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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 principales: Gonzalo-Gobernado, Rafael, Moreno-Martínez, Laura, González, Paz, Dopazo, Xose Manuel, Calvo, Ana Cristina, Pidal-Ladrón de Guevara, Isabel, Seisdedos, Elisa, Díaz-Muñoz, Rodrigo, Mellström, Britt, Osta, Rosario, Naranjo, José Ramón
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10648964/
https://www.ncbi.nlm.nih.gov/pubmed/37958767
http://dx.doi.org/10.3390/ijms242115783
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author Gonzalo-Gobernado, Rafael
Moreno-Martínez, Laura
González, Paz
Dopazo, Xose Manuel
Calvo, Ana Cristina
Pidal-Ladrón de Guevara, Isabel
Seisdedos, Elisa
Díaz-Muñoz, Rodrigo
Mellström, Britt
Osta, Rosario
Naranjo, José Ramón
author_facet Gonzalo-Gobernado, Rafael
Moreno-Martínez, Laura
González, Paz
Dopazo, Xose Manuel
Calvo, Ana Cristina
Pidal-Ladrón de Guevara, Isabel
Seisdedos, Elisa
Díaz-Muñoz, Rodrigo
Mellström, Britt
Osta, Rosario
Naranjo, José Ramón
author_sort Gonzalo-Gobernado, Rafael
collection PubMed
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.
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spelling pubmed-106489642023-10-30 Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice Gonzalo-Gobernado, Rafael Moreno-Martínez, Laura González, Paz Dopazo, Xose Manuel Calvo, Ana Cristina Pidal-Ladrón de Guevara, Isabel Seisdedos, Elisa Díaz-Muñoz, Rodrigo Mellström, Britt Osta, Rosario Naranjo, José Ramón Int J Mol Sci Article 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. MDPI 2023-10-30 /pmc/articles/PMC10648964/ /pubmed/37958767 http://dx.doi.org/10.3390/ijms242115783 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gonzalo-Gobernado, Rafael
Moreno-Martínez, Laura
González, Paz
Dopazo, Xose Manuel
Calvo, Ana Cristina
Pidal-Ladrón de Guevara, Isabel
Seisdedos, Elisa
Díaz-Muñoz, Rodrigo
Mellström, Britt
Osta, Rosario
Naranjo, José Ramón
Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice
title 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_short Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice
title_sort repaglinide induces atf6 processing and neuroprotection in transgenic sod1g93a mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10648964/
https://www.ncbi.nlm.nih.gov/pubmed/37958767
http://dx.doi.org/10.3390/ijms242115783
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