Motor uncoordination and neuropathology in a transgenic mouse model of Machado–Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products
Machado–Joseph disease (MJD) is a late-onset neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in the ataxin-3 protein. We generated two transgenic mouse lineages expressing the expanded human ataxin-3 under the control of the CMV promoter: CMVMJD83 and CMVMJD94, carrying Q83 an...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2010-10-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S096999611000183X |
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| author | Anabela Silva-Fernandes Maria do Carmo Costa Sara Duarte-Silva Pedro Oliveira Claudia M. Botelho Luís Martins José António Mariz Tiago Ferreira Filipa Ribeiro Margarida Correia-Neves Cristina Costa Patrícia Maciel |
| author_facet | Anabela Silva-Fernandes Maria do Carmo Costa Sara Duarte-Silva Pedro Oliveira Claudia M. Botelho Luís Martins José António Mariz Tiago Ferreira Filipa Ribeiro Margarida Correia-Neves Cristina Costa Patrícia Maciel |
| author_sort | Anabela Silva-Fernandes |
| collection | DOAJ |
| description | Machado–Joseph disease (MJD) is a late-onset neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in the ataxin-3 protein. We generated two transgenic mouse lineages expressing the expanded human ataxin-3 under the control of the CMV promoter: CMVMJD83 and CMVMJD94, carrying Q83 and Q94 stretches, respectively. Behavioral analysis revealed that the CMVMJD94 transgenic mice developed motor uncoordination, intergenerational instability of the CAG repeat and a tissue-specific increase in the somatic mosaicism of the repeat with aging. Histopathological analysis of MJD mice at early and late stages of the disease revealed neuronal atrophy and astrogliosis in several brain regions; however, we found no signs of microglial activation or neuroinflammatory response prior to the appearance of an overt phenotype. In our model, the appearance of MJD-like symptoms was also not associated with the presence of ataxin-3 cleavage products or intranuclear aggregates. We propose the transgenic CMVMJD94 mice as a useful model to study the early stages in the pathogenesis of MJD and to explore the molecular mechanisms involved in CAG repeat instability. |
| first_indexed | 2024-12-22T17:44:03Z |
| format | Article |
| id | doaj.art-f3264f0b5e094a06bad40803aa7cbf7e |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-22T17:44:03Z |
| publishDate | 2010-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-f3264f0b5e094a06bad40803aa7cbf7e2022-12-21T18:18:20ZengElsevierNeurobiology of Disease1095-953X2010-10-01401163176Motor uncoordination and neuropathology in a transgenic mouse model of Machado–Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage productsAnabela Silva-Fernandes0Maria do Carmo Costa1Sara Duarte-Silva2Pedro Oliveira3Claudia M. Botelho4Luís Martins5José António Mariz6Tiago Ferreira7Filipa Ribeiro8Margarida Correia-Neves9Cristina Costa10Patrícia Maciel11Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, PortugalLife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; Department of Neurology, University of Michigan, Ann Arbor, USALife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, PortugalDepartment of Production and Systems Engineering, School of Engineering, University of Minho, Braga, PortugalLife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, PortugalLife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, PortugalLife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, PortugalCentre for Research in Neuroscience, McGill University, Quebec, CanadaLife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, PortugalLife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, PortugalDepartment of Neurology, Hospital Prof. Fernando Fonseca, E.P.E., Amadora, PortugalLife and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; Corresponding author. Fax: +351 253604820.Machado–Joseph disease (MJD) is a late-onset neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in the ataxin-3 protein. We generated two transgenic mouse lineages expressing the expanded human ataxin-3 under the control of the CMV promoter: CMVMJD83 and CMVMJD94, carrying Q83 and Q94 stretches, respectively. Behavioral analysis revealed that the CMVMJD94 transgenic mice developed motor uncoordination, intergenerational instability of the CAG repeat and a tissue-specific increase in the somatic mosaicism of the repeat with aging. Histopathological analysis of MJD mice at early and late stages of the disease revealed neuronal atrophy and astrogliosis in several brain regions; however, we found no signs of microglial activation or neuroinflammatory response prior to the appearance of an overt phenotype. In our model, the appearance of MJD-like symptoms was also not associated with the presence of ataxin-3 cleavage products or intranuclear aggregates. We propose the transgenic CMVMJD94 mice as a useful model to study the early stages in the pathogenesis of MJD and to explore the molecular mechanisms involved in CAG repeat instability.http://www.sciencedirect.com/science/article/pii/S096999611000183XPolyglutamineNeuronal atrophyPathogenesisNeuroinflammationSpinocerebellar ataxiaNeurodegeneration |
| spellingShingle | Anabela Silva-Fernandes Maria do Carmo Costa Sara Duarte-Silva Pedro Oliveira Claudia M. Botelho Luís Martins José António Mariz Tiago Ferreira Filipa Ribeiro Margarida Correia-Neves Cristina Costa Patrícia Maciel Motor uncoordination and neuropathology in a transgenic mouse model of Machado–Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products Neurobiology of Disease Polyglutamine Neuronal atrophy Pathogenesis Neuroinflammation Spinocerebellar ataxia Neurodegeneration |
| title | Motor uncoordination and neuropathology in a transgenic mouse model of Machado–Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products |
| title_full | Motor uncoordination and neuropathology in a transgenic mouse model of Machado–Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products |
| title_fullStr | Motor uncoordination and neuropathology in a transgenic mouse model of Machado–Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products |
| title_full_unstemmed | Motor uncoordination and neuropathology in a transgenic mouse model of Machado–Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products |
| title_short | Motor uncoordination and neuropathology in a transgenic mouse model of Machado–Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products |
| title_sort | motor uncoordination and neuropathology in a transgenic mouse model of machado joseph disease lacking intranuclear inclusions and ataxin 3 cleavage products |
| topic | Polyglutamine Neuronal atrophy Pathogenesis Neuroinflammation Spinocerebellar ataxia Neurodegeneration |
| url | http://www.sciencedirect.com/science/article/pii/S096999611000183X |
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