Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease
Autor(a) principal: | |
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Data de Publicação: | 2008 |
Outros Autores: | , , , , , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10316/12710 https://doi.org/10.1093/hmg/ddn106 |
Resumo: | Machado-Joseph disease (MJD) is a fatal, dominant neurodegenerative disorder. MJD results from polyglutamine repeat expansion in the MJD-1 gene, conferring a toxic gain of function to the ataxin-3 protein. In this study, we aimed at overexpressing ataxin-3 in the rat brain using lentiviral vectors (LV), to generate an in vivo MJD genetic model and, to study the disorder in defined brain regions: substantia nigra, an area affected in MJD, cortex and striatum, regions not previously reported to be affected in MJD. LV encoding mutant or wild-type human ataxin-3 was injected in the brain of adult rats and the animals were tested for behavioral deficits and neuropathological abnormalities. Striatal pathology was confirmed in transgenic mice and human tissue. In substantia nigra, unilateral overexpression of mutant ataxin-3 led to: apomorphine-induced turning behavior; formation of ubiquitinated ataxin-3 aggregates; alpha-synuclein immunoreactivity; and loss of dopaminergic markers (TH and VMAT2). No neuropathological changes were observed upon wild-type ataxin-3 overexpression. Mutant ataxin-3 expression in striatum and cortex, resulted in accumulation of misfolded ataxin-3, and within striatum, loss of neuronal markers. Striatal pathology was confirmed by observation in MJD transgenic mice of ataxin-3 aggregates and substantial reduction of DARPP-32 immunoreactivity and, in human striata, by ataxin-3 inclusions, immunoreactive for ubiquitin and alpha-synuclein. This study demonstrates the use of LV encoding mutant ataxin-3 to produce a model of MJD and brings evidence of striatal pathology, suggesting that this region may contribute to dystonia and chorea observed in some MJD patients and may represent a target for therapies |
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Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph diseaseMachado-Joseph disease (MJD) is a fatal, dominant neurodegenerative disorder. MJD results from polyglutamine repeat expansion in the MJD-1 gene, conferring a toxic gain of function to the ataxin-3 protein. In this study, we aimed at overexpressing ataxin-3 in the rat brain using lentiviral vectors (LV), to generate an in vivo MJD genetic model and, to study the disorder in defined brain regions: substantia nigra, an area affected in MJD, cortex and striatum, regions not previously reported to be affected in MJD. LV encoding mutant or wild-type human ataxin-3 was injected in the brain of adult rats and the animals were tested for behavioral deficits and neuropathological abnormalities. Striatal pathology was confirmed in transgenic mice and human tissue. In substantia nigra, unilateral overexpression of mutant ataxin-3 led to: apomorphine-induced turning behavior; formation of ubiquitinated ataxin-3 aggregates; alpha-synuclein immunoreactivity; and loss of dopaminergic markers (TH and VMAT2). No neuropathological changes were observed upon wild-type ataxin-3 overexpression. Mutant ataxin-3 expression in striatum and cortex, resulted in accumulation of misfolded ataxin-3, and within striatum, loss of neuronal markers. Striatal pathology was confirmed by observation in MJD transgenic mice of ataxin-3 aggregates and substantial reduction of DARPP-32 immunoreactivity and, in human striata, by ataxin-3 inclusions, immunoreactive for ubiquitin and alpha-synuclein. This study demonstrates the use of LV encoding mutant ataxin-3 to produce a model of MJD and brings evidence of striatal pathology, suggesting that this region may contribute to dystonia and chorea observed in some MJD patients and may represent a target for therapiesOxford University Press2008-07-15info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://hdl.handle.net/10316/12710http://hdl.handle.net/10316/12710https://doi.org/10.1093/hmg/ddn106engHuman Molecular Genetics. 17:14 (2008) 2071-20831460-2083Alves, SandroRégulier, EtienneNascimento-Ferreira, IsabelHassig, RaymondeDufour, NoelleKoeppen, ArnulfCarvalho, Ana LuísaSimões, SérgioLima, Maria C. Pedroso deBrouillet, EmmanuelGould, Veronica ColomerDéglon, NicoleAlmeida, Luís Pereira deinfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2022-05-25T04:39:48Zoai:estudogeral.uc.pt:10316/12710Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T20:47:27.399066Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease |
title |
Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease |
spellingShingle |
Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease Alves, Sandro |
title_short |
Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease |
title_full |
Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease |
title_fullStr |
Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease |
title_full_unstemmed |
Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease |
title_sort |
Striatal and nigral pathology in a lentiviral rat model of Machado-Joseph disease |
author |
Alves, Sandro |
author_facet |
Alves, Sandro Régulier, Etienne Nascimento-Ferreira, Isabel Hassig, Raymonde Dufour, Noelle Koeppen, Arnulf Carvalho, Ana Luísa Simões, Sérgio Lima, Maria C. Pedroso de Brouillet, Emmanuel Gould, Veronica Colomer Déglon, Nicole Almeida, Luís Pereira de |
author_role |
author |
author2 |
Régulier, Etienne Nascimento-Ferreira, Isabel Hassig, Raymonde Dufour, Noelle Koeppen, Arnulf Carvalho, Ana Luísa Simões, Sérgio Lima, Maria C. Pedroso de Brouillet, Emmanuel Gould, Veronica Colomer Déglon, Nicole Almeida, Luís Pereira de |
author2_role |
author author author author author author author author author author author author |
dc.contributor.author.fl_str_mv |
Alves, Sandro Régulier, Etienne Nascimento-Ferreira, Isabel Hassig, Raymonde Dufour, Noelle Koeppen, Arnulf Carvalho, Ana Luísa Simões, Sérgio Lima, Maria C. Pedroso de Brouillet, Emmanuel Gould, Veronica Colomer Déglon, Nicole Almeida, Luís Pereira de |
description |
Machado-Joseph disease (MJD) is a fatal, dominant neurodegenerative disorder. MJD results from polyglutamine repeat expansion in the MJD-1 gene, conferring a toxic gain of function to the ataxin-3 protein. In this study, we aimed at overexpressing ataxin-3 in the rat brain using lentiviral vectors (LV), to generate an in vivo MJD genetic model and, to study the disorder in defined brain regions: substantia nigra, an area affected in MJD, cortex and striatum, regions not previously reported to be affected in MJD. LV encoding mutant or wild-type human ataxin-3 was injected in the brain of adult rats and the animals were tested for behavioral deficits and neuropathological abnormalities. Striatal pathology was confirmed in transgenic mice and human tissue. In substantia nigra, unilateral overexpression of mutant ataxin-3 led to: apomorphine-induced turning behavior; formation of ubiquitinated ataxin-3 aggregates; alpha-synuclein immunoreactivity; and loss of dopaminergic markers (TH and VMAT2). No neuropathological changes were observed upon wild-type ataxin-3 overexpression. Mutant ataxin-3 expression in striatum and cortex, resulted in accumulation of misfolded ataxin-3, and within striatum, loss of neuronal markers. Striatal pathology was confirmed by observation in MJD transgenic mice of ataxin-3 aggregates and substantial reduction of DARPP-32 immunoreactivity and, in human striata, by ataxin-3 inclusions, immunoreactive for ubiquitin and alpha-synuclein. This study demonstrates the use of LV encoding mutant ataxin-3 to produce a model of MJD and brings evidence of striatal pathology, suggesting that this region may contribute to dystonia and chorea observed in some MJD patients and may represent a target for therapies |
publishDate |
2008 |
dc.date.none.fl_str_mv |
2008-07-15 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/article |
format |
article |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10316/12710 http://hdl.handle.net/10316/12710 https://doi.org/10.1093/hmg/ddn106 |
url |
http://hdl.handle.net/10316/12710 https://doi.org/10.1093/hmg/ddn106 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Human Molecular Genetics. 17:14 (2008) 2071-2083 1460-2083 |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Oxford University Press |
publisher.none.fl_str_mv |
Oxford University Press |
dc.source.none.fl_str_mv |
reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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1799133752094359552 |