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Modeling the early phenotype at the neuromuscular junction of spinal muscular atrophy using patient-derived iPSCs

ABSTRACT: Spinal 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 motor neurons (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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE65470 | GEO | 2015/01/31

SECONDARY ACCESSION(S): PRJNA274131

REPOSITORIES: GEO

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Modeling the early phenotype at the neuromuscular junction of spinal muscular atrophy using patient-derived iPSCs (RNA-Seq)

Project description:Spinal 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 patientsM-bM-^@M-^Y motor neurons (MNs), and to identify drugs that can restore the normal condition. We generated NMJ-like structures using motor neurons (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.M-bM-^@M-^C to evaluate the effects of VPA on the expression profiles of the MNs

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Project description:Spinal 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 motor neurons (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.

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Project description:Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder that affects the spinal motor neurons and leads to progressive muscle wasting and atrophy. It is caused by a reduction in SMN protein levels due to the mutations in the survival motor neuron 1 (SMN1) gene. Human are unique as they possess a homologous pseudogene known as survival motor neuron 2 (SMN2) gene. MicroRNAs (miRNAs) play a role in either translational repression or mRNA degradation. It has been highlighted that dysregulation of miRNA has been a common feature of motor neuron disease such as SMA. Moreover, 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. However, there are still lacking of studies on the dysregulation of miRNAs in human SMA patients using iPSC cell models and how the miRNAs correlate with the SMN protein. Hence, we utilized miRNA microarray to identify the miRNAs dysregulated in SMA patients as compared to normal controls in both fibroblast and its derivative induced pluripotent stem cells (iPSCs). Human fibroblasts and iPSCs were cultured and their respective RNA were extracted.

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