{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T19:52:13Z","timestamp":1771617133945,"version":"3.50.1"},"reference-count":129,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T00:00:00Z","timestamp":1716336000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"New Zealand Ministry of Business Innovation and Employment"},{"name":"China Non-Communicable Diseases Research","award":["UOOX1601"],"award-info":[{"award-number":["UOOX1601"]}]},{"name":"Science Innovation 2030\u2014Brain Science and Brain-Inspired Intelligence Technology Major Project","award":["#2021ZD0201100"],"award-info":[{"award-number":["#2021ZD0201100"]}]},{"name":"Science Innovation 2030\u2014Brain Science and Brain-Inspired Intelligence Technology Major Project","award":["#2021ZD0201104"],"award-info":[{"award-number":["#2021ZD0201104"]}]},{"DOI":"10.13039\/100007225","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007225","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Huntington\u2019s disease (HD) is a neurodegenerative genetic disorder caused by an expansion in the CAG repeat tract of the huntingtin (HTT) gene resulting in behavioural, cognitive, and motor defects. Current knowledge of disease pathogenesis remains incomplete, and no disease course-modifying interventions are in clinical use. We have previously reported the development and characterisation of the OVT73 transgenic sheep model of HD. The 73 polyglutamine repeat is somatically stable and therefore likely captures a prodromal phase of the disease with an absence of motor symptomatology even at 5-years of age and no detectable striatal cell loss. To better understand the disease-initiating events we have undertaken a single nuclei transcriptome study of the striatum of an extensively studied cohort of 5-year-old OVT73 HD sheep and age matched wild-type controls. We have identified transcriptional upregulation of genes encoding N-methyl-D-aspartate (NMDA), \u03b1-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors in medium spiny neurons, the cell type preferentially lost early in HD. Further, we observed an upregulation of astrocytic glutamate uptake transporters and medium spiny neuron GABAA receptors, which may maintain glutamate homeostasis. Taken together, these observations support the glutamate excitotoxicity hypothesis as an early neurodegeneration cascade-initiating process but the threshold of toxicity may be regulated by several protective mechanisms. Addressing this biochemical defect early may prevent neuronal loss and avoid the more complex secondary consequences precipitated by cell death.<\/jats:p>","DOI":"10.1093\/hmg\/ddae087","type":"journal-article","created":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T22:46:16Z","timestamp":1716417976000},"source":"Crossref","is-referenced-by-count":4,"title":["Single nuclei RNA-seq reveals a medium spiny neuron glutamate excitotoxicity signature prior to the onset of neuronal death in an ovine Huntington\u2019s disease model"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7267-013X","authenticated-orcid":false,"given":"Andrew","family":"Jiang","sequence":"first","affiliation":[{"name":"Applied Translational Genetics Group , Centre for Brain Research, School of Biological Sciences, , 3 Symonds Street, Auckland 1010 , New Zealand"},{"name":"The University of Auckland , Centre for Brain Research, School of Biological Sciences, , 3 Symonds Street, Auckland 1010 , New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linya","family":"You","sequence":"additional","affiliation":[{"name":"Department of Human Anatomy & Histoembryology , School of Basic Medical Sciences, , 131 Dong'an Road, Shanghai 200032 , China"},{"name":"Fudan University , School of Basic Medical Sciences, , 131 Dong'an Road, Shanghai 200032 , China"},{"name":"Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention of Shanghai , 130 Dong'an Road, Shanghai 200032 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renee R","family":"Handley","sequence":"additional","affiliation":[{"name":"Applied Translational Genetics Group , Centre for Brain Research, School of Biological Sciences, , 3 Symonds Street, Auckland 1010 , New Zealand"},{"name":"The University of Auckland , Centre for Brain Research, School of Biological Sciences, , 3 Symonds Street, Auckland 1010 , New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victoria","family":"Hawkins","sequence":"additional","affiliation":[{"name":"Applied Translational Genetics Group , Centre for Brain Research, School of Biological Sciences, , 3 Symonds Street, Auckland 1010 , New Zealand"},{"name":"The University of Auckland , Centre for Brain Research, School of Biological Sciences, , 3 Symonds Street, Auckland 1010 , New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzanne J","family":"Reid","sequence":"additional","affiliation":[{"name":"Applied Translational Genetics Group , Centre for Brain Research, School of Biological Sciences, , 3 Symonds Street, Auckland 1010 , New Zealand"},{"name":"The University of Auckland , Centre for Brain Research, School of Biological Sciences, , 3 Symonds Street, Auckland 1010 , New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessie C","family":"Jacobsen","sequence":"additional","affiliation":[{"name":"Applied Translational Genetics Group , Centre for Brain Research, School of Biological Sciences, , 3 Symonds Street, Auckland 1010 , New Zealand"},{"name":"The University of Auckland , Centre for Brain Research, School of Biological Sciences, , 3 Symonds Street, Auckland 1010 , New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Patassini","sequence":"additional","affiliation":[{"name":"Applied Translational Genetics Group , Centre for Brain Research, School of Biological Sciences, , 3 Symonds Street, Auckland 1010 , New Zealand"},{"name":"The University of Auckland , Centre for Brain Research, School of Biological Sciences, , 3 Symonds Street, Auckland 1010 , New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Skye R","family":"Rudiger","sequence":"additional","affiliation":[{"name":"Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development Institute , 129 Holland Road, Adelaide, SA 5350 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clive J","family":"Mclaughlan","sequence":"additional","affiliation":[{"name":"Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development Institute , 129 Holland Road, Adelaide, SA 5350 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer M","family":"Kelly","sequence":"additional","affiliation":[{"name":"Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development Institute , 129 Holland Road, Adelaide, SA 5350 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul J","family":"Verma","sequence":"additional","affiliation":[{"name":"Aquatic and Livestock Sciences, South Australian Research and Development Institute , 129 Holland Road, Adelaide, SA 5350 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C Simon","family":"Bawden","sequence":"additional","affiliation":[{"name":"Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development Institute , 129 Holland Road, Adelaide, SA 5350 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0681-9263","authenticated-orcid":false,"given":"James F","family":"Gusella","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital , 185 Cambridge Street, Boston, MA 02114 , United States"},{"name":"Department of Genetics, Harvard Medical School , 25 Shattuck Street, Boston, MA 02115 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcy E","family":"MacDonald","sequence":"additional","affiliation":[{"name":"Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital , 185 Cambridge Street, Boston, MA 02114 , United States"},{"name":"Department of Neurology, Harvard Medical School , 25 Shattuck Street, Boston, MA 02115 , United States"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2165-8568","authenticated-orcid":false,"given":"Henry J","family":"Waldvogel","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Medical Imaging , Centre for Brain Research, Faculty of Medical and Health Science, , 85 Park Road, Auckland 1023 , New Zealand"},{"name":"The University of Auckland , Centre for Brain Research, Faculty of Medical and Health Science, , 85 Park Road, Auckland 1023 , New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard L M","family":"Faull","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Medical Imaging , Centre for Brain Research, Faculty of Medical and Health Science, , 85 Park Road, Auckland 1023 , New Zealand"},{"name":"The University of Auckland , Centre for Brain Research, Faculty of Medical and Health Science, , 85 Park Road, Auckland 1023 , New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus","family":"Lehnert","sequence":"additional","affiliation":[{"name":"Applied Translational Genetics Group , Centre for Brain Research, School of Biological Sciences, , 3 Symonds Street, Auckland 1010 , New Zealand"},{"name":"The University of Auckland , Centre for Brain Research, School of Biological Sciences, , 3 Symonds Street, Auckland 1010 , New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Russell G","family":"Snell","sequence":"additional","affiliation":[{"name":"Applied Translational Genetics Group , Centre for Brain Research, School of Biological Sciences, , 3 Symonds Street, Auckland 1010 , New Zealand"},{"name":"The University of Auckland , Centre for Brain Research, School of Biological Sciences, , 3 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