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J Huntingtons Dis. 2014;3(1):65-71. doi: 10.3233/JHD-140094.

Rhes suppression enhances disease phenotypes in Huntington's disease mice.

Author information

1
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.
2
Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
3
Department of Psychiatry, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
4
Department of Radiology, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
5
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 Neurology, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.

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.

KEYWORDS:

Huntington disease; RNA interference; Rhes; genetic therapies; neurodegenerative disease; rasd2

PMID:
25062765
PMCID:
PMC4139702
DOI:
10.3233/JHD-140094
[Indexed for MEDLINE]
Free PMC Article

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