{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T19:49:31Z","timestamp":1770493771488,"version":"3.49.0"},"reference-count":39,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T00:00:00Z","timestamp":1705363200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-17-RAR3-0008-01"],"award-info":[{"award-number":["ANR-17-RAR3-0008-01"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"publisher","award":["ANR-11-INBS-0011"],"award-info":[{"award-number":["ANR-11-INBS-0011"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>SpinoCerebellar Ataxia type 7 (SCA7) is an inherited disorder caused by CAG triplet repeats encoding polyglutamine expansion in the ATXN7 protein, which is part of the transcriptional coactivator complex SAGA. The mutation primarily causes neurodegeneration in the cerebellum and retina, as well as several forebrain structures. The SCA7<jats:sup>140Q\/5Q<\/jats:sup> knock-in mouse model recapitulates key disease features, including loss of vision and motor performance. To characterize the temporal progression of brain degeneration of this model, we performed a longitudinal study spanning from early to late symptomatic stages using high-resolution magnetic resonance imaging (MRI) and <jats:italic>in vivo<\/jats:italic> <jats:sup>1<\/jats:sup>H-magnetic resonance spectroscopy (<jats:sup>1<\/jats:sup>H-MRS). Compared to wild-type mouse littermates, MRI analysis of SCA7 mice shows progressive atrophy of defined brain structures, with the striatum, thalamus and cortex being the first and most severely affected. The volume loss of these structures coincided with increased motor impairments in SCA7 mice, suggesting an alteration of the sensory-motor network, as observed in SCA7 patients. MRI also reveals atrophy of the hippocampus and anterior commissure at mid-symptomatic stage and the midbrain and brain stem at late stage. <jats:sup>1<\/jats:sup>H-MRS of hippocampus, a brain region previously shown to be dysfunctional in patients, reveals early and progressive metabolic alterations in SCA7 mice. Interestingly, abnormal glutamine accumulation precedes the hippocampal atrophy and the reduction in myo-inositol and total N-acetyl-aspartate concentrations, two markers of glial and neuronal damage, respectively. Together, our results indicate that non-cerebellar alterations and glial and neuronal metabolic impairments may play a crucial role in the development of SCA7 mouse pathology, particularly at early stages of the disease. Degenerative features of forebrain structures in SCA7 mice correspond to current observations made in patients. Our study thus provides potential biomarkers that could be used for the evaluation of future therapeutic trials using the SCA7<jats:sup>140Q\/5Q<\/jats:sup> model.<\/jats:p>","DOI":"10.1371\/journal.pone.0296790","type":"journal-article","created":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T18:26:53Z","timestamp":1705429613000},"page":"e0296790","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Longitudinal MRI and 1H-MRS study of SCA7 mouse forebrain reveals progressive multiregional atrophy and early brain metabolite changes indicating early neuronal and glial dysfunction"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6066-2909","authenticated-orcid":true,"given":"Jean-Baptiste","family":"P\u00e9rot","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Niewiadomska-Cimicka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuel","family":"Brouillet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yvon","family":"Trottier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6412-3427","authenticated-orcid":true,"given":"Julien","family":"Flament","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2024,1,16]]},"reference":[{"key":"pone.0296790.ref001","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/B978-0-444-51892-7.00030-9","article-title":"\u00ab Spinocerebellar ataxia type 7","volume":"103","author":"J.-J. Martin","year":"2012","journal-title":"Handb Clin Neurol"},{"issue":"10","key":"pone.0296790.ref002","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1007\/s004150170082","article-title":"\u00ab Striking anticipation in spinocerebellar ataxia type 7: the infantile phenotype \u00bb","volume":"248","author":"B. P. van de Warrenburg","year":"2001","journal-title":"J Neurol"},{"issue":"2","key":"pone.0296790.ref003","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1093\/hmg\/7.2.165","article-title":"Molecular and Clinical Correlations in Autosomal Dominant Cerebellar Ataxia with Progressive Macular Dystrophy (SCA7)","volume":"7","author":"G. David","year":"1998","journal-title":"Human Molecular Genetics"},{"issue":"10","key":"pone.0296790.ref004","doi-asserted-by":"crossref","first-page":"3199","DOI":"10.1111\/ejn.14148","article-title":"\u00ab Motor and cognitive impairments in spinocerebellar ataxia type 7 and its correlations with cortical volumes \u00bb","volume":"48","author":"A. Chirino","year":"2018","journal-title":"Eur J Neurosci"},{"issue":"1\u20114","key":"pone.0296790.ref005","first-page":"154","article-title":"Spinocerebellar ataxia 7 (SCA7)","volume":"100","author":"A.-S. Lebre et A","year":"2003","journal-title":"BriceCGR"},{"issue":"4","key":"pone.0296790.ref006","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1007\/s13311-019-00778-5","article-title":"\u00ab Molecular Targets and Therapeutic Strategies in Spinocerebellar Ataxia Type 7","volume":"16","author":"A. Niewiadomska-Cimicka et Y","year":"2019","journal-title":"Neurotherapeutics"},{"issue":"3","key":"pone.0296790.ref007","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S0896-6273(02)01190-X","article-title":"\u00ab SCA7 Knockin Mice Model Human SCA7 and Reveal Gradual Accumulation of Mutant Ataxin-7 in Neurons and Abnormalities in Short-Term Plasticity \u00bb","volume":"37","author":"S.-Y. Yoo","year":"2003","journal-title":"Neuron"},{"issue":"22","key":"pone.0296790.ref008","doi-asserted-by":"crossref","first-page":"4910","DOI":"10.1523\/JNEUROSCI.1882-20.2021","article-title":"\u00ab SCA7 Mouse Cerebellar Pathology Reveals Preferential Downregulation of Key Purkinje Cell-Identity Genes and Shared Disease Signature with SCA1 and SCA2 \u00bb","volume":"41","author":"A. Niewiadomska-Cimicka","year":"2021","journal-title":"J. Neurosci."},{"issue":"7","key":"pone.0296790.ref009","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/S1474-4422(13)70088-7","article-title":"\u00ab 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 \u00bb","volume":"12","author":"S. J. Tabrizi","year":"2013","journal-title":"Lancet Neurol"},{"key":"pone.0296790.ref010","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1016\/j.nicl.2018.06.011","article-title":"Autosomal dominant cerebellar ataxias: Imaging biomarkers with high effect sizes","volume":"19","author":"I. M. Adanyeguh","year":"2018","journal-title":"NeuroImage: Clinical"},{"issue":"5","key":"pone.0296790.ref011","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1002\/mds.26181","article-title":"\u00ab In vivo neurometabolic profiling in patients with spinocerebellar ataxia types 1, 2, 3, and 7 \u00bb","volume":"30","author":"I. M. Adanyeguh","year":"2015","journal-title":"Movement Disorders"},{"issue":"7","key":"pone.0296790.ref012","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1111\/j.1528-1157.1996.tb00622.x","article-title":"\u00ab Magnetic resonance spectroscopy \u00bb","volume":"37","author":"J. S. Duncan","year":"1996","journal-title":"Epilepsia"},{"issue":"21","key":"pone.0296790.ref013","doi-asserted-by":"crossref","first-page":"123193","DOI":"10.1172\/jci.insight.123193","article-title":"\u00ab Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles","volume":"3","author":"J. Friedrich","year":"2018","journal-title":"JCI Insight"},{"issue":"1","key":"pone.0296790.ref014","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/s40478-022-01329-4","article-title":"\u00ab Cerebellar morphometric and spectroscopic biomarkers for Machado-Joseph Disease \u00bb","volume":"10","author":"C. O. Miranda","year":"2022","journal-title":"Acta Neuropathol Commun"},{"key":"pone.0296790.ref015","doi-asserted-by":"crossref","first-page":"e4301","DOI":"10.1002\/nbm.4301","article-title":"\u00ab Complementarity of gluCEST and 1 H-MRS for the study of mouse models of Huntington\u2019s disease \u00bb","author":"J. P\u00e9pin","year":"2020","journal-title":"NMR Biomed"},{"issue":"3","key":"pone.0296790.ref016","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1038\/jcbfm.2011.157","article-title":"\u00ab Cortical metabolites as biomarkers in the R6\/2 model of Huntington\u2019s disease \u00bb","volume":"32","author":"L. Zacharoff","year":"2012","journal-title":"J Cereb Blood Flow Metab"},{"key":"pone.0296790.ref017","doi-asserted-by":"crossref","DOI":"10.3389\/fninf.2020.00024","article-title":"Sammba-MRI: A Library for Processing SmAll-MaMmal BrAin MRI Data in Python \u00bb","volume":"14","author":"M. Celestine","year":"2020","journal-title":"Front. Neuroinform"},{"key":"pone.0296790.ref018","article-title":"Identification of the key role of white matter alteration in the pathogenesis of Huntington\u2019s Disease","author":"J.-B. P\u00e9rot","year":"2021"},{"issue":"6","key":"pone.0296790.ref019","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1002\/mrm.1910300604","article-title":"\u00ab Estimation of metabolite concentrations from localized in vivo proton NMR spectra \u00bb","volume":"30","author":"S. W. Provencher","year":"1993","journal-title":"Magn Reson Med"},{"issue":"7","key":"pone.0296790.ref020","doi-asserted-by":"crossref","first-page":"e69782","DOI":"10.1371\/journal.pone.0069782","article-title":"The C57BL\/6J Mouse Exhibits Sporadic Congenital Portosystemic Shunts","volume":"8","author":"C. Cudalbu","year":"2013","journal-title":"PLOS ONE"},{"issue":"1","key":"pone.0296790.ref021","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s00401-001-0514-4","article-title":"\u00ab Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals \u00bb","volume":"104","author":"J. Jonasson","year":"2002","journal-title":"Acta Neuropathol"},{"issue":"3","key":"pone.0296790.ref022","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1602\/neurorx.2.3.465","article-title":"Knock-in mouse models of Huntington\u2019s disease","volume":"2","author":"L. B. Menalled","year":"2005","journal-title":"NeuroRx"},{"key":"pone.0296790.ref023","doi-asserted-by":"crossref","first-page":"658339","DOI":"10.3389\/fnmol.2021.658339","article-title":"\u00ab Broad Influence of Mutant Ataxin-3 on the Proteome of the Adult Brain, Young Neurons, and Axons Reveals Central Molecular Processes and Biomarkers in SCA3\/MJD Using Knock-In Mouse Model \u00bb","volume":"14","author":"K. Wiatr","year":"2021","journal-title":"Front Mol Neurosci"},{"issue":"2","key":"pone.0296790.ref024","doi-asserted-by":"crossref","first-page":"e0148839","DOI":"10.1371\/journal.pone.0148839","article-title":"\u00ab Characterization of Behavioral, Neuropathological, Brain Metabolic and Key Molecular Changes in zQ175 Knock-In Mouse Model of Huntington\u2019s Disease \u00bb","volume":"11","author":"Q. Peng","year":"2016","journal-title":"PLOS ONE"},{"key":"pone.0296790.ref025","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.neurobiolaging.2021.02.006","article-title":"\u00ab Evaluation of early microstructural changes in the R6\/1 mouse model of Huntington\u2019s disease by ultra-high field diffusion MR imaging \u00bb","volume":"102","author":"R. G. Gatto","year":"2021","journal-title":"Neurobiology of Aging"},{"key":"pone.0296790.ref026","doi-asserted-by":"crossref","DOI":"10.3389\/fneur.2014.00094","article-title":"Studies on the Q175 Knock-in Model of Huntington\u2019s Disease Using Functional Imaging in Awake Mice: Evidence of Olfactory Dysfunction","volume":"5","author":"C. F. Ferris","year":"2014","journal-title":"Front. Neurol"},{"key":"pone.0296790.ref027","first-page":"ddac036","article-title":"\u00ab Longitudinal multimodal MRI characterization of a knock-in mouse model of Huntington\u2019s disease reveals early grey and white matter alterations \u00bb","author":"J.-B. P\u00e9rot","year":"2022","journal-title":"Hum Mol Genet"},{"key":"pone.0296790.ref028","doi-asserted-by":"crossref","first-page":"102561","DOI":"10.1016\/j.nicl.2021.102561","article-title":"In vivo assessment of neurodegeneration in Spinocerebellar Ataxia type 7","volume":"29","author":"J. A. Parker","year":"2021","journal-title":"NeuroImage: Clinical"},{"issue":"12","key":"pone.0296790.ref029","doi-asserted-by":"crossref","first-page":"3748","DOI":"10.1093\/brain\/awaa312","article-title":"\u00ab Brain network remodelling reflects tau-related pathology prior to memory deficits in Thy-Tau22 mice \u00bb","volume":"143","author":"L. Degiorgis","year":"2020","journal-title":"Brain"},{"issue":"12","key":"pone.0296790.ref030","doi-asserted-by":"crossref","first-page":"1708","DOI":"10.1002\/mds.25618","article-title":"\u00ab Disruption of visual and motor connectivity in spinocerebellar ataxia type 7 \u00bb","volume":"28","author":"C. R. Hernandez-Castillo","year":"2013","journal-title":"Movement Disorders"},{"key":"pone.0296790.ref031","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/2053-8871-1-2","article-title":"\u00ab Whole-brain connectivity analysis and classification of spinocerebellar ataxia type 7 by functional MRI \u00bb","volume":"1","author":"C. R. Hernandez-Castillo","year":"2014","journal-title":"Cerebellum Ataxias"},{"issue":"3","key":"pone.0296790.ref032","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s00415-015-8014-y","article-title":"\u00ab Motor network structure and function are associated with motor performance in Huntington\u2019s disease \u00bb","volume":"263","author":"H.-P. M\u00fcller","year":"2016","journal-title":"J Neurol"},{"issue":"11","key":"pone.0296790.ref033","doi-asserted-by":"crossref","first-page":"2050","DOI":"10.3174\/ajnr.A4903","article-title":"\u00ab Ataxia Severity Correlates with White Matter Degeneration in Spinocerebellar Ataxia Type 7 \u00bb","volume":"37","author":"C. R. Hernandez-Castillo","year":"2016","journal-title":"American Journal of Neuroradiology"},{"key":"pone.0296790.ref034","article-title":"\u00ab Glial Glutamine Homeostasis in Health and Disease \u00bb","author":"J. V. Andersen et A","year":"2022","journal-title":"Neurochem Res"},{"issue":"4","key":"pone.0296790.ref035","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1002\/(SICI)1097-4547(19991115)58:4<576::AID-JNR10>3.0.CO;2-D","article-title":"Richter-Landsberg, \u00ab Oxidative stress-induced metabolic alterations in rat brain astrocytes studied by multinuclear NMR spectroscopy \u00bb","volume":"58","author":"A. Brand","year":"1999","journal-title":"Journal of Neuroscience Research"},{"issue":"10","key":"pone.0296790.ref036","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1002\/mds.28140","article-title":"\u00ab In Vivo Molecular Signatures of Cerebellar Pathology in Spinocerebellar Ataxia Type 3 \u00bb","volume":"35","author":"M. do C","year":"2020","journal-title":"Movement Disorders"},{"issue":"2","key":"pone.0296790.ref037","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1002\/nbm.1443","article-title":"\u00ab Longitudinal MRI and MRSI characterization of the quinolinic acid rat model for excitotoxicity: peculiar apparent diffusion coefficients and recovery of N-acetyl aspartate levels \u00bb","volume":"23","author":"N. Shemesh","year":"2010","journal-title":"NMR Biomed"},{"issue":"5","key":"pone.0296790.ref038","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1002\/mds.26181","article-title":"\u00ab In vivo neurometabolic profiling in patients with spinocerebellar ataxia type 1, 2, 3 and 7 \u00bb","volume":"30","author":"I. M. Adanyeguh","year":"2015","journal-title":"Mov Disord"},{"issue":"12","key":"pone.0296790.ref039","doi-asserted-by":"crossref","DOI":"10.1002\/nbm.3045","article-title":"\u00ab Glutamate and Glutamine: A Review of In Vivo MRS in the Human Brain \u00bb","volume":"26","author":"S. Ramadan","year":"2013","journal-title":"NMR Biomed"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0296790","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,16]],"date-time":"2024-01-16T18:27:11Z","timestamp":1705429631000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0296790"}},"subtitle":[],"editor":[{"given":"Stephen D.","family":"Ginsberg","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2024,1,16]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1,16]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0296790","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,16]]}}}