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

doi:10.3233/JHD-140094

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Rhes suppression enhances disease phenotypes in Huntington's disease mice

Journal article

Open access

Peer reviewed

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 and Beverly L Davidson

Journal of Huntington's disease, Vol.3(1), pp.65-71

2014

DOI: 10.3233/JHD-140094

PMCID: PMC4139702

PMID: 25062765

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https://doi.org/10.3233/JHD-140094View

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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.

Magnetic Resonance Imaging

Phenotype

Genetic Therapy

Neostriatum - pathology

GTP-Binding Proteins - antagonists & inhibitors

Mutant Proteins - metabolism

Nuclear Proteins - metabolism

Huntington Disease - metabolism

Atrophy

Behavior, Animal

Nerve Tissue Proteins - metabolism

Huntingtin Protein

Animals

MicroRNAs

Huntington Disease - genetics

Anxiety - metabolism

Disease Models, Animal

Details

Title: Subtitle: Rhes suppression enhances disease phenotypes in Huntington's disease mice
Creators: John H Lee - 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
Matthew J Sowada - Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA
Ryan L Boudreau - Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA
Andrea M Aerts - Department of Psychiatry, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA
Daniel R Thedens - Department of Radiology, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA
Peg Nopoulos - Department of Psychiatry, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA
Beverly L Davidson - 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
Resource Type: Journal article
Publication Details: Journal of Huntington's disease, Vol.3(1), pp.65-71
Publisher: Netherlands
DOI: 10.3233/JHD-140094
PMID: 25062765
PMCID: PMC4139702
ISSN: 1879-6397
eISSN: 1879-6400
Grant note: NS050568-03 / NINDS NIH HHS NS076631 / NINDS NIH HHS P01 NS050210 / NINDS NIH HHS T32 HL007121 / NHLBI NIH HHS T32 GM007337 / NIGMS NIH HHS R01 NS055903 / NINDS NIH HHS R01 NS050568 / NINDS NIH HHS R01 NS076631 / NINDS NIH HHS NS50210 / NINDS NIH HHS
Language: English
Date published: 2014
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Neurology; Radiology; Electrical and Computer Engineering; Psychiatry; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984065486302771

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