Elucidating the regulatory effect of miRNA on survival motor neuron (SMN) protein in spinal muscular atropy (SMA) Human iPSC-Derived Fibroblast

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy due to the mutations in the survival motor neuron 1 gene which encodes the full-length form of the SMN protein. Studies demonstrated that the in vitro loss of survival motor neuron (SMN) proteins leads to severe defects, such as motor neuron survival and neurite extension. Recent findings demonstrated the role for miRNA in the pathogenesis of motor neuron diseases, including SMA. Due to the recent advances in cell technology, induced pluripotent stem cells (iPSCs) offer the opportunity to generate and directly analyze the role of miRNA in healthy and disease states. This leads to the objective of this study which is to investigate the dysregulation of targeted miRNAs expression in iPSC which may contribute to the pathophysiology of SMA and its effect on SMN protein level. In this study, differential expression analysis of mRNA microarray and miRNA-Seq will be done to detect enriched disease phenotypes. The correlations between the expression data and shared pathways between mRNA and miRNA will be performed using Ingenuity Pathway Analysis. Finally, transfection of miRNA mimics or inhibitors into the SMA human iPSC-derived fibroblast will be done to investigate the potential neuroprotective effect of specific miRNA expression modulations by checking the level of SMN protein. It is speculated that the dysregulation of miRNAs expression contributes to the pathophysiology of SMA and the vulnerability of SMN protein can be altered by the modulation of specific miRNA. From this study, it may provide an insight into the role of miRNA in SMN protein restoration and could improve morphological defects associated with motor neurons such as neuromuscular junction, motor function and motor neuron viability. These results will provide further insights into the complex RNA regulatory mechanism associated with SMA.