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Single nuclei RNA-seq reveals a medium spiny neuron glutamate excitotoxicity signature prior to the onset of neuronal death in an ovine Huntington's disease model.

التفاصيل البيبلوغرافية
العنوان: Single nuclei RNA-seq reveals a medium spiny neuron glutamate excitotoxicity signature prior to the onset of neuronal death in an ovine Huntington's disease model.
المؤلفون: Jiang A; Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand., You L; Department of Human Anatomy & Histoembryology, School of Basic Medical Sciences, Fudan University, 131 Dong'an Road, Shanghai 200032, China.; Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention of Shanghai, 130 Dong'an Road, Shanghai 200032, China., Handley RR; Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand., Hawkins V; Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand., Reid SJ; Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand., Jacobsen JC; Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand., Patassini S; Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand., Rudiger SR; Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development Institute, 129 Holland Road, Adelaide, SA 5350, Australia., Mclaughlan CJ; Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development Institute, 129 Holland Road, Adelaide, SA 5350, Australia., Kelly JM; Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development Institute, 129 Holland Road, Adelaide, SA 5350, Australia., Verma PJ; Aquatic and Livestock Sciences, South Australian Research and Development Institute, 129 Holland Road, Adelaide, SA 5350, Australia., Bawden CS; Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development Institute, 129 Holland Road, Adelaide, SA 5350, Australia., Gusella JF; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, United States.; Department of Genetics, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, United States., MacDonald ME; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, United States.; Department of Neurology, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, United States., Waldvogel HJ; Department of Anatomy and Medical Imaging, Centre for Brain Research, Faculty of Medical and Health Science, The University of Auckland, 85 Park Road, Auckland 1023, New Zealand., Faull RLM; Department of Anatomy and Medical Imaging, Centre for Brain Research, Faculty of Medical and Health Science, The University of Auckland, 85 Park Road, Auckland 1023, New Zealand., Lehnert K; Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand., Snell RG; Applied Translational Genetics Group, Centre for Brain Research, School of Biological Sciences, The University of Auckland, 3 Symonds Street, Auckland 1010, New Zealand.
المصدر: Human molecular genetics [Hum Mol Genet] 2024 Aug 18; Vol. 33 (17), pp. 1524-1539.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: IRL Press at Oxford University Press Country of Publication: England NLM ID: 9208958 Publication Model: Print Cited Medium: Internet ISSN: 1460-2083 (Electronic) Linking ISSN: 09646906 NLM ISO Abbreviation: Hum Mol Genet Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Oxford, England ; New York : IRL Press at Oxford University Press, c1992-
مواضيع طبية MeSH: Huntington Disease*/genetics , Huntington Disease*/metabolism , Huntington Disease*/pathology , Disease Models, Animal* , Neurons*/metabolism , Neurons*/pathology , Glutamic Acid*/metabolism , Receptors, N-Methyl-D-Aspartate*/genetics , Receptors, N-Methyl-D-Aspartate*/metabolism, Animals ; Sheep ; RNA-Seq ; Receptors, AMPA/genetics ; Receptors, AMPA/metabolism ; Cell Death/genetics ; Corpus Striatum/metabolism ; Corpus Striatum/pathology ; Animals, Genetically Modified ; Huntingtin Protein/genetics ; Huntingtin Protein/metabolism ; Humans ; Transcriptome/genetics ; Receptors, Kainic Acid/genetics ; Receptors, Kainic Acid/metabolism ; Cell Nucleus/metabolism ; Cell Nucleus/genetics ; Medium Spiny Neurons
مستخلص: Huntington's 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), α-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.
(© The Author(s) 2024. Published by Oxford University Press.)
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معلومات مُعتمدة: New Zealand Ministry of Business Innovation and Employment; UOOX1601 China Non-Communicable Diseases Research; #2021ZD0201100 Science Innovation 2030-Brain Science and Brain-Inspired Intelligence Technology Major Project; Ministry of Science and Technology
فهرسة مساهمة: Keywords: Huntington's disease; glutamate excitotoxicity; prodromal; single nuclei RNA-seq
المشرفين على المادة: 3KX376GY7L (Glutamic Acid)
0 (Receptors, N-Methyl-D-Aspartate)
0 (Receptors, AMPA)
0 (Huntingtin Protein)
0 (Receptors, Kainic Acid)
تواريخ الأحداث: Date Created: 20240522 Date Completed: 20240821 Latest Revision: 20240823
رمز التحديث: 20240823
مُعرف محوري في PubMed: PMC11336116
DOI: 10.1093/hmg/ddae087
PMID: 38776957
قاعدة البيانات: MEDLINE
الوصف
تدمد:1460-2083
DOI:10.1093/hmg/ddae087