Modulation of tau isoforms by RNA reprogramming: Functional consequences and therapeutic perspectives

Autores
Avale, Maria Elena; Damianich, Ana; Facal, Carolina Lucia; Loch, Delfina; Ferrario, Juan Esteban; Espindola, Sonia Lorena
Año de publicación
2019
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Tauopathies are neurodegenerative diseases characterized by the presence of intraneuronal aggregates of the protein tau in insoluble neurofibrillary tangles (NFTs). Tau is a microtubule-associated protein predominantly expressed in neurons, which participates in microtubule polymerization and axonal transport. Alternative splicing of exon 10 (E10) in the Tau transcript produces protein isoforms with three (3R) or four (4R) microtubule binding repeats, which are expressed in equal amounts in the normal adult human brain. Several tauopathies are associated with mutations affecting exon 10 alternative splicing, leading to an imbalance between 3R and 4R isoforms. Correction of that imbalance represent a potential therapeutical approach for those tauopathies.Here we present our achievements using a trans-splicing RNA reprogramming strategy to modulate the 3R:4R tau ratio, either in cultured post-mitotic human neurons differentiated in vitro or into the mouse brain. Lentiviral vectors were used to express molecules that modulate E10 inclusion/exclusion by RNA trans-splicing with the endogenous tau transcript. Tau isoforms were quantified by qPCR and western blot. Morphological analyses and live imaging axonal transport indicate that perturbations in the tau 3R:4R ratio in human neurons impaired axonal transport dynamics without altering neuronal morphology. In a mouse model of tauopathy (htau mice) local modulation of E10 inclusion in the prefrontal cortex improved cognitive deficit, restored neuronal firing patterns and reduced insoluble and hyperphosphorylated tau contents. Moreover, local shifting of 3R to 4R tau in the striatum improved motor coordination deficits in htau mice.Together, our results evidence some of the (dys)functional consequences of tau 3R:4R imbalance and rise the potential use of RNA reprogramming to correct tau mis-splicing in human tauopathies.
Fil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Damianich, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Facal, Carolina Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Loch, Delfina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Ferrario, Juan Esteban. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Espindola, Sonia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
10th IBRO World Congress of Neuroscience
Daegu
Corea del Sur
International Brain Research Organization
Materia
TAU
GENE THERAPY
MOTOR COORDINATION
SPLICING
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/234333
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/234333
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Modulation of tau isoforms by RNA reprogramming: Functional consequences and therapeutic perspectivesAvale, Maria ElenaDamianich, AnaFacal, Carolina LuciaLoch, DelfinaFerrario, Juan EstebanEspindola, Sonia LorenaTAUGENE THERAPYMOTOR COORDINATIONSPLICINGhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Tauopathies are neurodegenerative diseases characterized by the presence of intraneuronal aggregates of the protein tau in insoluble neurofibrillary tangles (NFTs). Tau is a microtubule-associated protein predominantly expressed in neurons, which participates in microtubule polymerization and axonal transport. Alternative splicing of exon 10 (E10) in the Tau transcript produces protein isoforms with three (3R) or four (4R) microtubule binding repeats, which are expressed in equal amounts in the normal adult human brain. Several tauopathies are associated with mutations affecting exon 10 alternative splicing, leading to an imbalance between 3R and 4R isoforms. Correction of that imbalance represent a potential therapeutical approach for those tauopathies.Here we present our achievements using a trans-splicing RNA reprogramming strategy to modulate the 3R:4R tau ratio, either in cultured post-mitotic human neurons differentiated in vitro or into the mouse brain. Lentiviral vectors were used to express molecules that modulate E10 inclusion/exclusion by RNA trans-splicing with the endogenous tau transcript. Tau isoforms were quantified by qPCR and western blot. Morphological analyses and live imaging axonal transport indicate that perturbations in the tau 3R:4R ratio in human neurons impaired axonal transport dynamics without altering neuronal morphology. In a mouse model of tauopathy (htau mice) local modulation of E10 inclusion in the prefrontal cortex improved cognitive deficit, restored neuronal firing patterns and reduced insoluble and hyperphosphorylated tau contents. Moreover, local shifting of 3R to 4R tau in the striatum improved motor coordination deficits in htau mice.Together, our results evidence some of the (dys)functional consequences of tau 3R:4R imbalance and rise the potential use of RNA reprogramming to correct tau mis-splicing in human tauopathies.Fil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Damianich, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Facal, Carolina Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Loch, Delfina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Ferrario, Juan Esteban. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Espindola, Sonia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina10th IBRO World Congress of NeuroscienceDaeguCorea del SurInternational Brain Research OrganizationElsevier2019info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/234333Modulation of tau isoforms by RNA reprogramming: Functional consequences and therapeutic perspectives; 10th IBRO World Congress of Neuroscience; Daegu; Corea del Sur; 2019; 105-1062451-8301CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.ibror.2019.07.342Internacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:02:21Zoai:ri.conicet.gov.ar:11336/234333instacron: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 10:02:22.13CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Modulation of tau isoforms by RNA reprogramming: Functional consequences and therapeutic perspectives
title Modulation of tau isoforms by RNA reprogramming: Functional consequences and therapeutic perspectives
spellingShingle Modulation of tau isoforms by RNA reprogramming: Functional consequences and therapeutic perspectives
Avale, Maria Elena
TAU
GENE THERAPY
MOTOR COORDINATION
SPLICING
title_short Modulation of tau isoforms by RNA reprogramming: Functional consequences and therapeutic perspectives
title_full Modulation of tau isoforms by RNA reprogramming: Functional consequences and therapeutic perspectives
title_fullStr Modulation of tau isoforms by RNA reprogramming: Functional consequences and therapeutic perspectives
title_full_unstemmed Modulation of tau isoforms by RNA reprogramming: Functional consequences and therapeutic perspectives
title_sort Modulation of tau isoforms by RNA reprogramming: Functional consequences and therapeutic perspectives
dc.creator.none.fl_str_mv Avale, Maria Elena
Damianich, Ana
Facal, Carolina Lucia
Loch, Delfina
Ferrario, Juan Esteban
Espindola, Sonia Lorena
author Avale, Maria Elena
author_facet Avale, Maria Elena
Damianich, Ana
Facal, Carolina Lucia
Loch, Delfina
Ferrario, Juan Esteban
Espindola, Sonia Lorena
author_role author
author2 Damianich, Ana
Facal, Carolina Lucia
Loch, Delfina
Ferrario, Juan Esteban
Espindola, Sonia Lorena
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv TAU
GENE THERAPY
MOTOR COORDINATION
SPLICING
topic TAU
GENE THERAPY
MOTOR COORDINATION
SPLICING
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Tauopathies are neurodegenerative diseases characterized by the presence of intraneuronal aggregates of the protein tau in insoluble neurofibrillary tangles (NFTs). Tau is a microtubule-associated protein predominantly expressed in neurons, which participates in microtubule polymerization and axonal transport. Alternative splicing of exon 10 (E10) in the Tau transcript produces protein isoforms with three (3R) or four (4R) microtubule binding repeats, which are expressed in equal amounts in the normal adult human brain. Several tauopathies are associated with mutations affecting exon 10 alternative splicing, leading to an imbalance between 3R and 4R isoforms. Correction of that imbalance represent a potential therapeutical approach for those tauopathies.Here we present our achievements using a trans-splicing RNA reprogramming strategy to modulate the 3R:4R tau ratio, either in cultured post-mitotic human neurons differentiated in vitro or into the mouse brain. Lentiviral vectors were used to express molecules that modulate E10 inclusion/exclusion by RNA trans-splicing with the endogenous tau transcript. Tau isoforms were quantified by qPCR and western blot. Morphological analyses and live imaging axonal transport indicate that perturbations in the tau 3R:4R ratio in human neurons impaired axonal transport dynamics without altering neuronal morphology. In a mouse model of tauopathy (htau mice) local modulation of E10 inclusion in the prefrontal cortex improved cognitive deficit, restored neuronal firing patterns and reduced insoluble and hyperphosphorylated tau contents. Moreover, local shifting of 3R to 4R tau in the striatum improved motor coordination deficits in htau mice.Together, our results evidence some of the (dys)functional consequences of tau 3R:4R imbalance and rise the potential use of RNA reprogramming to correct tau mis-splicing in human tauopathies.
Fil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Damianich, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Facal, Carolina Lucia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Loch, Delfina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Ferrario, Juan Esteban. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Espindola, Sonia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
10th IBRO World Congress of Neuroscience
Daegu
Corea del Sur
International Brain Research Organization
description Tauopathies are neurodegenerative diseases characterized by the presence of intraneuronal aggregates of the protein tau in insoluble neurofibrillary tangles (NFTs). Tau is a microtubule-associated protein predominantly expressed in neurons, which participates in microtubule polymerization and axonal transport. Alternative splicing of exon 10 (E10) in the Tau transcript produces protein isoforms with three (3R) or four (4R) microtubule binding repeats, which are expressed in equal amounts in the normal adult human brain. Several tauopathies are associated with mutations affecting exon 10 alternative splicing, leading to an imbalance between 3R and 4R isoforms. Correction of that imbalance represent a potential therapeutical approach for those tauopathies.Here we present our achievements using a trans-splicing RNA reprogramming strategy to modulate the 3R:4R tau ratio, either in cultured post-mitotic human neurons differentiated in vitro or into the mouse brain. Lentiviral vectors were used to express molecules that modulate E10 inclusion/exclusion by RNA trans-splicing with the endogenous tau transcript. Tau isoforms were quantified by qPCR and western blot. Morphological analyses and live imaging axonal transport indicate that perturbations in the tau 3R:4R ratio in human neurons impaired axonal transport dynamics without altering neuronal morphology. In a mouse model of tauopathy (htau mice) local modulation of E10 inclusion in the prefrontal cortex improved cognitive deficit, restored neuronal firing patterns and reduced insoluble and hyperphosphorylated tau contents. Moreover, local shifting of 3R to 4R tau in the striatum improved motor coordination deficits in htau mice.Together, our results evidence some of the (dys)functional consequences of tau 3R:4R imbalance and rise the potential use of RNA reprogramming to correct tau mis-splicing in human tauopathies.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Congreso
Journal
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/234333
Modulation of tau isoforms by RNA reprogramming: Functional consequences and therapeutic perspectives; 10th IBRO World Congress of Neuroscience; Daegu; Corea del Sur; 2019; 105-106
2451-8301
CONICET Digital
CONICET
url http://hdl.handle.net/11336/234333
identifier_str_mv Modulation of tau isoforms by RNA reprogramming: Functional consequences and therapeutic perspectives; 10th IBRO World Congress of Neuroscience; Daegu; Corea del Sur; 2019; 105-106
2451-8301
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.ibror.2019.07.342
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.coverage.none.fl_str_mv Internacional
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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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