Researchers have understood the genetic basis of spinal muscular atrophy (SMA) for many years. Mutations in the gene that encodes the protein survival motor neuron (SMN1) are the most usual cause of disease, as a mutation leads to a deficiency of SMN. Without this protein, motor neurons die, leading to poor communication between the nervous and muscular systems. However, what is not understood is how exactly the loss of SMN so specifically affects motor neurons.
As a result of work conducted at a laboratory in Italy, researchers have come closer to understanding how SMA pathogenesis works in the most commonly used mouse model of severe SMA: SMNΔ7. In the study, “A Perturbed MicroRNA Expression Pattern Characterizes Embryonic Neural Stem Cells Derived from a Severe Mouse Model of Spinal Muscular Atrophy (SMA),” that was published in International Journal of Molecular Sciences, lead author Dr. Andrea Luchetti explains that “miRNAs may be related to the proliferation differences characterizing SMNΔ7 neural stem cells (NSCs), and may be potentially involved in the molecular mechanisms of SMA.” In other words, special molecules (miRNAs) produced within the cell type that differentiates into motor neurons (NSCs) may be affecting the growth of these cells in SMA patients.
Since NSCs are cells that can turn into motor neurons, they are an ideal study model to understand SMA. Dr. Luchetti and her colleagues at University of Rome Tor Vergata, Bambino Gesù Children’s Hospital, and Istituto Superiore di Sanità conducted extensive characterization of NSCs derived from mice with the SMNΔ7 mutation that leads to an SMA-like disease state. During their experiments, the team noted that although the diseased NSCs behaved similar to NSCs isolated from normal mice, they had an altered cell cycle that caused rapid expansion.
In addition to altered growth, the diseased NSCs synthesized less of two miRNA molecules: miR-335-5p and miR-100-5p. Since miRNAs regulate protein synthesis in cells, this differential expression may affect neuronal function. Specifically, miR-100-5p reduces the production of insulin-like growth factor 1 receptor (IGF1R). Therefore, a decrease in miR-100-5p would lead to an increase in IGF1R, consequently leading to an increase in cellular proliferation.
Synthetic molecules called silencing RNA (siRNA) act similar to miRNA. With the results of this study understood, a feasible treatment approach that creates siRNAs based on miRNA-335-5p and miR100-5p may help individuals suffering with SMA.