{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T17:05:38Z","timestamp":1788282338714,"version":"build-2803163510"},"reference-count":66,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T00:00:00Z","timestamp":1634169600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Huntington\u2019s 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.<\/jats:p>","DOI":"10.1371\/journal.pone.0258486","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T18:01:57Z","timestamp":1634234517000},"page":"e0258486","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Global Rhes knockout in the Q175 Huntington\u2019s disease mouse model"],"prefix":"10.1371","volume":"16","author":[{"given":"Taneli","family":"Heikkinen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8634-0297","authenticated-orcid":true,"given":"Timo","family":"Bragge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juha","family":"Kuosmanen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teija","family":"Parkkari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanna","family":"Gustafsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Kwan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose","family":"Beltran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afshin","family":"Ghavami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivasa","family":"Subramaniam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1907-4811","authenticated-orcid":true,"given":"Neelam","family":"Shahani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uri Nimrod","family":"Ram\u00edrez-Jarqu\u00edn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larry","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Mu\u00f1oz-Sanju\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2071-1064","authenticated-orcid":true,"given":"Deanna M.","family":"Marchionini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,10,14]]},"reference":[{"issue":"6","key":"pone.0258486.ref001","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/0092-8674(93)90585-E","article-title":"A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington\u2019s disease chromosomes. The Huntington\u2019s Disease Collaborative Research Group","volume":"72","year":"1993","journal-title":"Cell"},{"key":"pone.0258486.ref002","doi-asserted-by":"crossref","first-page":"15005","DOI":"10.1038\/nrdp.2015.5","article-title":"Huntington disease","volume":"1","author":"G.P. Bates","year":"2015","journal-title":"Nat Rev Dis Primers"},{"issue":"6","key":"pone.0258486.ref003","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1097\/00005072-198511000-00003","article-title":"Neuropathological classification of Huntington\u2019s disease","volume":"44","author":"J.P. Vonsattel","year":"1985","journal-title":"J Neuropathol Exp Neurol"},{"issue":"3","key":"pone.0258486.ref004","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1212\/WNL.38.3.341","article-title":"Clinical and neuropathologic assessment of severity in Huntington\u2019s disease","volume":"38","author":"R.H. Myers","year":"1988","journal-title":"Neurology"},{"key":"pone.0258486.ref005","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.nbd.2012.11.014","article-title":"Regional vulnerability in Huntington\u2019s disease: fMRI-guided molecular analysis in patients and a mouse model of disease","volume":"52","author":"N.M. Lewandowski","year":"2013","journal-title":"Neurobiol Dis"},{"issue":"6","key":"pone.0258486.ref006","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1002\/(SICI)1097-4547(19990915)57:6<782::AID-JNR3>3.0.CO;2-9","article-title":"Rhes: A striatal-specific Ras homolog related to Dexras1","volume":"57","author":"J.D. Falk","year":"1999","journal-title":"J Neurosci Res"},{"issue":"31","key":"pone.0258486.ref007","doi-asserted-by":"crossref","first-page":"23421","DOI":"10.1074\/jbc.C000322200","article-title":"Activation of heterotrimeric G-protein signaling by a ras-related protein. Implications for signal integration","volume":"275","author":"M.J. Cismowski","year":"2000","journal-title":"J Biol Chem"},{"issue":"6","key":"pone.0258486.ref008","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1093\/hmg\/ddl013","article-title":"Regional and cellular gene expression changes in human Huntington\u2019s disease brain","volume":"15","author":"A. Hodges","year":"2006","journal-title":"Hum Mol Genet"},{"issue":"1","key":"pone.0258486.ref009","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3233\/JHD-140094","article-title":"Rhes suppression enhances disease phenotypes in Huntington\u2019s disease mice","volume":"3","author":"J.H. Lee","year":"2014","journal-title":"J Huntingtons Dis"},{"issue":"2","key":"pone.0258486.ref010","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.neuron.2014.12.019","article-title":"Reinstating aberrant mTORC1 activity in Huntington\u2019s disease mice improves disease phenotypes","volume":"85","author":"J.H. Lee","year":"2015","journal-title":"Neuron"},{"issue":"5932","key":"pone.0258486.ref011","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1126\/science.1172871","article-title":"Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity","volume":"324","author":"S. Subramaniam","year":"2009","journal-title":"Science"},{"issue":"27","key":"pone.0258486.ref012","doi-asserted-by":"crossref","first-page":"20428","DOI":"10.1074\/jbc.C110.127191","article-title":"Rhes, a physiologic regulator of sumoylation, enhances cross-sumoylation between the basic sumoylation enzymes E1 and Ubc9","volume":"285","author":"S. Subramaniam","year":"2010","journal-title":"J Biol Chem"},{"key":"pone.0258486.ref013","author":"O Rivera","year":"2020","journal-title":"Rhes, a Striatal Enriched Protein, Regulates Post-Translational Small-Ubiquitin-like-Modifier (SUMO) Modification of Nuclear Proteins and Alters Gene Expression"},{"issue":"5667","key":"pone.0258486.ref014","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1126\/science.1092194","article-title":"SUMO modification of Huntingtin and Huntington\u2019s disease pathology","volume":"304","author":"J.S. Steffan","year":"2004","journal-title":"Science"},{"issue":"12","key":"pone.0258486.ref015","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1038\/nm.2056","article-title":"Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin","volume":"15","author":"S. Okamoto","year":"2009","journal-title":"Nat Med"},{"issue":"7","key":"pone.0258486.ref016","doi-asserted-by":"crossref","first-page":"e22231","DOI":"10.1371\/journal.pone.0022231","article-title":"Decreased striatal RGS2 expression is neuroprotective in Huntington\u2019s disease (HD) and exemplifies a compensatory aspect of HD-induced gene regulation","volume":"6","author":"T. Seredenina","year":"2011","journal-title":"PLoS One"},{"issue":"5","key":"pone.0258486.ref017","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.celrep.2013.08.001","article-title":"Golgi protein ACBD3 mediates neurotoxicity associated with Huntington\u2019s disease","volume":"4","author":"J.I. Sbodio","year":"2013","journal-title":"Cell Rep"},{"issue":"5","key":"pone.0258486.ref018","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1096\/fj.12-219220","article-title":"A novel human embryonic stem cell-derived Huntington\u2019s disease neuronal model exhibits mutant huntingtin (mHTT) aggregates and soluble mHTT-dependent neurodegeneration","volume":"27","author":"B. Lu","year":"2013","journal-title":"FASEB J"},{"key":"pone.0258486.ref019","unstructured":"Argenti, M., THE ROLE OF MITOCHONDRIAL DYSFUNCTION IN HUNTINGTON\u2019S DISEASE PATHOGENESIS AND ITS RELATION WITH STRIATAL RHES PROTEIN. Ph.D Thesis, Universit\u00e0 degli Studi di Padova, Padova PD, Italy, 2014."},{"issue":"2","key":"pone.0258486.ref020","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1038\/nn.2994","article-title":"Rhes, a striatal-enriched small G protein, mediates mTOR signaling and L-DOPA-induced dyskinesia","volume":"15","author":"S. Subramaniam","year":"2011","journal-title":"Nat Neurosci"},{"key":"pone.0258486.ref021","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.nbd.2015.10.020","article-title":"Genetic deletion of Rhes or pharmacological blockade of mTORC1 prevent striato-nigral neurons activation in levodopa-induced dyskinesia","volume":"85","author":"A. Brugnoli","year":"2016","journal-title":"Neurobiol Dis"},{"key":"pone.0258486.ref022","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/S1874-6047(10)27003-8","article-title":"Rheb G-Proteins and the Activation of mTORC1","volume":"27","author":"N. Parmar","year":"2010","journal-title":"Enzymes"},{"issue":"349","key":"pone.0258486.ref023","doi-asserted-by":"crossref","first-page":"ra103","DOI":"10.1126\/scisignal.2005633","article-title":"Huntingtin promotes mTORC1 signaling in the pathogenesis of Huntington\u2019s disease","volume":"7","author":"W.M. Pryor","year":"2014","journal-title":"Sci Signal"},{"issue":"7\u20138","key":"pone.0258486.ref024","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/j.neuropharm.2010.10.025","article-title":"Huntington\u2019s disease is a disorder of the corpus striatum: focus on Rhes (Ras homologue enriched in the striatum)","volume":"60","author":"S. Subramaniam","year":"2011","journal-title":"Neuropharmacology"},{"issue":"9","key":"pone.0258486.ref025","doi-asserted-by":"crossref","first-page":"4206","DOI":"10.1523\/JNEUROSCI.3730-12.2013","article-title":"Rhes deletion is neuroprotective in the 3-nitropropionic acid model of Huntington\u2019s disease","volume":"33","author":"R.G. Mealer","year":"2013","journal-title":"J Neurosci"},{"issue":"1","key":"pone.0258486.ref026","doi-asserted-by":"crossref","first-page":"e53606","DOI":"10.1371\/journal.pone.0053606","article-title":"Attenuation of Rhes activity significantly delays the appearance of behavioral symptoms in a mouse model of Huntington\u2019s disease","volume":"8","author":"B.A. Baiamonte","year":"2013","journal-title":"PLoS One"},{"key":"pone.0258486.ref027","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.nbd.2015.05.011","article-title":"Ectopic expression of the striatal-enriched GTPase Rhes elicits cerebellar degeneration and an ataxia phenotype in Huntington\u2019s disease","volume":"82","author":"S. Swarnkar","year":"2015","journal-title":"Neurobiol Dis"},{"issue":"33","key":"pone.0258486.ref028","doi-asserted-by":"crossref","first-page":"20265","DOI":"10.1073\/pnas.2002283117","article-title":"Loss of Hap1 selectively promotes striatal degeneration in Huntington disease mice","volume":"117","author":"Q. Liu","year":"2020","journal-title":"Proc Natl Acad Sci U S A"},{"key":"pone.0258486.ref029","author":"D, V. Howland","journal-title":"Partial genetic reduction of mutant HTT gene expression in the zQ175 knock-in mouse model does not have significant impact on molecular and behavioral outcome measures of disease"},{"issue":"13","key":"pone.0258486.ref030","doi-asserted-by":"crossref","first-page":"5788","DOI":"10.1128\/MCB.24.13.5788-5796.2004","article-title":"Rhes is involved in striatal function","volume":"24","author":"D. Spano","year":"2004","journal-title":"Mol Cell Biol"},{"issue":"12","key":"pone.0258486.ref031","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0243052","article-title":"Rapid and robust patterns of spontaneous locomotor deficits in mouse models of Huntington\u2019s disease","volume":"15","author":"T Heikkinen","year":"2020","journal-title":"PLoS One"},{"issue":"3","key":"pone.0258486.ref032","doi-asserted-by":"crossref","first-page":"e0194423","DOI":"10.1371\/journal.pone.0194423","article-title":"Quantifying autophagy using novel LC3B and p62 TR-FRET assays","volume":"13","author":"A. Bresciani","year":"2018","journal-title":"PLoS One"},{"issue":"1","key":"pone.0258486.ref033","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.ab.2009.08.001","article-title":"Single-step detection of mutant huntingtin in animal and human tissues: a bioassay for Huntington\u2019s disease","volume":"395","author":"A. Weiss","year":"2009","journal-title":"Anal Biochem"},{"issue":"3\u20134","key":"pone.0258486.ref034","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/S0361-9230(01)00599-8","article-title":"New anti-huntingtin monoclonal antibodies: implications for huntingtin conformation and its binding proteins","volume":"56","author":"J. Ko","year":"2001","journal-title":"Brain Res Bull"},{"issue":"2","key":"pone.0258486.ref035","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1016\/j.chembiol.2011.12.020","article-title":"TR-FRET-based duplex immunoassay reveals an inverse correlation of soluble and aggregated mutant huntingtin in huntington\u2019s disease","volume":"19","author":"B. Baldo","year":"2012","journal-title":"Chem Biol"},{"issue":"5","key":"pone.0258486.ref036","doi-asserted-by":"crossref","first-page":"e96854","DOI":"10.1371\/journal.pone.0096854","article-title":"Quantification assays for total and polyglutamine-expanded huntingtin proteins","volume":"9","author":"D. Macdonald","year":"2014","journal-title":"PLoS One"},{"issue":"12","key":"pone.0258486.ref037","doi-asserted-by":"crossref","first-page":"e50717","DOI":"10.1371\/journal.pone.0050717","article-title":"Characterization of neurophysiological and behavioral changes, MRI brain volumetry and 1H MRS in zQ175 knock-in mouse model of Huntington\u2019s disease","volume":"7","author":"T. Heikkinen","year":"2012","journal-title":"PLoS One"},{"issue":"7","key":"pone.0258486.ref038","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1002\/cne.25023","article-title":"Progression of basal ganglia pathology in heterozygous Q175 knock-in Huntington\u2019s disease mice","volume":"529","author":"Y. Deng","year":"2021","journal-title":"J Comp Neurol"},{"issue":"1","key":"pone.0258486.ref039","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.neuroscience.2008.08.041","article-title":"Extensive early motor and non-motor behavioral deficits are followed by striatal neuronal loss in knock-in Huntington\u2019s disease mice","volume":"157","author":"M.A. Hickey","year":"2008","journal-title":"Neuroscience"},{"issue":"454","key":"pone.0258486.ref040","doi-asserted-by":"crossref","first-page":"ra111","DOI":"10.1126\/scisignal.aaf6670","article-title":"RasGRP1 promotes amphetamine-induced motor behavior through a Rhes interaction network (\"Rhesactome\") in the striatum","volume":"9","author":"N. Shahani","year":"2016","journal-title":"Sci Signal"},{"key":"pone.0258486.ref041","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.neuroscience.2012.12.062","article-title":"Effects of the Ras homolog Rhes on Akt\/protein kinase B and glycogen synthase kinase 3 phosphorylation in striatum","volume":"236","author":"L.M. Harrison","year":"2013","journal-title":"Neuroscience"},{"issue":"18","key":"pone.0258486.ref042","doi-asserted-by":"crossref","first-page":"eaaz7001","DOI":"10.1126\/sciadv.aaz7001","article-title":"RasGRP1 is a causal factor in the development of l-DOPA-induced dyskinesia in Parkinson\u2019s disease","volume":"6","author":"M. Eshraghi","year":"2020","journal-title":"Sci Adv"},{"key":"pone.0258486.ref043","doi-asserted-by":"crossref","first-page":"e01020","DOI":"10.7554\/eLife.01020","article-title":"Rasgrp1 mutation increases naive T-cell CD44 expression and drives mTOR-dependent accumulation of Helios(+) T cells and autoantibodies","volume":"2","author":"S.R. Daley","year":"2013","journal-title":"Elife"},{"issue":"4","key":"pone.0258486.ref044","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1042\/BST20130037","article-title":"Rheb and Rags come together at the lysosome to activate mTORC1","volume":"41","author":"M.J. Groenewoud","year":"2013","journal-title":"Biochem Soc Trans"},{"key":"pone.0258486.ref045","doi-asserted-by":"crossref","first-page":"163","DOI":"10.3389\/fnagi.2018.00163","article-title":"Rhes Counteracts Dopamine Neuron Degeneration and Neuroinflammation Depending on Gender and Age","volume":"10","author":"G. Costa","year":"2018","journal-title":"Front Aging Neurosci"},{"issue":"7","key":"pone.0258486.ref046","doi-asserted-by":"crossref","DOI":"10.3390\/ijms20071556","article-title":"Lack of Rhes Increases MDMA-Induced Neuroinflammation and Dopamine Neuron Degeneration: Role of Gender and Age","volume":"20","author":"G. Costa","year":"2019","journal-title":"Int J Mol Sci"},{"key":"pone.0258486.ref047","doi-asserted-by":"crossref","first-page":"10933","DOI":"10.1038\/srep10933","article-title":"Rhes influences striatal cAMP\/PKA-dependent signaling and synaptic plasticity in a gender-sensitive fashion","volume":"5","author":"V. Ghiglieri","year":"2015","journal-title":"Sci Rep"},{"key":"pone.0258486.ref048","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1750-1326-5-26","article-title":"The mTOR kinase inhibitor Everolimus decreases S6 kinase phosphorylation but fails to reduce mutant huntingtin levels in brain and is not neuroprotective in the R6\/2 mouse model of Huntington\u2019s disease","volume":"5","author":"J.H. Fox","year":"2010","journal-title":"Mol Neurodegener"},{"issue":"2","key":"pone.0258486.ref049","doi-asserted-by":"crossref","first-page":"e1000838","DOI":"10.1371\/journal.pgen.1000838","article-title":"Deletion of the huntingtin polyglutamine stretch enhances neuronal autophagy and longevity in mice","volume":"6","author":"S. 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Sarkar","year":"2013","journal-title":"Biochem Soc Trans"},{"issue":"1","key":"pone.0258486.ref058","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/cdd.2008.110","article-title":"Rapamycin and mTOR-independent autophagy inducers ameliorate toxicity of polyglutamine-expanded huntingtin and related proteinopathies","volume":"16","author":"S. Sarkar","year":"2009","journal-title":"Cell Death Differ"},{"issue":"6","key":"pone.0258486.ref059","doi-asserted-by":"crossref","first-page":"3547","DOI":"10.1074\/jbc.M113.536912","article-title":"Rhes, a striatal-selective protein implicated in Huntington disease, binds beclin-1 and activates autophagy","volume":"289","author":"R.G. Mealer","year":"2014","journal-title":"J Biol Chem"},{"issue":"47","key":"pone.0258486.ref060","doi-asserted-by":"crossref","first-page":"23760","DOI":"10.1073\/pnas.1912868116","article-title":"Rhes, a striatal-enriched protein, promotes mitophagy via Nix","volume":"116","author":"M. 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