Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice

The interaction of the activating transcription factor 6 (ATF6), a key effector of the unfolded protein response (UPR) in the endoplasmic reticulum, with the neuronal calcium sensor Downstream Regulatory Element Antagonist Modulator (DREAM) is a potential therapeutic target in neurodegeneration. Mod...

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Autores: Gonzalo-Gobernado, Rafael, Moreno-Martínez, Laura, González Pérez, Paz, Dopazo, Xose M., Calvo, Ana Cristina, Pidal-Ladrón de Guevara, Isabel, Seisdedos, Elisa, Díaz-Muñoz, Rodrigo, Mellström, Britt, Osta, Rosario, Naranjo, José Ramón
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/338350
Acceso en línea:http://hdl.handle.net/10261/338350
Access Level:acceso abierto
Palabra clave:ALS
Repaglinide
DREAM
ATF6
SOD1
UPR
Motoneurons
Microglia
Astroglia
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repository_id_str
spelling Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A MiceGonzalo-Gobernado, RafaelMoreno-Martínez, LauraGonzález Pérez, PazDopazo, Xose M.Calvo, Ana CristinaPidal-Ladrón de Guevara, IsabelSeisdedos, ElisaDíaz-Muñoz, RodrigoMellström, BrittOsta, RosarioNaranjo, José RamónALSRepaglinideDREAMATF6SOD1UPRMotoneuronsMicrogliaAstrogliaThe interaction of the activating transcription factor 6 (ATF6), a key effector of the unfolded protein response (UPR) in the endoplasmic reticulum, with the neuronal calcium sensor Downstream Regulatory Element Antagonist Modulator (DREAM) is a potential therapeutic target in neurodegeneration. Modulation of the ATF6–DREAM interaction with repaglinide (RP) induced neuroprotection in a model of Huntington’s disease. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no cure, characterized by the progressive loss of motoneurons resulting in muscle denervation, atrophy, paralysis, and death. The aim of this work was to investigate the potential therapeutic significance of DREAM as a target for intervention in ALS. We found that the expression of the DREAM protein was reduced in the spinal cord of SOD1G93A mice compared to wild-type littermates. RP treatment improved motor strength and reduced the expression of the ALS progression marker collagen type XIXα1 (Col19α1 mRNA) in the quadriceps muscle in SOD1G93A mice. Moreover, treated SOD1G93A mice showed reduced motoneuron loss and glial activation and increased ATF6 processing in the spinal cord. These results indicate that the modulation of the DREAM–ATF6 interaction ameliorates ALS symptoms in SOD1G93A mice.This research was funded by Instituto de Salud Carlos III CIBERNED (RO and JRN) and PI21/00372 (RO); by Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa” from the European Union (RO); by the Consolidated Groups Program from Gobierno de Aragón (RO); and by the Innovation Program from Asahi Kasei Pharma (JRN). R.G.-G. was supported by a post-doctoral contract from the Severo Ochoa Excellence Program (Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación).Peer reviewedMultidisciplinary Digital Publishing InstituteInstituto de Salud Carlos IIIEuropean CommissionGobierno de AragónAsahi Kasei CorporationMinisterio de Ciencia e Innovación (España)Agencia Estatal de Investigación (España)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2023202320232023info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/338350reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.3390/ijms242115783Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3383502026-05-22T06:33:51Z
dc.title.none.fl_str_mv Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice
title Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice
spellingShingle Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice
Gonzalo-Gobernado, Rafael
ALS
Repaglinide
DREAM
ATF6
SOD1
UPR
Motoneurons
Microglia
Astroglia
title_short Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice
title_full Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice
title_fullStr Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice
title_full_unstemmed Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice
title_sort Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice
dc.creator.none.fl_str_mv Gonzalo-Gobernado, Rafael
Moreno-Martínez, Laura
González Pérez, Paz
Dopazo, Xose M.
Calvo, Ana Cristina
Pidal-Ladrón de Guevara, Isabel
Seisdedos, Elisa
Díaz-Muñoz, Rodrigo
Mellström, Britt
Osta, Rosario
Naranjo, José Ramón
author Gonzalo-Gobernado, Rafael
author_facet Gonzalo-Gobernado, Rafael
Moreno-Martínez, Laura
González Pérez, Paz
Dopazo, Xose M.
Calvo, Ana Cristina
Pidal-Ladrón de Guevara, Isabel
Seisdedos, Elisa
Díaz-Muñoz, Rodrigo
Mellström, Britt
Osta, Rosario
Naranjo, José Ramón
author_role author
author2 Moreno-Martínez, Laura
González Pérez, Paz
Dopazo, Xose M.
Calvo, Ana Cristina
Pidal-Ladrón de Guevara, Isabel
Seisdedos, Elisa
Díaz-Muñoz, Rodrigo
Mellström, Britt
Osta, Rosario
Naranjo, José Ramón
author2_role author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
European Commission
Gobierno de Aragón
Asahi Kasei Corporation
Ministerio de Ciencia e Innovación (España)
Agencia Estatal de Investigación (España)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv ALS
Repaglinide
DREAM
ATF6
SOD1
UPR
Motoneurons
Microglia
Astroglia
topic ALS
Repaglinide
DREAM
ATF6
SOD1
UPR
Motoneurons
Microglia
Astroglia
description The interaction of the activating transcription factor 6 (ATF6), a key effector of the unfolded protein response (UPR) in the endoplasmic reticulum, with the neuronal calcium sensor Downstream Regulatory Element Antagonist Modulator (DREAM) is a potential therapeutic target in neurodegeneration. Modulation of the ATF6–DREAM interaction with repaglinide (RP) induced neuroprotection in a model of Huntington’s disease. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with no cure, characterized by the progressive loss of motoneurons resulting in muscle denervation, atrophy, paralysis, and death. The aim of this work was to investigate the potential therapeutic significance of DREAM as a target for intervention in ALS. We found that the expression of the DREAM protein was reduced in the spinal cord of SOD1G93A mice compared to wild-type littermates. RP treatment improved motor strength and reduced the expression of the ALS progression marker collagen type XIXα1 (Col19α1 mRNA) in the quadriceps muscle in SOD1G93A mice. Moreover, treated SOD1G93A mice showed reduced motoneuron loss and glial activation and increased ATF6 processing in the spinal cord. These results indicate that the modulation of the DREAM–ATF6 interaction ameliorates ALS symptoms in SOD1G93A mice.
publishDate 2023
dc.date.none.fl_str_mv 2023
2023
2023
2023
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/10261/338350
url http://hdl.handle.net/10261/338350
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.3390/ijms242115783
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
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 15.812455

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