Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons

Autores
Lacovich, Valentina; Espindola, Sonia Lorena; Alloatti, Matías; Pozo Devoto, Victorio Martin; Cromberg, Lucas Eneas; Carna, Mária E.; Forte, Giancarlo; Gallo, Jean Marc; Bruno, Luciana; Stokin, Xgorazd B.; Avale, Maria Elena; Falzone, Tomas Luis
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically inAPPdynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes.
Fil: Lacovich, Valentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina. International Clinical Research Center; Estados Unidos
Fil: Espindola, Sonia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Alloatti, Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina
Fil: Pozo Devoto, Victorio Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina
Fil: Cromberg, Lucas Eneas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina
Fil: Carna, Mária E.. International Clinical Research Center; Estados Unidos
Fil: Forte, Giancarlo. International Clinical Research Center; Estados Unidos
Fil: Gallo, Jean Marc. King's College London; Reino Unido
Fil: Bruno, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentina
Fil: Stokin, Xgorazd B.. Anne's University Hospital; República Checa
Fil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Materia
Alzheimer&Rsquo;S
App
Axonal Transport
Splicing
Tau
Tauopathies
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/45565
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/45565
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neuronsLacovich, ValentinaEspindola, Sonia LorenaAlloatti, MatíasPozo Devoto, Victorio MartinCromberg, Lucas EneasCarna, Mária E.Forte, GiancarloGallo, Jean MarcBruno, LucianaStokin, Xgorazd B.Avale, Maria ElenaFalzone, Tomas LuisAlzheimer&Rsquo;SAppAxonal TransportSplicingTauTauopathieshttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically inAPPdynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes.Fil: Lacovich, Valentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina. International Clinical Research Center; Estados UnidosFil: Espindola, Sonia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; ArgentinaFil: Alloatti, Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Pozo Devoto, Victorio Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Cromberg, Lucas Eneas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; ArgentinaFil: Carna, Mária E.. International Clinical Research Center; Estados UnidosFil: Forte, Giancarlo. International Clinical Research Center; Estados UnidosFil: Gallo, Jean Marc. King's College London; Reino UnidoFil: Bruno, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Stokin, Xgorazd B.. Anne's University Hospital; República ChecaFil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; ArgentinaFil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaSociety for Neuroscience2016-11info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/45565Lacovich, Valentina; Espindola, Sonia Lorena; Alloatti, Matías; Pozo Devoto, Victorio Martin; Cromberg, Lucas Eneas; et al.; Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons; Society for Neuroscience; Journal of Neuroscience; 37; 1; 11-2016; 58-690270-6474CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1523/JNEUROSCI.2305-16.2017info:eu-repo/semantics/altIdentifier/url/http://www.jneurosci.org/content/37/1/58info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:09:06Zoai:ri.conicet.gov.ar:11336/45565instacron: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:34982025-09-03 10:09:06.541CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons
title Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons
spellingShingle Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons
Lacovich, Valentina
Alzheimer&Rsquo;S
App
Axonal Transport
Splicing
Tau
Tauopathies
title_short Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons
title_full Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons
title_fullStr Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons
title_full_unstemmed Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons
title_sort Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons
dc.creator.none.fl_str_mv Lacovich, Valentina
Espindola, Sonia Lorena
Alloatti, Matías
Pozo Devoto, Victorio Martin
Cromberg, Lucas Eneas
Carna, Mária E.
Forte, Giancarlo
Gallo, Jean Marc
Bruno, Luciana
Stokin, Xgorazd B.
Avale, Maria Elena
Falzone, Tomas Luis
author Lacovich, Valentina
author_facet Lacovich, Valentina
Espindola, Sonia Lorena
Alloatti, Matías
Pozo Devoto, Victorio Martin
Cromberg, Lucas Eneas
Carna, Mária E.
Forte, Giancarlo
Gallo, Jean Marc
Bruno, Luciana
Stokin, Xgorazd B.
Avale, Maria Elena
Falzone, Tomas Luis
author_role author
author2 Espindola, Sonia Lorena
Alloatti, Matías
Pozo Devoto, Victorio Martin
Cromberg, Lucas Eneas
Carna, Mária E.
Forte, Giancarlo
Gallo, Jean Marc
Bruno, Luciana
Stokin, Xgorazd B.
Avale, Maria Elena
Falzone, Tomas Luis
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Alzheimer&Rsquo;S
App
Axonal Transport
Splicing
Tau
Tauopathies
topic Alzheimer&Rsquo;S
App
Axonal Transport
Splicing
Tau
Tauopathies
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically inAPPdynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes.
Fil: Lacovich, Valentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina. International Clinical Research Center; Estados Unidos
Fil: Espindola, Sonia Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Alloatti, Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina
Fil: Pozo Devoto, Victorio Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina
Fil: Cromberg, Lucas Eneas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina
Fil: Carna, Mária E.. International Clinical Research Center; Estados Unidos
Fil: Forte, Giancarlo. International Clinical Research Center; Estados Unidos
Fil: Gallo, Jean Marc. King's College London; Reino Unido
Fil: Bruno, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentina
Fil: Stokin, Xgorazd B.. Anne's University Hospital; República Checa
Fil: Avale, Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular ; Argentina
Fil: Falzone, Tomas Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia ; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
description Tau, as a microtubule (MT)-associated protein, participates in key neuronal functions such as the regulation of MT dynamics, axonal transport, and neurite outgrowth. Alternative splicing of exon 10 in the tau primary transcript gives rise to protein isoforms with three (3R) or four (4R) MT binding repeats. Although tau isoforms are balanced in the normal adult human brain, imbalances in 3R:4R ratio have been tightly associated with the pathogenesis of several neurodegenerative disorders, yet the underlying molecular mechanisms remain elusive. Several studies exploiting tau overexpression and/or mutations suggested that perturbations in tau metabolism impair axonal transport. Nevertheless, no physiological model has yet demonstrated the consequences of altering the endogenous relative content of tau isoforms over axonal transport regulation. Here, we addressed this issue using a trans-splicing strategy that allows modulating tau exon 10 inclusion/exclusion in differentiated human-derived neurons. Upon changes in 3R:4R tau relative content, neurons showed no morphological changes, but live imaging studies revealed that the dynamics of the amyloid precursor protein (APP) were significantly impaired. Single trajectory analyses of the moving vesicles showed that predominance of 3R tau favored the anterograde movement of APP vesicles, increasing anterograde run lengths and reducing retrograde runs and segmental velocities. Conversely, the imbalance toward the 4R isoform promoted a retrograde bias by a significant reduction of anterograde velocities. These findings suggest that changes in 3R:4R tau ratio has an impact on the regulation of axonal transport and specifically inAPPdynamics, which might link tau isoform imbalances with APP abnormal metabolism in neurodegenerative processes.
publishDate 2016
dc.date.none.fl_str_mv 2016-11
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/11336/45565
Lacovich, Valentina; Espindola, Sonia Lorena; Alloatti, Matías; Pozo Devoto, Victorio Martin; Cromberg, Lucas Eneas; et al.; Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons; Society for Neuroscience; Journal of Neuroscience; 37; 1; 11-2016; 58-69
0270-6474
CONICET Digital
CONICET
url http://hdl.handle.net/11336/45565
identifier_str_mv Lacovich, Valentina; Espindola, Sonia Lorena; Alloatti, Matías; Pozo Devoto, Victorio Martin; Cromberg, Lucas Eneas; et al.; Tau isoforms imbalance impairs the axonal transport of the amyloid precursor protein in human neurons; Society for Neuroscience; Journal of Neuroscience; 37; 1; 11-2016; 58-69
0270-6474
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1523/JNEUROSCI.2305-16.2017
info:eu-repo/semantics/altIdentifier/url/http://www.jneurosci.org/content/37/1/58
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Society for Neuroscience
publisher.none.fl_str_mv Society for Neuroscience
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 13.13397

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