title: Rhes suppression enhances disease phenotypes in Huntington's disease mice.
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.
authors: 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.
authors: John H
authors: JH
authors: Lee
authors: Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
authors: Matthew J
authors: MJ
authors: Sowada
authors: Department of Internal Medicine, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
authors: Ryan L
authors: RL
authors: Boudreau
authors: Department of Psychiatry, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
authors: Andrea M
authors: AM
authors: Aerts
authors: Department of Radiology, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
authors: Daniel R
authors: DR
authors: Thedens
authors: Department of Psychiatry, Roy J and Lucille A Carver College of Medicine, Iowa City, IA, USA.
authors: Peg
authors: P
authors: Nopoulos
authors: 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.
authors: Beverly L
authors: BL
authors: Davidson
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism; D001284:Atrophy; D001522:Behavior, Animal; D004195:Disease Models, Animal; D019204:GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D015316:Genetic Therapy; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D035683:MicroRNAs; D050505:Mutant Proteins / Q000378:metabolism*; D017072:Neostriatum / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D035683:MicroRNAs; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D019204:GTP-Binding Proteins; C488189:Rasd2 protein, mouse
keywords: Huntington disease; RNA interference; Rhes; genetic therapies; neurodegenerative disease; rasd2