Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing

Autores
Avale, Maria Elena; Rodrigez Martin, Teresa; Gallo, Jean-Marc
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Abnormal metabolism of the tau protein is central to the pathogenesis of a number of dementias, including Alzheimer's disease. Aberrant alternative splicing of exon 10 in the tau pre-mRNA resulting in an imbalance of tau isoforms is one of the molecular causes of the inherited tauopathy, FTDP-17. We showed previously in heterologous systems that exon 10 inclusion in tau mRNA could be modulated by spliceosome-mediated RNA trans-splicing (SMaRT). Here, we evaluated the potential of trans-splicing RNA reprogramming to correct tau mis-splicing in differentiated neurons in a mouse model of tau mis-splicing, the htau transgenic mouse line, expressing the human MAPT gene in a null mouse Mapt background. Trans-splicing molecules designed to increase exon 10 inclusion were delivered to neurons using lentiviral vectors. We demonstrate reprogramming of tau transcripts at the RNA level after transduction of cultured neurons or after direct delivery and long-term expression of viral vectors into the brain of htau mice in vivo. Tau RNA trans-splicing resulted in an increase in exon 10 inclusion in the mature tau mRNA. Importantly, we also show that the trans-spliced product is translated into a full-length chimeric tau protein. These results validate the potential of SMaRT to correct tau mis-splicing and provide a framework for its therapeutic application to neurodegenerative conditions linked to aberrant RNA processing.
Fil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Institute of Psychiatry. King’s College London. Centre for Neurodegeneration Research. Department of Clinical Neuroscience; Reino Unido
Fil: Rodrigez Martin, Teresa. Institute of Psychiatry. King’s College London. Centre for Neurodegeneration Research. Department of Clinical Neuroscience; Reino Unido
Fil: Gallo, Jean-Marc. Institute of Psychiatry. King’s College London. Centre for Neurodegeneration Research. Department of Clinical Neuroscience; Reino Unido
Materia
Alternative splicing
Gene therapy
Neurodegeneration
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/4019
Acceder
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network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicingAvale, Maria ElenaRodrigez Martin, TeresaGallo, Jean-MarcAlternative splicingGene therapyNeurodegenerationhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Abnormal metabolism of the tau protein is central to the pathogenesis of a number of dementias, including Alzheimer's disease. Aberrant alternative splicing of exon 10 in the tau pre-mRNA resulting in an imbalance of tau isoforms is one of the molecular causes of the inherited tauopathy, FTDP-17. We showed previously in heterologous systems that exon 10 inclusion in tau mRNA could be modulated by spliceosome-mediated RNA trans-splicing (SMaRT). Here, we evaluated the potential of trans-splicing RNA reprogramming to correct tau mis-splicing in differentiated neurons in a mouse model of tau mis-splicing, the htau transgenic mouse line, expressing the human MAPT gene in a null mouse Mapt background. Trans-splicing molecules designed to increase exon 10 inclusion were delivered to neurons using lentiviral vectors. We demonstrate reprogramming of tau transcripts at the RNA level after transduction of cultured neurons or after direct delivery and long-term expression of viral vectors into the brain of htau mice in vivo. Tau RNA trans-splicing resulted in an increase in exon 10 inclusion in the mature tau mRNA. Importantly, we also show that the trans-spliced product is translated into a full-length chimeric tau protein. These results validate the potential of SMaRT to correct tau mis-splicing and provide a framework for its therapeutic application to neurodegenerative conditions linked to aberrant RNA processing.Fil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Institute of Psychiatry. King’s College London. Centre for Neurodegeneration Research. Department of Clinical Neuroscience; Reino UnidoFil: Rodrigez Martin, Teresa. Institute of Psychiatry. King’s College London. Centre for Neurodegeneration Research. Department of Clinical Neuroscience; Reino UnidoFil: Gallo, Jean-Marc. Institute of Psychiatry. King’s College London. Centre for Neurodegeneration Research. Department of Clinical Neuroscience; Reino UnidoOxford University Press2013-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/4019Avale, Maria Elena; Rodrigez Martin, Teresa; Gallo, Jean-Marc; Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing; Oxford University Press; Human Molecular Genetics; 22; 13; 7-2013; 2603-26110964-6906enginfo:eu-repo/semantics/altIdentifier/url/http://hmg.oxfordjournals.org/content/22/13/2603.longinfo:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674800/info:eu-repo/semantics/altIdentifier/doi/10.1093%2Fhmg%2Fddt108info:eu-repo/semantics/altIdentifier/issn/0964-6906info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:55:38Zoai:ri.conicet.gov.ar:11336/4019instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:55:38.888CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing
title Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing
spellingShingle Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing
Avale, Maria Elena
Alternative splicing
Gene therapy
Neurodegeneration
title_short Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing
title_full Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing
title_fullStr Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing
title_full_unstemmed Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing
title_sort Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing
dc.creator.none.fl_str_mv Avale, Maria Elena
Rodrigez Martin, Teresa
Gallo, Jean-Marc
author Avale, Maria Elena
author_facet Avale, Maria Elena
Rodrigez Martin, Teresa
Gallo, Jean-Marc
author_role author
author2 Rodrigez Martin, Teresa
Gallo, Jean-Marc
author2_role author
author
dc.subject.none.fl_str_mv Alternative splicing
Gene therapy
Neurodegeneration
topic Alternative splicing
Gene therapy
Neurodegeneration
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Abnormal metabolism of the tau protein is central to the pathogenesis of a number of dementias, including Alzheimer's disease. Aberrant alternative splicing of exon 10 in the tau pre-mRNA resulting in an imbalance of tau isoforms is one of the molecular causes of the inherited tauopathy, FTDP-17. We showed previously in heterologous systems that exon 10 inclusion in tau mRNA could be modulated by spliceosome-mediated RNA trans-splicing (SMaRT). Here, we evaluated the potential of trans-splicing RNA reprogramming to correct tau mis-splicing in differentiated neurons in a mouse model of tau mis-splicing, the htau transgenic mouse line, expressing the human MAPT gene in a null mouse Mapt background. Trans-splicing molecules designed to increase exon 10 inclusion were delivered to neurons using lentiviral vectors. We demonstrate reprogramming of tau transcripts at the RNA level after transduction of cultured neurons or after direct delivery and long-term expression of viral vectors into the brain of htau mice in vivo. Tau RNA trans-splicing resulted in an increase in exon 10 inclusion in the mature tau mRNA. Importantly, we also show that the trans-spliced product is translated into a full-length chimeric tau protein. These results validate the potential of SMaRT to correct tau mis-splicing and provide a framework for its therapeutic application to neurodegenerative conditions linked to aberrant RNA processing.
Fil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular; Argentina. Institute of Psychiatry. King’s College London. Centre for Neurodegeneration Research. Department of Clinical Neuroscience; Reino Unido
Fil: Rodrigez Martin, Teresa. Institute of Psychiatry. King’s College London. Centre for Neurodegeneration Research. Department of Clinical Neuroscience; Reino Unido
Fil: Gallo, Jean-Marc. Institute of Psychiatry. King’s College London. Centre for Neurodegeneration Research. Department of Clinical Neuroscience; Reino Unido
description Abnormal metabolism of the tau protein is central to the pathogenesis of a number of dementias, including Alzheimer's disease. Aberrant alternative splicing of exon 10 in the tau pre-mRNA resulting in an imbalance of tau isoforms is one of the molecular causes of the inherited tauopathy, FTDP-17. We showed previously in heterologous systems that exon 10 inclusion in tau mRNA could be modulated by spliceosome-mediated RNA trans-splicing (SMaRT). Here, we evaluated the potential of trans-splicing RNA reprogramming to correct tau mis-splicing in differentiated neurons in a mouse model of tau mis-splicing, the htau transgenic mouse line, expressing the human MAPT gene in a null mouse Mapt background. Trans-splicing molecules designed to increase exon 10 inclusion were delivered to neurons using lentiviral vectors. We demonstrate reprogramming of tau transcripts at the RNA level after transduction of cultured neurons or after direct delivery and long-term expression of viral vectors into the brain of htau mice in vivo. Tau RNA trans-splicing resulted in an increase in exon 10 inclusion in the mature tau mRNA. Importantly, we also show that the trans-spliced product is translated into a full-length chimeric tau protein. These results validate the potential of SMaRT to correct tau mis-splicing and provide a framework for its therapeutic application to neurodegenerative conditions linked to aberrant RNA processing.
publishDate 2013
dc.date.none.fl_str_mv 2013-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/4019
Avale, Maria Elena; Rodrigez Martin, Teresa; Gallo, Jean-Marc; Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing; Oxford University Press; Human Molecular Genetics; 22; 13; 7-2013; 2603-2611
0964-6906
url http://hdl.handle.net/11336/4019
identifier_str_mv Avale, Maria Elena; Rodrigez Martin, Teresa; Gallo, Jean-Marc; Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing; Oxford University Press; Human Molecular Genetics; 22; 13; 7-2013; 2603-2611
0964-6906
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://hmg.oxfordjournals.org/content/22/13/2603.long
info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674800/
info:eu-repo/semantics/altIdentifier/doi/10.1093%2Fhmg%2Fddt108
info:eu-repo/semantics/altIdentifier/issn/0964-6906
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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