Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice

Rafael Gonzalo-Gobernado
† ,
Laura Moreno-Martinez
† ORCID logo ,
Paz González
,
Xose Manuel DOPAZO
,
Ana Cristina Calvo
ORCID logo ,
Isabel PIDAL-LADRON DE GUEVARA
,
Elisa SEISDEDOS
,
Rodrigo DIAZ-MUÑOZ
ORCID logo ,
Britt MELLSTROM
,
Rosario Osta
* ORCID logo ,
Jose Ramon NARANJO
*
†
These authors have contributed equally to this work.
Version 1 : Received: 27 September 2023 / Approved: 27 September 2023 / Online: 28 September 2023 (04:56:07 CEST)

A peer-reviewed article of this Preprint also exists.

Gonzalo-Gobernado, R.; Moreno-Martínez, L.; González, P.; Dopazo, X.M.; Calvo, A.C.; Pidal-Ladrón de Guevara, I.; Seisdedos, E.; Díaz-Muñoz, R.; Mellström, B.; Osta, R.; Naranjo, J.R. Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice. Int. J. Mol. Sci. 2023, 24, 15783. Gonzalo-Gobernado, R.; Moreno-Martínez, L.; González, P.; Dopazo, X.M.; Calvo, A.C.; Pidal-Ladrón de Guevara, I.; Seisdedos, E.; Díaz-Muñoz, R.; Mellström, B.; Osta, R.; Naranjo, J.R. Repaglinide Induces ATF6 Processing and Neuroprotection in Transgenic SOD1G93A Mice. Int. J. Mol. Sci. 2023, 24, 15783.

Abstract

: 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 interaction ATF6-DREAM 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 XIX1 (Col191 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.

Keywords

ALS; Repaglinide; DREAM; ATF6; SOD1; UPR; motoneurons; microglia; astroglia

Subject

Medicine and Pharmacology, Neuroscience and Neurology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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