Moreno-Martínez, LauraGaja-Capdevila, NúriaMosqueira-Martín, LauraHerrando-Grabulosa, MireiaRodríguez-Gómez, LauraGonzález-Imaz, KlaudiaCalvo, Ana C.Sagartzazu-Aizpurua, MaialenMoreno-García, LeticiaFuentes, José ManuelAcevedo-Arozena, AbrahamAizpurua, Jesús M.Miranda, José IgnacioLópez de Muniain, AdolfoVallejo-Illarramendi, AinaraNavarro, XavierOsta, RosarioGil Bea, Francisco Javier2025-07-172025-07-172025-06-01Moreno-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.17448.0007-118810.1111/bph.17448https://academica-e.unavarra.es/handle/2454/54416Background 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.application/pdfeng© 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.ALSCalciumFKBP12RyRSOD1info:eu-repo/semantics/article2025-07-17info:eu-repo/semantics/openAccess