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Rhes Suppression Enhances Disease Phenotypes in Huntington's Disease Mice

Article type: Research Article

Authors: Lee, John H.; | Sowada, Matthew J. | Boudreau, Ryan L. | Aerts, Andrea M. | Thedens, Daniel R. | Nopoulos, Peg | Davidson, Beverly L.; ;

Affiliations: Medical Scientist Training Program, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA | Department of Molecular Physiology & Biophysics, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA | Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA | Department of Psychiatry, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA | Department of Radiology, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA | Department of Neurology, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA

Note: [] Correspondence to: Beverly L. Davidson, 200 Eckstein Medical Research Building, Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52240, USA. Tel.: +1 319 353 5573; Fax: +1 319 353 3372; E-mail: [email protected]

Keywords: Huntington disease, Rhes, rasd2, neurodegenerative disease, genetic therapies, RNA interference

DOI: 10.3233/JHD-140094

Journal: Journal of Huntington's Disease, vol. 3, no. 1, pp. 65-71, 2014

Published: 2014
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Abstract

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 increased 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.

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