Abstract
Huntington's disease (HD) results from an expansion mutation in the polyglutamine tract in huntingtin. Although huntingtin is ubiquitously expressed in the body, the striatum suffers the most severe pathology. Rhes is a Ras-related small GTP-binding protein highly expressed in the striatum that has been reported to modulate mTOR and sumoylation of mutant huntingtin to alter HD mouse model pathogenesis. Reports have varied on whether Rhes reduction is desirable for HD. Here we characterize multiple behavioral and molecular endpoints in the Q175 HD mouse model with genetic Rhes knockout (KO). Genetic RhesKO in the Q175 female mouse resulted in both subtle attenuation of Q175 phenotypic features, and detrimental effects on other kinematic features. The Q175 females exhibited measurable pathogenic deficits, as measured by MRI, MRS and DARPP32, however, RhesKO had no effect on these readouts. Additionally, RhesKO in Q175 mixed gender mice deficits did not affect mTOR signaling, autophagy or mutant huntingtin levels. We conclude that global RhesKO does not substantially ameliorate or exacerbate HD mouse phenotypes in Q175 mice.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biomechanical Phenomena
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Body Weight
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Brain / physiology
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Disease Models, Animal
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Dopamine and cAMP-Regulated Phosphoprotein 32 / metabolism
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Female
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GTP-Binding Proteins / deficiency
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GTP-Binding Proteins / genetics*
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GTP-Binding Proteins / metabolism
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Huntingtin Protein / metabolism
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Huntington Disease / metabolism
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Huntington Disease / pathology*
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Magnetic Resonance Imaging
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Phenotype
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Signal Transduction
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TOR Serine-Threonine Kinases / metabolism
Substances
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Dopamine and cAMP-Regulated Phosphoprotein 32
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Htt protein, mouse
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Huntingtin Protein
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Ppp1r1b protein, mouse
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TOR Serine-Threonine Kinases
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GTP-Binding Proteins
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Rasd2 protein, mouse
Grants and funding
CHDI Foundation is a not-for-profit biomedical research organization exclusively dedicated to discovering and developing therapeutics that slow the progression of Huntington’s disease. The research described was conducted by Charles River and Psychogenics Inc. under a fee-for-service agreement for CHDI Foundation in collaboration with and funded by CHDI Foundation. The funder, through CHDI Management, fully participated in study design, data collection and analysis, the decision to publish, and preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.