Modeling the Early Phenotype at the Neuromuscular Junction of Spinal Muscular Atrophy Using Patient-Derived iPSCs

Abstract

SummarySpinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations of the survival of motor neuron 1 (SMN1) gene. In the pathogenesis of SMA, pathological changes of the neuromuscular junction (NMJ) precede the motor neuronal loss. Therefore, it is critical to evaluate the NMJ formed by SMA patients’ motor neurons (MNs), and to identify drugs that can restore the normal condition. We generated NMJ-like structures using MNs derived from SMA patient-specific induced pluripotent stem cells (iPSCs), and found that the clustering of the acetylcholine receptor (AChR) is significantly impaired. Valproic acid and antisense oligonucleotide treatment ameliorated the AChR clustering defects, leading to an increase in the level of full-length SMN transcripts. Thus, the current in vitro model of AChR clustering using SMA patient-derived iPSCs is useful to dissect the pathophysiological mechanisms underlying the development of SMA, and to evaluate the efficacy of new therapeutic approaches.

Induced pluripotent stem cells for modeling neurological disorders

“…Valproic acid (1 mmol/L) and Tobramycin (320 umol/L) drugs, both previously described in the treatment of SMA patients [54] , were tested and appeared to increase the production of SMN protein in iPSC-derived motor neurons. Valproic acid and anti-sense oligo treatment help improve defects in AChR clustering, increasing levels of SMN transcripts [55] . The neuronal differentiation of SMA iPSCs show reduced capacity to produce motor neurons [51] , therefore, applying gene correcting technology may aid in overcoming these methodological shortcomings.…”

Creating Interactions between Tissue-Engineered Skeletal Muscle and the Peripheral Nervous System

“…In cases such as this, the possibility of generating cells carrying patient-specific mutations may enable more accurate recapitulation of the disease phenotype, leading to more informative mechanistic studies and predictive novel therapeutic screening applications. Effective models of complex conditions such as ALS have yet to be achieved, but diseased NMJ models have been established for myotonic dystrophy [Marteyn et al, 2011] and spinal muscular atrophy [Yoshida et al, 2015], demonstrating that such model systems are possible.…”

Advances and Current Challenges Associated with the Use of Human Induced Pluripotent Stem Cells in Modeling Neurodegenerative Disease

“…Human iPSC-derived motor neurons have been cocultured with skeletal muscle from various human and nonhuman sources as a means to study neuromuscular junction formation and function [Demestre et al, 2015;Puttonen et al, 2015;Santhanam et al, 2018]. Such models can be used to test the efficacy of pharmacological agents as well as to model synaptic breakdown in cases of neuromuscular disorders, such as spinal muscular atrophy [Yoshida et al, 2015]. As our ability to promote skeletal muscle differentiation and maturation from hiPSC sources improves [Chal et al, 2015[Chal et al, , 2016Xi et al, 2017], we can expect further advances in modeling of neuromuscular development, function, and breakdown to occur.…”