Novel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1G93A amyotrophic lateral sclerosis (ALS) mice

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dc.contributor.authorMoreno-Martínez, Laura
dc.contributor.authorGaja-Capdevila, Núria
dc.contributor.authorMosqueira-Martín, Laura
dc.contributor.authorHerrando-Grabulosa, Mireia
dc.contributor.authorRodríguez-Gómez, Laura
dc.contributor.authorGonzález-Imaz, Klaudia
dc.contributor.authorCalvo, Ana C.
dc.contributor.authorSagartzazu-Aizpurua, Maialen
dc.contributor.authorMoreno-García, Leticia
dc.contributor.authorFuentes, José Manuel
dc.contributor.authorAcevedo-Arozena, Abraham
dc.contributor.authorAizpurua, Jesús M.
dc.contributor.authorMiranda, José Ignacio
dc.contributor.authorLópez de Muniain, Adolfo
dc.contributor.authorVallejo-Illarramendi, Ainara
dc.contributor.authorNavarro, Xavier
dc.contributor.authorOsta, Rosario
dc.contributor.authorGil Bea, Francisco Javier
dc.contributor.departmentCiencias de la Saludes_ES
dc.contributor.departmentOsasun Zientziakeu
dc.contributor.funderUniversidad Pública de Navarra / Nafarroako Unibertsitate Publikoa
dc.date.accessioned2025-07-17T18:01:15Z
dc.date.available2025-07-17T18:01:15Z
dc.date.issued2025-06-01
dc.date.updated2025-07-17T17:35:15Z
dc.description.abstractBackground and Purpose: Amyotrophic lateral sclerosis (ALS) is a devastating neu-rodegenerative disease with limited treatment options. ALS pathogenesis involvesintricate processes within motor neurons, characterized by dysregulated Ca 2+ influxand buffering in early ALS-affected motor neurones. This study proposes the modu-lation of ryanodine receptors (RyRs), key mediators of intracellular Ca 2+, as a thera-peutic target.Experimental Approach: A novel class of novel FKBP12 ligands that show activityas cytosolic calcium modulators through stabilizing RyR channel activity, weretested in the superoxide dismutase 1 (SOD1) G93A mouse model of ALS. Differentoutcomes were used to assess treatment efficacy, including electrophysiology, his-topathology, neuromuscular function and survival.Key Results: Among the novel FKBP12 ligands, MP-010 was chosen for its centralnervous system availability and favourable in vitro pharmaco-toxicological profile.Chronic administration of MP-010 to SOD1 G93A mice produced preservation ofmotor nerve conduction, with the 61-mg kg 1 dose significantly delaying the onsetof motor impairment. This was accompanied by improved motor coordination,increased innervated endplates and significant preservation of motor neurones inthe spinal cord of treated mice. Notably, MP-010 treatment significantly extendedlifespan by an average of 10 days compared to vehicle.Conclusions and Implications: FKBP12 ligands, particularly MP-010, exhibit prom-ising neuroprotective effects in ALS, highlighting their potential as novel therapeuticagents. Further investigations into the molecular mechanisms and clinical translat-ability of these compounds are needed for their application in ALS treatment.en
dc.description.sponsorshipThis work was funded by project CIBER-CALSPI2020/08-1, Grants CB06/05/1105 and CB06/05/0041 from the Instituto de Salud Carlos III of Spain, Grants PID2022-140354OB-I00 and PID2020-119780RB-100 from the Agencia Estatal de Investigación, co-funded by European Union (NextGenerationEU, Recovery, Transformation and Resilience Plan), and Grant IT1732-22 from the Basque Government - Eusko Jaurlaritza. F. J. G.-B. was funded byFundacion Roche Stop Fuga de Cerebros programme (BIO19/ROCHE/017/BD) and received support from the IKERBASQUE, Basque Foundation for Science (IKERBASQUE/PP/2022/003). L. M.-M. holds a PhD fellowship from the Euskal Herriko Univertsitatea (UPV/EHU) (PIF19/184). Open access funding provided by Universidad Pública de Navarra.
dc.format.mimetypeapplication/pdf
dc.identifier.citationMoreno-Martínez, L., Gaja-Capdevila, N., Mosqueira-Martín, L., Herrando-Grabulosa, M., Rodríguez-Gómez, L., González-Imaz, K., Calvo, A. C., Sagartzazu-Aizpurua, M., Moreno-García, L., Fuentes, J. M., Acevedo-Arozena, A., Aizpurua, J. M., Miranda, J. I., López de Muniain, A., Vallejo-Illarramendi, A., Navarro, X., Osta, R., Gil-Bea, F. J. (2025) Novel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1G93A amyotrophic lateral sclerosis (ALS) mice. British Journal of Pharmacology, 182(11), 2466-2486. https://doi.org/10.1111/bph.17448.
dc.identifier.doi10.1111/bph.17448
dc.identifier.issn0007-1188
dc.identifier.urihttps://academica-e.unavarra.es/handle/2454/54416
dc.language.isoeng
dc.publisherWiley
dc.relation.ispartofBritish Journal of Pharmacology 2025, 182(11), 2466–2486
dc.relation.projectIDinfo:eu-repo/grantAgreement/MSC//CB06%2F05%2F1105/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/MSC//CB06%2F05%2F0041/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-140354OB-I00/ES/
dc.relation.projectIDinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2020-119780RB-I00/ES/
dc.relation.publisherversionhttps://doi.org/10.1111/bph.17448
dc.rights© 2025 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in anymedium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectALSen
dc.subjectCalciumen
dc.subjectFKBP12en
dc.subjectRyRen
dc.subjectSOD1en
dc.titleNovel FKBP prolyl isomerase 1A (FKBP12) ligand promotes functional improvement in SOD1G93A amyotrophic lateral sclerosis (ALS) miceen
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dspace.entity.typePublication
relation.isAuthorOfPublicationb7d8829a-1055-49d1-b2af-c051914c8ebb
relation.isAuthorOfPublication.latestForDiscoveryb7d8829a-1055-49d1-b2af-c051914c8ebb

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