Repaglinide induces 003726 processing and neuroprotection in transgenic SOD1G93A mice

Gonzalo-Gobernado, Rafael ; Moreno-Martínez, Laura (Universidad de Zaragoza) ; González, Paz ; Dopazo, Xose Manuel ; Calvo, Ana Cristina (Universidad de Zaragoza) ; Pidal-Ladrón de Guevara, Isabel ; Seisdedos, Elisa ; Díaz-Muñoz, Rodrigo ; Mellström, Britt ; Osta, Rosario (Universidad de Zaragoza) ; Naranjo, José Ramón

Resumen: 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.

Idioma: Inglés

DOI: 10.3390/ijms242115783

Año: 2023

Publicado en: International Journal of Molecular Sciences 24, 21 (2023), 15783 [16 pp.]
ISSN: 1661-6596

Factor impacto JCR: 4.9 (2023)

Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 66 / 313 = 0.211 (2023) - Q1 - T1
Categ. JCR: CHEMISTRY, MULTIDISCIPLINARY rank: 68 / 231 = 0.294 (2023) - Q2 - T1

Factor impacto CITESCORE: 8.1 - Spectroscopy (Q1) - Computer Science Applications (Q1) - Physical and Theoretical Chemistry (Q1) - Inorganic Chemistry (Q1) - Organic Chemistry (Q1) - Molecular Biology (Q2) - Catalysis (Q2)

Factor impacto SCIMAGO: 1.179 - Medicine (miscellaneous) (Q1) - Physical and Theoretical Chemistry (Q1) - Computer Science Applications (Q1) - Inorganic Chemistry (Q1) - Spectroscopy (Q1) - Organic Chemistry (Q1) - Molecular Biology (Q2) - Catalysis (Q2)

Financiación: info:eu-repo/grantAgreement/ES/ISCIII/FEDER/PI21-00372

Tipo y forma: Article (Published version)

Área (Departamento): Área Genética (Dpto. Anatom.,Embri.Genét.Ani.)
Área (Departamento): Área Farmacología (Dpto. Farmac.Fisiol.y Med.L.F.)