Tau-positive nuclear indentations in P301S tauopathy mice

Increased incidence of neuronal nuclear indentations is a well-known feature of the striatum of Huntington's disease (HD) brains and, in Alzheimer's disease (AD), neuronal nuclear indentations have recently been reported to correlate with neurotoxicity caused by improper cytoskeletal/nucle...

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Autores: Fernández-Nogales, Marta, Santos-Galindo, María, Merchán-Rubira, Jesús, Hoozemans, Jeroen J. M., Rábano, Alberto, Ferrer, Isidro, Ávila, Jesús, Hernández, Félix, Lucas, José Javier
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2017
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/214164
Acceso en línea:http://hdl.handle.net/10261/214164
Access Level:acceso abierto
Palabra clave:Tau, TNR (tau nuclear rod)
Nuclear indentations
TNI (tau-immunopositive nuclear indentation)
Tauopathy
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spelling Tau-positive nuclear indentations in P301S tauopathy miceFernández-Nogales, MartaSantos-Galindo, MaríaMerchán-Rubira, JesúsHoozemans, Jeroen J. M.Rábano, AlbertoFerrer, IsidroÁvila, JesúsHernández, FélixLucas, José JavierTau, TNR (tau nuclear rod)Nuclear indentationsTNI (tau-immunopositive nuclear indentation)TauopathyIncreased incidence of neuronal nuclear indentations is a well-known feature of the striatum of Huntington's disease (HD) brains and, in Alzheimer's disease (AD), neuronal nuclear indentations have recently been reported to correlate with neurotoxicity caused by improper cytoskeletal/nucleoskeletal coupling. Initial detection of rod-shaped tau immunostaining in nuclei of cortical and striatal neurons of HD brains and in hippocampal neurons of early Braak stage AD led us to coin the term “tau nuclear rods (TNRs).” Although TNRs traverse nuclear space, they in fact occupy narrow cytoplasmic extensions that fill indentations of the nuclear envelope and we will here refer to this histological hallmark as Tau-immunopositive nuclear indentations (TNIs). We reasoned that TNI formation is likely secondary to tau alterations as TNI detection in HD correlates with an increase in total tau, particularly of the isoforms with four tubulin binding repeats (4R-tau). Here we analyze transgenic mice that overexpress human 4R-tau with a frontotemporal lobar degeneration-tau point mutation (P301S mice) to explore whether tau alteration is sufficient for TNI formation. Immunohistochemistry with various tau antibodies, immunoelectron microscopy and double tau-immunofluorescence/DAPI-nuclear counterstaining confirmed that excess 4R-tau in P301S mice is sufficient for the detection of abundant TNIs that fill nuclear indentations. Interestingly, this does not correlate with an increase in the number of nuclear indentations, thus suggesting that excess total tau or an isoform imbalance in favor of 4R-tau facilitates tau detection inside preexisting nuclear indentations but does not induce formation of the latter. In summary, here we demonstrate that tau alteration is sufficient for TNI detection and our results suggest that the neuropathological finding of TNIs becomes a possible indicator of increased total tau and/or increased 4R/3R-tau ratio in the affected neurons apart from being an efficient way to monitor pathology-associated nuclear indentations.Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CiberNed-Instituto de salud Carlos III) collaborative grant PI2013/09-2, CoEN grant (NEURO-MIR) and by grants from Spanish Ministery of Economy and Competitiveness (MINECO, SAF2012-34177 and SAF2015-65371-R), Fundación BBVA and Fundación Ramón Areces.Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España)Instituto de Salud Carlos IIIMinisterio de Economía y Competitividad (España)Fundación BBVAConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2020202020172020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Postprintinfo:eu-repo/semantics/acceptedVersionhttp://hdl.handle.net/10261/214164reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1111/bpa.12407Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2141642026-05-22T06:33:51Z
dc.title.none.fl_str_mv Tau-positive nuclear indentations in P301S tauopathy mice
title Tau-positive nuclear indentations in P301S tauopathy mice
spellingShingle Tau-positive nuclear indentations in P301S tauopathy mice
Fernández-Nogales, Marta
Tau, TNR (tau nuclear rod)
Nuclear indentations
TNI (tau-immunopositive nuclear indentation)
Tauopathy
title_short Tau-positive nuclear indentations in P301S tauopathy mice
title_full Tau-positive nuclear indentations in P301S tauopathy mice
title_fullStr Tau-positive nuclear indentations in P301S tauopathy mice
title_full_unstemmed Tau-positive nuclear indentations in P301S tauopathy mice
title_sort Tau-positive nuclear indentations in P301S tauopathy mice
dc.creator.none.fl_str_mv Fernández-Nogales, Marta
Santos-Galindo, María
Merchán-Rubira, Jesús
Hoozemans, Jeroen J. M.
Rábano, Alberto
Ferrer, Isidro
Ávila, Jesús
Hernández, Félix
Lucas, José Javier
author Fernández-Nogales, Marta
author_facet Fernández-Nogales, Marta
Santos-Galindo, María
Merchán-Rubira, Jesús
Hoozemans, Jeroen J. M.
Rábano, Alberto
Ferrer, Isidro
Ávila, Jesús
Hernández, Félix
Lucas, José Javier
author_role author
author2 Santos-Galindo, María
Merchán-Rubira, Jesús
Hoozemans, Jeroen J. M.
Rábano, Alberto
Ferrer, Isidro
Ávila, Jesús
Hernández, Félix
Lucas, José Javier
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España)
Instituto de Salud Carlos III
Ministerio de Economía y Competitividad (España)
Fundación BBVA
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Tau, TNR (tau nuclear rod)
Nuclear indentations
TNI (tau-immunopositive nuclear indentation)
Tauopathy
topic Tau, TNR (tau nuclear rod)
Nuclear indentations
TNI (tau-immunopositive nuclear indentation)
Tauopathy
description Increased incidence of neuronal nuclear indentations is a well-known feature of the striatum of Huntington's disease (HD) brains and, in Alzheimer's disease (AD), neuronal nuclear indentations have recently been reported to correlate with neurotoxicity caused by improper cytoskeletal/nucleoskeletal coupling. Initial detection of rod-shaped tau immunostaining in nuclei of cortical and striatal neurons of HD brains and in hippocampal neurons of early Braak stage AD led us to coin the term “tau nuclear rods (TNRs).” Although TNRs traverse nuclear space, they in fact occupy narrow cytoplasmic extensions that fill indentations of the nuclear envelope and we will here refer to this histological hallmark as Tau-immunopositive nuclear indentations (TNIs). We reasoned that TNI formation is likely secondary to tau alterations as TNI detection in HD correlates with an increase in total tau, particularly of the isoforms with four tubulin binding repeats (4R-tau). Here we analyze transgenic mice that overexpress human 4R-tau with a frontotemporal lobar degeneration-tau point mutation (P301S mice) to explore whether tau alteration is sufficient for TNI formation. Immunohistochemistry with various tau antibodies, immunoelectron microscopy and double tau-immunofluorescence/DAPI-nuclear counterstaining confirmed that excess 4R-tau in P301S mice is sufficient for the detection of abundant TNIs that fill nuclear indentations. Interestingly, this does not correlate with an increase in the number of nuclear indentations, thus suggesting that excess total tau or an isoform imbalance in favor of 4R-tau facilitates tau detection inside preexisting nuclear indentations but does not induce formation of the latter. In summary, here we demonstrate that tau alteration is sufficient for TNI detection and our results suggest that the neuropathological finding of TNIs becomes a possible indicator of increased total tau and/or increased 4R/3R-tau ratio in the affected neurons apart from being an efficient way to monitor pathology-associated nuclear indentations.
publishDate 2017
dc.date.none.fl_str_mv 2017
2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Postprint
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/214164
url http://hdl.handle.net/10261/214164
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1111/bpa.12407
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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