Tideglusib, a non-ATP competitive inhibitor of GSK-3β as a drug candidate for the treatment of amyotrophic lateral sclerosis

14 p.-6 fig.-2 tab.

Detalles Bibliográficos
Autores: Martínez-González, Loreto, Gonzalo-Consuegra, Claudia, Gómez-Almería, Marta, Porras, Gracia, De Lago, E., Martín-Requero, Ángeles, Martínez Gil, Ana
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/263677
Acceso en línea:http://hdl.handle.net/10261/263677
Access Level:acceso abierto
Palabra clave:ALS
GSK-3β
Tideglusib
TDP-43
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spelling Tideglusib, a non-ATP competitive inhibitor of GSK-3β as a drug candidate for the treatment of amyotrophic lateral sclerosisMartínez-González, LoretoGonzalo-Consuegra, ClaudiaGómez-Almería, MartaPorras, GraciaDe Lago, E.Martín-Requero, ÁngelesMartínez Gil, AnaALSGSK-3βTideglusibTDP-4314 p.-6 fig.-2 tab.Amyotrophic Lateral Sclerosis (ALS) is the most common degenerative motor neuron disease in adults. About 97% of ALS patients present TDP-43 aggregates with post-translational modifications, such as hyperphosphorylation, in the cytoplasm of affected cells. GSK-3β is one of the protein kinases involved in TDP-43 phosphorylation. Up-regulation of its expression and activity is reported on spinal cord and cortex tissues of ALS patients. Here, we propose the repurposing of Tideglusib, an in-house non-ATP competitive GSK-3β inhibitor that is currently in clinical trials for autism and myotonic dystrophy, as a promising therapeutic strategy for ALS. With this aim we have evaluated the efficacy of Tideglusib in different experimental ALS models both in vitro and in vivo. Moreover, we observed that GSK-3β activity is increased in lymphoblasts from sporadic ALS patients, with a simultaneous increase in TDP-43 phosphorylation and cytosolic TDP-43 accumulation. Treatment with Tideglusib decreased not only phospho-TDP-43 levels but also recovered its nuclear localization in ALS lymphoblasts and in a human TDP-43 neuroblastoma model. Additionally, we found that chronic oral treatment with Tideglusib is able to reduce the increased TDP-43 phosphorylation in the spinal cord of Prp-hTDP-43A315T mouse model. Therefore, we consider Tideglusib as a promising drug candidate for ALS, being proposed to start a clinical trial phase II by the end of the year.This research was funded by Madrid Community (B2017/BMD3813 ELA-Madrid), ISCiii (CIBERNED CB18/05/00040 and CB06/05/0089) and AEI (grant RTI2018-096100-B-I00 to Á.M.-R., PID2019-105600RB-I00 to A.M. and RTI2018-0988885-B-I00 to E.d.L.).Peer reviewedMultidisciplinary Digital Publishing InstituteComunidad de MadridInstituto de Salud Carlos IIIAgencia Estatal de Investigación (España)Martínez-González, Loreto [0000-0003-4593-4889]Gonzalo-Consuegra, Claudia [0000-0002-4062-7516]De Lago, E. [0000-0002-6260-3777]Martín-Requero, Ángeles [0000-0002-3416-9440]Martínez, Ana [0000-0002-2707-8110]Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202220222021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/263677reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#B2017/BMD3813/ELA-Madridinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-096100-B-I00info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105600RB-I00https://doi.org/10.3390/ijms22168975Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2636772026-05-22T06:33:51Z
dc.title.none.fl_str_mv Tideglusib, a non-ATP competitive inhibitor of GSK-3β as a drug candidate for the treatment of amyotrophic lateral sclerosis
title Tideglusib, a non-ATP competitive inhibitor of GSK-3β as a drug candidate for the treatment of amyotrophic lateral sclerosis
spellingShingle Tideglusib, a non-ATP competitive inhibitor of GSK-3β as a drug candidate for the treatment of amyotrophic lateral sclerosis
Martínez-González, Loreto
ALS
GSK-3β
Tideglusib
TDP-43
title_short Tideglusib, a non-ATP competitive inhibitor of GSK-3β as a drug candidate for the treatment of amyotrophic lateral sclerosis
title_full Tideglusib, a non-ATP competitive inhibitor of GSK-3β as a drug candidate for the treatment of amyotrophic lateral sclerosis
title_fullStr Tideglusib, a non-ATP competitive inhibitor of GSK-3β as a drug candidate for the treatment of amyotrophic lateral sclerosis
title_full_unstemmed Tideglusib, a non-ATP competitive inhibitor of GSK-3β as a drug candidate for the treatment of amyotrophic lateral sclerosis
title_sort Tideglusib, a non-ATP competitive inhibitor of GSK-3β as a drug candidate for the treatment of amyotrophic lateral sclerosis
dc.creator.none.fl_str_mv Martínez-González, Loreto
Gonzalo-Consuegra, Claudia
Gómez-Almería, Marta
Porras, Gracia
De Lago, E.
Martín-Requero, Ángeles
Martínez Gil, Ana
author Martínez-González, Loreto
author_facet Martínez-González, Loreto
Gonzalo-Consuegra, Claudia
Gómez-Almería, Marta
Porras, Gracia
De Lago, E.
Martín-Requero, Ángeles
Martínez Gil, Ana
author_role author
author2 Gonzalo-Consuegra, Claudia
Gómez-Almería, Marta
Porras, Gracia
De Lago, E.
Martín-Requero, Ángeles
Martínez Gil, Ana
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Comunidad de Madrid
Instituto de Salud Carlos III
Agencia Estatal de Investigación (España)
Martínez-González, Loreto [0000-0003-4593-4889]
Gonzalo-Consuegra, Claudia [0000-0002-4062-7516]
De Lago, E. [0000-0002-6260-3777]
Martín-Requero, Ángeles [0000-0002-3416-9440]
Martínez, Ana [0000-0002-2707-8110]
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv ALS
GSK-3β
Tideglusib
TDP-43
topic ALS
GSK-3β
Tideglusib
TDP-43
description 14 p.-6 fig.-2 tab.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/263677
url http://hdl.handle.net/10261/263677
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
B2017/BMD3813/ELA-Madrid
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-096100-B-I00
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-105600RB-I00
https://doi.org/10.3390/ijms22168975
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
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 15,811543

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