MIR-206 REDUCES THE SEVERITY OF MOTOR NEURON DEGENERATION IN THE FACIAL NUCLEI OF THE BRAIN STEM IN A MOUSE MODEL OF SMA

Abstract Spinal muscular atrophy (SMA) is a severe neuromuscular disease affecting infants, caused by alterations of the survival motor neuron gene, which results in progressive degeneration of motor neurons (MNs). Although an effective treatment for SMA patients has been recently developed, the molecular pathway involved in selective MNs degeneration has not been yet elucidated. In particular, miRNA-206 has been demonstrated to play a relevant role in the regeneration of neuromuscular junction in several MNs diseases and particularly it is up-regulated in the quadriceps, tibialis anterior, spinal cord and serum of SMA mice. In the present paper, we demonstrated that miRNA-206 was transiently up-regulated also in the brain stem of a mouse model of SMA, in the early phase of the disease, paralleling MNs degeneration. In order to prevent miRNA-206 down-regulation occurring in the symptomatic phase of the disease, we intracerebroventricularly injected miR-206 in SMA pups, demonstrating that miR-206 reduced the severity of SMA pathology, slowing down disease progression, increasing survival rate and improving behavioral performance of mice. Interestingly, miRNA-206 up-regulation induced a reduction of the predicted target sodium calcium exchanger isoform 2, NCX2, one of the main regulators of intracellular [Ca2+] and [Na+]. Therefore, we hypothesized that miR-206 might exert part of its neuroprotective effect modulating NCX2 expression in SMA disease.