Rhes Suppression Enhances Disease Phenotypes in Huntington's Disease Mice

John H. Lee, Matthew J. Sowada, Ryan L. Boudreau, Andrea M. Aerts, Daniel R. Thedens, Peg Nopoulos, Beverly L. Davidson
2014 Journal of Huntington's Disease  
In Huntington's disease (HD) mutant HTT is ubiquitously expressed yet the striatum undergoes profound early degeneration. Cell culture studies suggest that a striatal-enriched protein, Rhes, may account for this vulnerability. We investigated the therapeutic potential of silencing Rhes in vivo using inhibitory RNAs (miRhes). While Rhes suppression was tolerated in wildtype mice, it failed to improve rotarod function in two distinct HD mouse models. Additionally, miRhes treated HD mice had
more » ... sed anxiety-like behaviors and enhanced striatal atrophy as measured by longitudinal MRI when compared to control treated mice. These findings raise caution regarding the long-term implementation of inhibiting Rhes as a therapy for HD.
doi:10.3233/jhd-140094 pmid:25062765 pmcid:PMC4139702 fatcat:setrnrqlunhsxmopvc5hwrxvoe