{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T13:26:53Z","timestamp":1790342813604,"version":"4.1.0"},"reference-count":50,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2017,4,28]],"date-time":"2017-04-28T00:00:00Z","timestamp":1493337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100005725","name":"CHDI Foundation","doi-asserted-by":"publisher","award":["A-8339"],"award-info":[{"award-number":["A-8339"]}],"id":[{"id":"10.13039\/100005725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009836","name":"Huntington Society of Canada","doi-asserted-by":"publisher","award":["New Pathways"],"award-info":[{"award-number":["New Pathways"]}],"id":[{"id":"10.13039\/100009836","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"DOI":"10.1371\/journal.pone.0175968","type":"journal-article","created":{"date-parts":[[2017,4,28]],"date-time":"2017-04-28T13:29:50Z","timestamp":1493386190000},"page":"e0175968","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":22,"title":["Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.HttQ111\/+ mouse model of Huntington\u2019s disease"],"prefix":"10.1371","volume":"12","author":[{"given":"Sydney R.","family":"Coffey","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Bragg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn","family":"Minnig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth A.","family":"Ament","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey P.","family":"Cantle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Glickenhaus","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Shelnut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 M.","family":"Carrillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic D.","family":"Shuttleworth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie-Anne","family":"Rodier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimihiro","family":"Noguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Frank","family":"Bennett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan D.","family":"Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly B.","family":"Kordasiewicz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1711-8868","authenticated-orcid":true,"given":"Jeffrey B.","family":"Carroll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2017,4,28]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","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's Disease Collaborative Research Group","volume":"72","year":"1993","journal-title":"Cell"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1038\/nrneurol.2014.24","article-title":"Huntington disease: natural history, biomarkers and prospects for therapeutics","volume":"10","author":"CA Ross","year":"2014","journal-title":"Nat Rev Neurol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"735","DOI":"10.2217\/fnl.10.41","article-title":"Corticostriatal circuit dysfunction in Huntington\u2019s disease: intersection of glutamate, dopamine and calcium","volume":"5","author":"BR Miller","year":"2010","journal-title":"Future Neurol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1615","DOI":"10.1212\/01.WNL.0000065888.88988.6E","article-title":"Evidence for more widespread cerebral pathology in early HD: An MRI-based morphometric analysis","volume":"60","author":"HD Rosas","year":"2003","journal-title":"Neurology"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1097\/00005072-198511000-00003","article-title":"Neuropathological Classification of Huntington\u02bcs Disease","volume":"44","author":"J-P Vonsattel","year":"1985","journal-title":"J Neuropathol Exp Neurol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1016\/S1474-4422(13)70088-7","article-title":"Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington\u2019s disease in the TRACK-HD study: analysis of 36-month observational data","volume":"12","author":"SJ Tabrizi","year":"2013","journal-title":"Lancet Neurol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"78","DOI":"10.3389\/fnagi.2014.00078","article-title":"Clinical and Biomarker Changes in Premanifest Huntington Disease Show Trial Feasibility: A Decade of the PREDICT-HD Study","volume":"6","author":"JS Paulsen","year":"2014","journal-title":"Front Aging Neurosci"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1016\/S1474-4422(09)70178-4","article-title":"Beyond the brain: widespread pathology in Huntington\u2019s disease","volume":"8","author":"JMM van der Burg","year":"2009","journal-title":"Lancet Neurol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1135","DOI":"10.1016\/S1474-4422(15)00177-5","article-title":"Treating the whole body in Huntington\u2019s disease","volume":"14","author":"JB Carroll","year":"2015","journal-title":"Lancet Neurol"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1869","DOI":"10.1084\/jem.20080178","article-title":"A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington\u2019s disease","volume":"205","author":"M Bj\u00f6rkqvist","year":"2008","journal-title":"J Exp Med"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1002\/mds.25862","article-title":"Progressive hepatic mitochondrial dysfunction in premanifest Huntington\u2019s disease","volume":"29","author":"R Hoffmann","year":"2014","journal-title":"Mov Disord"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1212\/WNL.0b013e318282514e","article-title":"Hepatic mitochondrial dysfunction in manifest and premanifest Huntington disease","volume":"80","author":"SH Stuwe","year":"2013","journal-title":"Neurology"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1534","DOI":"10.1007\/s00415-008-0964-x","article-title":"Use of hand-held dynamometry in the evaluation of lower limb muscle strength in people with Huntington\u2019s disease","volume":"255","author":"ME Busse","year":"2008","journal-title":"J Neurol"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1093\/hmg\/8.1.115","article-title":"Length-dependent gametic CAG repeat instability in the Huntington\u2019s disease knock-in mouse","volume":"8","author":"VC Wheeler","year":"1999","journal-title":"Hum Mol Genet"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1038\/nn.4256","article-title":"Integrated genomics and proteomics define huntingtin CAG length\u2013dependent networks in mice","volume":"19","author":"P Langfelder","year":"2016","journal-title":"Nat Neurosci"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"41570","DOI":"10.1038\/srep41570","article-title":"Motivational, proteostatic and transcriptional deficits precede synapse loss, gliosis and neurodegeneration in the B6.HttQ111\/ model of Huntington\u2019s disease","volume":"7","author":"RM Bragg","year":"2017","journal-title":"Sci Rep"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1146\/annurev.pharmtox.010909.105654","article-title":"RNA Targeting Therapeutics: Molecular Mechanisms of Antisense Oligonucleotides as a Therapeutic Platform","volume":"50","author":"CF Bennett","year":"2010","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/S0022-3565(25)39459-0","article-title":"Disposition of the 14C-labeled phosphorothioate oligonucleotide ISIS 2105 after intravenous administration to rats","volume":"267","author":"PA Cossum","year":"1993","journal-title":"J Pharmacol Exp Ther"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1002\/cphy.c130024","article-title":"Energy metabolism in the liver","volume":"4","author":"L Rui","year":"2014","journal-title":"Compr Physiol"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.bbrc.2015.10.140","article-title":"Identification of elevated urea as a severe, ubiquitous metabolic defect in the brain of patients with Huntington\u2019s disease","volume":"468","author":"S Patassini","year":"2015","journal-title":"Biochem Biophys Res Commun"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1093\/hmg\/ddl481","article-title":"Dysregulation of C\/EBPalpha by mutant Huntingtin causes the urea cycle deficiency in Huntington\u2019s disease","volume":"16","author":"M-C Chiang","year":"2007","journal-title":"Hum Mol Genet"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1038\/nrn3587","article-title":"Hepatic encephalopathy: effects of liver failure on brain function","volume":"14","author":"V Felipo","year":"2013","journal-title":"Nat Rev Neurosci"},{"key":"ref23","doi-asserted-by":"publisher","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"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1080\/10543406.2011.607751","article-title":"On using the bootstrap for multiple comparisons","volume":"21","author":"PH Westfall","year":"2011","journal-title":"J Biopharm Stat"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1090\/conm\/622\/12431","article-title":"On multiple contrast tests and simultaneous confidence intervals in high-dimensional repeated measures designs","author":"F Konietschke","year":"2014","journal-title":"Contemporary Mathematics"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"e80923","DOI":"10.1371\/journal.pone.0080923","article-title":"A Broad Phenotypic Screen Identifies Novel Phenotypes Driven by a Single Mutant Allele in Huntington\u2019s Disease CAG Knock-In Mice","volume":"8","author":"SM H\u00f6lter","year":"2013","journal-title":"PLoS One. Public Library of Science"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/ncb2979","article-title":"Cargo recognition and trafficking in selective autophagy","volume":"16","author":"A Stolz","year":"2014","journal-title":"Nat Cell Biol"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1242\/dev.116.1.201","article-title":"NeuN, a neuronal specific nuclear protein in vertebrates","volume":"116","author":"RJ Mullen","year":"1992","journal-title":"Development"},{"key":"ref29","first-page":"274","article-title":"Microglia density decreases with age in a mouse model of Huntington\u2019s disease","volume":"43","author":"L Ma","year":"2003"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"1638","DOI":"10.1212\/01.wnl.0000222734.56412.17","article-title":"Microglial activation correlates with severity in Huntington disease: a clinical and PET study","volume":"66","author":"N Pavese","year":"2006","journal-title":"Neurology"},{"key":"ref31","first-page":"161","article-title":"Early and progressive accumulation of reactive microglia in the Huntington disease brain","volume":"60","author":"E Sapp","year":"2001"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"1759","DOI":"10.1093\/brain\/awm044","article-title":"Microglial activation in presymptomatic Huntington\u2019s disease gene carriers","volume":"130","author":"YF Tai","year":"2007","journal-title":"Brain"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/0166-4328(94)90008-6","article-title":"Thigmotaxis as an index of anxiety in mice. Influence of dopaminergic transmissions","volume":"61","author":"P Simon","year":"1994","journal-title":"Behav Brain Res"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"4411","DOI":"10.1172\/JCI74809","article-title":"Neurotrophin receptor p75NTR mediates Huntington\u2019s disease\u2013associated synaptic and memory dysfunction","volume":"124","author":"V Brito","year":"2014","journal-title":"J Clin Invest"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1523\/JNEUROSCI.4846-11.2012","article-title":"Bone Marrow Transplantation Confers Modest Benefits in Mouse Models of Huntington\u2019s Disease","volume":"32","author":"W Kwan","year":"2012","journal-title":"Journal of Neuroscience"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1038\/nature10485","article-title":"Peripheral SMN restoration is essential for long-term rescue of a severe spinal muscular atrophy mouse model","volume":"478","author":"Y Hua","year":"2011","journal-title":"Nature"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.neuron.2014.03.001","article-title":"Muscle expression of mutant androgen receptor accounts for systemic and motor neuron disease phenotypes in spinal and bulbar muscular atrophy","volume":"82","author":"CJ Cortes","year":"2014","journal-title":"Neuron"},{"key":"ref38","article-title":"A mixed fixed ratio\/progressive ratio procedure reveals an apathy phenotype in the BAC HD and the z_Q175 KI mouse models of Huntington\u2019s disease","volume":"4","author":"S Oakeshott","year":"2012","journal-title":"PLoS Curr"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"e0164072","DOI":"10.1371\/journal.pone.0164072","article-title":"A Longitudinal Operant Assessment of Cognitive and Behavioural Changes in the HdhQ111 Mouse Model of Huntington\u2019s Disease","volume":"11","author":"E Yhnell","year":"2016","journal-title":"PLoS One"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1176\/jnp.14.1.37","article-title":"Behavior in Huntington\u2019s disease: dissociating cognition-based and mood-based changes","volume":"14","author":"JC Thompson","year":"2002","journal-title":"J Neuropsychiatry Clin Neurosci"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"3359","DOI":"10.1073\/pnas.1524575113","article-title":"Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis","volume":"113","author":"G Wang","year":"2016","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1513","DOI":"10.1093\/hmg\/ddl072","article-title":"Body weight is modulated by levels of full-length huntingtin","volume":"15","author":"JM Van Raamsdonk","year":"2006","journal-title":"Hum Mol Genet"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/ng0297-197","article-title":"Instability of highly expanded CAG repeats in mice transgenic for the Huntington\u2019s disease mutation","volume":"15","author":"L Mangiarini","year":"1997","journal-title":"Nat Genet"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1093\/hmg\/2.6.637","article-title":"Improved PCR conditions for the stretch of (CAG) n repeats causing Huntington\u2019s disease","volume":"2","author":"O Riess","year":"1993","journal-title":"Hum Mol Genet"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"398","DOI":"10.3758\/BF03195394","article-title":"EthoVision: a versatile video tracking system for automation of behavioral experiments","volume":"33","author":"LP Noldus","year":"2001","journal-title":"Behav Res Methods Instrum Comput"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1093\/hmg\/dds397","article-title":"A fully humanized transgenic mouse model of Huntington disease","volume":"22","author":"AL Southwell","year":"2013","journal-title":"Hum Mol Genet"},{"key":"ref47","unstructured":"R Core Team. R: A language and environment for statistical computing. 2016;"},{"key":"ref48","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-24277-4","article-title":"ggplot2: Elegant Graphics for Data Analysis","author":"H Wickham","year":"2016"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"ME Ritchie","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"R80","DOI":"10.1186\/gb-2004-5-10-r80","article-title":"Bioconductor: open software development for computational biology and bioinformatics","volume":"5","author":"RC Gentleman","year":"2004","journal-title":"Genome Biol"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pone.0175968","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,17]],"date-time":"2025-06-17T21:13:36Z","timestamp":1750194816000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0175968"}},"subtitle":[],"editor":[{"given":"David","family":"Blum","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2017,4,28]]},"references-count":50,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2017,4,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0175968","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/096990","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,28]]}}}