Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph disease
Autor(a) principal: | |
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Data de Publicação: | 2014 |
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/1822/32850 |
Resumo: | Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease currently with no treatment. We describe a novel mouse model of MJD which expresses mutant human ataxin-3 at near endogenous levels and manifests MJD-like motor symptoms that appear gradually and progress over time. CMVMJD135 mice show ataxin-3 intranuclear inclusions in the CNS and neurodegenerative changes in key disease regions, such as the pontine and dentate nuclei. Hsp90 inhibition has shown promising outcomes in some neurodegenerative diseases, but nothing is known about its effects in MJD. Chronic treatment of CMVMJD mice with Hsp90 inhibitor 17-DMAG resulted in a delay in the progression of their motor coordination deficits and, at 22 and 24 weeks of age, was able to rescue the uncoordination phenotype to wild-type levels; in parallel, a reduction in neuropathology was observed in treated animals. We observed limited induction of heat-shock proteins with treatment, but found evidence that 17-DMAG may be acting through autophagy, as LC3-II (both at mRNA and protein levels) and beclin-1 were induced in the brain of treated animals. This resulted in decreased levels of the mutant ataxin-3 and reduced intranuclear aggregation of this protein. Our data validate this novel mouse model as a relevant tool for the study of MJD pathogenesis and for pre-clinical studies, and show that Hsp90 inhibition is a promising therapeutic strategy for MJD. |
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Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph diseasePolyglutamineAnimal modelsAtaxiaBehaviorTherapyAutophagyScience & TechnologyMachado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease currently with no treatment. We describe a novel mouse model of MJD which expresses mutant human ataxin-3 at near endogenous levels and manifests MJD-like motor symptoms that appear gradually and progress over time. CMVMJD135 mice show ataxin-3 intranuclear inclusions in the CNS and neurodegenerative changes in key disease regions, such as the pontine and dentate nuclei. Hsp90 inhibition has shown promising outcomes in some neurodegenerative diseases, but nothing is known about its effects in MJD. Chronic treatment of CMVMJD mice with Hsp90 inhibitor 17-DMAG resulted in a delay in the progression of their motor coordination deficits and, at 22 and 24 weeks of age, was able to rescue the uncoordination phenotype to wild-type levels; in parallel, a reduction in neuropathology was observed in treated animals. We observed limited induction of heat-shock proteins with treatment, but found evidence that 17-DMAG may be acting through autophagy, as LC3-II (both at mRNA and protein levels) and beclin-1 were induced in the brain of treated animals. This resulted in decreased levels of the mutant ataxin-3 and reduced intranuclear aggregation of this protein. Our data validate this novel mouse model as a relevant tool for the study of MJD pathogenesis and for pre-clinical studies, and show that Hsp90 inhibition is a promising therapeutic strategy for MJD.We would like to thank to Dr. Henry Paulson for providing the anti-ataxin-3 serum, Dr. Monica Sousa for the pCMV vector and to Eng. Lucilia Goreti Pinto, Lu s Martins, Miguel Carneiro and Celina Barros for technical assistance. This work was supported by Fundacao para a Ciencia e Tecnologia through the projects FEDER/FCT, POCI/SAU-MMO/60412/2004 and PTDC/SAU-GMG/64076/2006. This work was supported by Fundacao para a Ciencia e Tecnologia through fellowships SFRH/BPD/91562/2012 to A.S-F., SFRH/BD/78388/2011 to S. D-S., SFRH/BD/51059/2010 to A.N-C., and SFRH/BPD/79469/2011 to A.T-C..SpringerUniversidade do MinhoFernandes, Anabela SilvaSilva, Sara DuarteCarvalho, Andreia NevesAmorim, MarinaCunha, Carina SoaresOliveira, PedroThirstrup, KennethCastro, Andreia Cristiana Teixeira deMaciel, P.20142014-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/1822/32850eng1933-721310.1007/s13311-013-0255-924477711http://www.springer.cominfo: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:RCAAP2023-07-21T12:15:01Zoai:repositorium.sdum.uminho.pt:1822/32850Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T19:07:24.076034Repositório 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 |
Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph disease |
title |
Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph disease |
spellingShingle |
Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph disease Fernandes, Anabela Silva Polyglutamine Animal models Ataxia Behavior Therapy Autophagy Science & Technology |
title_short |
Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph disease |
title_full |
Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph disease |
title_fullStr |
Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph disease |
title_full_unstemmed |
Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph disease |
title_sort |
Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph disease |
author |
Fernandes, Anabela Silva |
author_facet |
Fernandes, Anabela Silva Silva, Sara Duarte Carvalho, Andreia Neves Amorim, Marina Cunha, Carina Soares Oliveira, Pedro Thirstrup, Kenneth Castro, Andreia Cristiana Teixeira de Maciel, P. |
author_role |
author |
author2 |
Silva, Sara Duarte Carvalho, Andreia Neves Amorim, Marina Cunha, Carina Soares Oliveira, Pedro Thirstrup, Kenneth Castro, Andreia Cristiana Teixeira de Maciel, P. |
author2_role |
author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade do Minho |
dc.contributor.author.fl_str_mv |
Fernandes, Anabela Silva Silva, Sara Duarte Carvalho, Andreia Neves Amorim, Marina Cunha, Carina Soares Oliveira, Pedro Thirstrup, Kenneth Castro, Andreia Cristiana Teixeira de Maciel, P. |
dc.subject.por.fl_str_mv |
Polyglutamine Animal models Ataxia Behavior Therapy Autophagy Science & Technology |
topic |
Polyglutamine Animal models Ataxia Behavior Therapy Autophagy Science & Technology |
description |
Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease currently with no treatment. We describe a novel mouse model of MJD which expresses mutant human ataxin-3 at near endogenous levels and manifests MJD-like motor symptoms that appear gradually and progress over time. CMVMJD135 mice show ataxin-3 intranuclear inclusions in the CNS and neurodegenerative changes in key disease regions, such as the pontine and dentate nuclei. Hsp90 inhibition has shown promising outcomes in some neurodegenerative diseases, but nothing is known about its effects in MJD. Chronic treatment of CMVMJD mice with Hsp90 inhibitor 17-DMAG resulted in a delay in the progression of their motor coordination deficits and, at 22 and 24 weeks of age, was able to rescue the uncoordination phenotype to wild-type levels; in parallel, a reduction in neuropathology was observed in treated animals. We observed limited induction of heat-shock proteins with treatment, but found evidence that 17-DMAG may be acting through autophagy, as LC3-II (both at mRNA and protein levels) and beclin-1 were induced in the brain of treated animals. This resulted in decreased levels of the mutant ataxin-3 and reduced intranuclear aggregation of this protein. Our data validate this novel mouse model as a relevant tool for the study of MJD pathogenesis and for pre-clinical studies, and show that Hsp90 inhibition is a promising therapeutic strategy for MJD. |
publishDate |
2014 |
dc.date.none.fl_str_mv |
2014 2014-01-01T00:00:00Z |
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/1822/32850 |
url |
http://hdl.handle.net/1822/32850 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
1933-7213 10.1007/s13311-013-0255-9 24477711 http://www.springer.com |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Springer |
publisher.none.fl_str_mv |
Springer |
dc.source.none.fl_str_mv |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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