Further Molecular Characterisation of the OVT73 Transgenic Sheep Model of Huntington's Disease Identifies Cortical Aggregates
| Autor: | Russell G. Snell, A. Jennifer Morton, Clive J. McLaughlan, Suzanne J. Reid, Marcy E. MacDonald, Richard L.M. Faull, Stefano Patassini, Henry J. Waldvogel, Jessie C Jacobsen, Renee R. Handley, Andreas Weiss, Alexander P. Osmand, James F. Gusella, C. Simon Bawden, Skye R. Rudiger |
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| Rok vydání: | 2013 |
| Předmět: |
Pathology
medicine.medical_specialty Transgene Intranuclear Inclusion Bodies Nerve Tissue Proteins Striatum Biology Animals Genetically Modified Cellular and Molecular Neuroscience Huntington's disease Cortex (anatomy) Piriform cortex Neuropil medicine Huntingtin Protein Animals Humans Sheep Domestic Cerebral Cortex medicine.disease Disease Models Animal Huntington Disease Globus pallidus medicine.anatomical_structure nervous system Neurology (clinical) |
| Zdroj: | Journal of Huntington's Disease. 2:279-295 |
| ISSN: | 1879-6397 |
| DOI: | 10.3233/jhd-130067 |
| Popis: | Background: Huntington’s disease is a neurodegenerative disorder, typically with clinical manifestations in adult years, caused by an expanded polyglutamine-coding repeat in HTT. There are no treatments that delay or prevent the onset or progression of this devastating disease. Objective and Methods: In order to study its pre-symptomatic molecular progression and provide a large mammalian model for determining natural history of the disease and for therapeutic testing, we generated and previously reported on lines of transgenic sheep carrying a full length human HTT cDNA transgene, with expression driven by a minimal HTT promoter. We report here further characterization of our preferred line, OVT73. Results: This line reliably expresses the expanded human huntingtin protein at modest, but readily detectable levels throughout the brain, including the striatum and cortex. Transmission of the 73 unit glutamine coding repeat was relatively stable over three generations. At the first time-point of a longitudinal study, animals sacrificed at 6 months (7 transgenic, 7 control) showed reduced striatum GABAA 1 receptor, and globus pallidus leu-enkephalin immunoreactivity. Two of three 18 month old animals sacrificed revealed cortical neuropil aggregates. Furthermore, neuronal intranuclear inclusions were identified in the piriform cortex of a single 36 month old animal in addition to cortical neuropil aggregates. Conclusions: Taken together, these data indicate that the OVT73 transgenic sheep line will progressively reveal early HD pathology and allow therapeutic testing over a period of time relevant to human patients. |
| Databáze: | OpenAIRE |
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