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dc.contributor.author
Avale, Maria Elena
dc.contributor.author
Rodrigez Martin, Teresa
dc.contributor.author
Gallo, Jean-Marc
dc.date.available
2016-02-03T20:34:50Z
dc.date.issued
2013-07
dc.identifier.citation
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
dc.identifier.issn
0964-6906
dc.identifier.uri
http://hdl.handle.net/11336/4019
dc.description.abstract
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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Oxford University Press
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by/2.5/ar/
dc.subject
Alternative Splicing
dc.subject
Gene Therapy
dc.subject
Neurodegeneration
dc.subject.classification
Bioquímica y Biología Molecular
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Ciencias Biológicas
dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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Genética Humana
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Medicina Básica
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CIENCIAS MÉDICAS Y DE LA SALUD
dc.title
Trans-splicing correction of tau isoform imbalance in a mouse model of tau mis-splicing
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2016-03-30 10:35:44.97925-03
dc.journal.volume
22
dc.journal.number
13
dc.journal.pagination
2603-2611
dc.journal.pais
Reino Unido
dc.journal.ciudad
Oxford
dc.conicet.avisoEditorial
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/ 3.0/), which permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.description.fil
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
dc.description.fil
Fil: Rodrigez Martin, Teresa. Institute of Psychiatry. King’s College London. Centre for Neurodegeneration Research. Department of Clinical Neuroscience; Reino Unido
dc.description.fil
Fil: Gallo, Jean-Marc. Institute of Psychiatry. King’s College London. Centre for Neurodegeneration Research. Department of Clinical Neuroscience; Reino Unido
dc.journal.title
Human Molecular Genetics
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://hmg.oxfordjournals.org/content/22/13/2603.long
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674800/
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1093%2Fhmg%2Fddt108
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/issn/0964-6906
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