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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

2015-02-03 | E-GEOD-65508 | biostudies-arrayexpress

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

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 compare the gene expression pattern between control and patient derived iPSCs

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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 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.

2015-02-03 | GSE65508 | GEO

Selective Death in Spinal Muscular Atrophy: Genome-Wide RNA-Seq Using Purified Patient-Derived Motor Neurons

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Transcriptome profiling of severe spinal muscular atrophy mouse embryonic stem cell-derived motor neurons

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Alternative splicing and gene expression defects in motorneurons derived from DM1 hiPSCs and MBNL knockouts hiPSCs generated by CRISPR/Cas9.

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Transcriptome profiling of severe spinal muscular atrophy mouse embryonic stem cell-derived motor neurons

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Next Generation Sequencing of human SMA and healthy control Motor Neurons

Project description:Spinal muscular atrophy (SMA) is a motor neuron (MN) disorder caused by mutations in SMN1. The reasons of MNs selective vulnerability linked to SMN reduction remain unclear. To address this question, we performed deep RNA sequencing on SMA human MNs to detect specific altered splicing/expressed genes and to identify the presence of a common sequence motif in these genes. Many deregulated genes, such as Neurexin and Synaptotagmin families, are implicated in critical MN-function like axonogenesis and synapses. Motif-enrichment analyses of differentially expressed/spliced genes, including Neurexin2 (NRXN2), revealed a common Motif, Motif-7, which is target of SYNCRIP protein. Interestingly, SYNCRIP interacts only with full-length SMN, binding and modulating several MN transcripts, including SMN itself. SYNCRIP overexpression rescued SMA-MNs, due to the consequent increase of SMN and their down-stream target NRXN2, through a positive loop mechanism. SMN/SYNCRIP complex through motif-7 might account for selective MN degeneration and represent a potential therapeutic target.

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Mitochondrial defects contribute to impaired translational in SMA motor neurons

Project description:Spinal muscular atrophy (SMA) is a neuromuscular disease, characterized by loss of lower alpha motoneurons, which leads to proximal muscle weakness. SMA is caused by reduced levels of Survival of Motor Neuron protein due to biallelic deletions or mutations in the SMN1 gene. Dysfunctional mitochondria can harm cells by decreased ATP production, but also by increased oxidative stress due to elevated production of reactive oxygen species (ROS). In this study, whole proteome analysis was performed using the Taiwanese SMA mouse model on an FVB/N background to identify changes in the proteome related to oxidative stress. Therefore, primary WT and SMA motoneurons were treated with a known anti-oxidant N-Acetylcysteine, the ROS inducer menadione and the cell culture supplement sodium pyruvate. Furthermore, this study aims to investigate changes in mRNA translation initiation affected by oxidative stress in SMA.

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