Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis.
Genetic Correction of SOD1 Mutant iPSCs Reveals ERK and JNK Activated AP1 as a Driver of Neurodegeneration in Amyotrophic Lateral Sclerosis.
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DOI：
10.1016/j.stemcr.2017.02.019
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发表时间：
2017-04-11
影响因子：
5.9
通讯作者：
Stanton LW
中科院分区：
文献类型：
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作者：
Bhinge A;Namboori SC;Zhang X;VanDongen AMJ;Stanton LW
虽然已知具有不同功能的几个基因的突变会导致肌萎缩侧索硬化症（ALS），但尚不清楚因果突变在多大程度上影响了驱动运动神经元（MN）特异性神经变性的共同途径。在这项研究中，我们将基于诱导多能干细胞的疾病建模与基因组工程和深度RNA测序相结合，以确定人类MN中突变SOD 1失调的途径。基因表达谱分析和途径分析，随后进行药理学筛选，将激活的ERK和JNK信号转导鉴定为突变体SOD 1 MN中神经变性的关键驱动因素。与非MN相比，观察到ERK/JNK下游靶点AP 1复合体成员JUN在MN中高度表达，这为MN的特异性变性提供了机制上的见解。重要的是，对突变型FUS MN的研究鉴定了活化的p38和ERK，表明由ALS引起的突变诱导的网络扰动部分地会聚在一些特定的药物应答途径上，并提供了巨大的治疗潜力。SOD 1 E100 G突变的基因组校正校正MN中的ALS表型ALS MN中MAPK、AP 1、WNT、细胞周期和p53信号传导的激活药理学筛选揭示ERK和JNK信号传导作为治疗靶MN对变性的敏感性可能是由于MN中JUN活性升高。及其同事使用患者来源的iPSC的基因组编辑来体外模拟ALS表型缺陷。疾病MN的转录组学分析揭示了ALS MN中MAPK、AP 1、WNT、细胞周期和p53信号传导的激活。药理学筛选揭示了激活的ERK和JNK信号转导作为ALS的治疗靶点。
Although mutations in several genes with diverse functions have been known to cause amyotrophic lateral sclerosis (ALS), it is unknown to what extent causal mutations impinge on common pathways that drive motor neuron (MN)-specific neurodegeneration. In this study, we combined induced pluripotent stem cells-based disease modeling with genome engineering and deep RNA sequencing to identify pathways dysregulated by mutant SOD1 in human MNs. Gene expression profiling and pathway analysis followed by pharmacological screening identified activated ERK and JNK signaling as key drivers of neurodegeneration in mutant SOD1 MNs. The AP1 complex member JUN, an ERK/JNK downstream target, was observed to be highly expressed in MNs compared with non-MNs, providing a mechanistic insight into the specific degeneration of MNs. Importantly, investigations of mutant FUS MNs identified activated p38 and ERK, indicating that network perturbations induced by ALS-causing mutations converge partly on a few specific pathways that are drug responsive and provide immense therapeutic potential. Genome correction of SOD1 E100G mutation corrects ALS phenotypes in MNs Activation of MAPK, AP1, WNT, cell-cycle, and p53 signaling in ALS MNs Pharmacological screening uncovers ERK and JNK signaling as therapeutic targets Susceptibility of MNs to degeneration may be due to heightened JUN activity in MNs In this article, Bhinge, Stanton, and colleagues use genome editing of patient-derived iPSCs to model ALS phenotypic defects in vitro. Transcriptomic analysis of disease MNs reveals activation of MAPK, AP1, WNT, cell-cycle, and p53 signaling in ALS MNs. Pharmacological screening uncovers activated ERK and JNK signaling as therapeutic targets in ALS.