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

Abstract

Background 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.This 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