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

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.