons disease (HD) is a dominantly inherited
neurodegenerative disorder characterized by motor, cognitive and
psychiatric symptoms [1]. The underlying cause is the expansion
.35 repeats of a polymorphic CAG repeat within HTT gene that
lengthens a glutamine tract in the huntingtin protein [2]. Stringent
statistical analyses in a large HD patient data set indicate that the
CAG expansion determines onset age in a fully dominant fashion
with no evidence for a major role of either the wild-type allele or
a second mutant allele [3]. While mutant huntingtin exerts its toxic
effects in many brain regions as well as peripheral tissues over the
course of the disease, medium-spiny GABA-ergic projection
neurons (MSNs) in the striatum are the most vulnerable [46].
Therefore, the factors that contribute to this neuronal
susceptibility are likely to provide clues to pathogenesis. Despite being caused
by a single gene defect the disease is clearly complex, with
a multitude of cellular pathways disrupted in response to mutant
huntingtin [7]. Discerning those events that are critical to
pathogenesis in order to design rational therapeutics remains
a challenge.
An alternative to targeting downstream pathways that are
disrupted during the course of disease is to target the CAG repeat
mutation itself. Given that onset age and disease severity are highly
correlated with the length of the expanded CAG repeat [3,8], one
would predict that reducing CAG length, even within the disease
range, would have a beneficial effect. Notably, the mutant HTT
CAG repeat exhibits both intergenerational and somatic instability
[817]. The latter is highly biased towards expansions and is
tissue-specific, with the greatest expansions seen in the striatum
[13]. The striatum appears to be particularly susceptible to
expansion in several trinucleotide repeat diseases [1820],
consistent with findings that expansion reflects an intrinsic
property of this tissue rather than being a consequence of ongoing
pathogenesis [21]. However, (...truncated)