Please use this identifier to cite or link to this item: http://hdl.handle.net/1822/29574

TitleMotor uncoordination and neuropathology in a transgenic mouse model of Machado-Joseph disease lacking intranuclear inclusions and ataxin-3 cleavage products
Author(s)Fernandes, Anabela Silva
Costa, Maria do Carmo
Silva, Sara Carina Duarte
Oliveira, Pedro
Botelho, C. M.
Martins, Luís Filipe Forte Oliveira
Mariz, José
Ferreira, Tiago
Ribeiro, Filipa Pinto
Neves, Margarida Correia
Maciel, P.
Costa, Cristina
KeywordsPolyglutamine
Neuronal atrophy
Pathogenesis
Neuroinflammation
Spinocerebellar ataxia
Neurodegeneration
Genetic instability
Triplet repeats
Issue dateOct-2010
PublisherElsevier
JournalNeurobiology of Disease
Abstract(s)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.
TypeArticle
URIhttp://hdl.handle.net/1822/29574
DOI10.1016/j.nbd.2010.05.021
ISSN0969-9961
Publisher versionhttp://www.sciencedirect.com/science/article/pii/S096999611000183X
Peer-Reviewedyes
AccessOpen access
Appears in Collections:ICVS - Artigos em Revistas Internacionais com Referee

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