Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells
Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells
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DOI：
10.1126/scitranslmed.3004052
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发表时间：
2012-08-01
影响因子：
17.1
通讯作者：
Inoue, Haruhisa
中科院分区：
文献类型：
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作者：
Egawa, Naohiro;Kitaoka, Shiho;Inoue, Haruhisa
肌萎缩侧索硬化症（ALS）是一种迟发性、致命的疾病，其中运动神经元退化。由于缺乏ALS患者的运动神经元和适当的疾病模型，用于治疗ALS的新药的发现受到阻碍。我们从家族性ALS患者的诱导多能干细胞（iPSC）中产生运动神经元，这些患者携带Tar DNA结合蛋白-43（TDP-43）突变。ALS患者特异性iPSC衍生的运动神经元形成类似于ALS患者死后组织中所见的胞质聚集体，并表现出较短的神经突，如在ALS的斑马鱼模型中所见。ALS运动神经元的特征在于增加的突变TDP-43蛋白的洗涤剂不溶性形式结合到剪接体因子SNRPB 2。表达阵列分析检测到参与RNA代谢的基因表达的小幅增加和编码细胞骨架蛋白的基因表达的减少。我们检查了四种化合物，发现一种叫做漆树酸的组蛋白乙酰转移酶抑制剂拯救了异常的ALS运动神经元表型。这些发现表明，从ALS患者来源的iPSC产生的运动神经元可能为阐明ALS疾病发病机制和筛选候选药物提供有用的工具。
Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal disorder in which the motor neurons degenerate. The discovery of new drugs for treating ALS has been hampered by a lack of access to motor neurons from ALS patients and appropriate disease models. We generate motor neurons from induced pluripotent stem cells (iPSCs) from familial ALS patients, who carry mutations in Tar DNA binding protein-43 (TDP-43). ALS patient-specific iPSC-derived motor neurons formed cytosolic aggregates similar to those seen in postmortem tissue from ALS patients and exhibited shorter neurites as seen in a zebrafish model of ALS. The ALS motor neurons were characterized by increased mutant TDP-43 protein in a detergent-insoluble form bound to a spliceosomal factor SNRPB2. Expression array analyses detected small increases in the expression of genes involved in RNA metabolism and decreases in the expression of genes encoding cytoskeletal proteins. We examined four chemical compounds and found that a histone acetyltransferase inhibitor called anacardic acid rescued the abnormal ALS motor neuron phenotype. These findings suggest that motor neurons generated from ALS patient-derived iPSCs may provide a useful tool for elucidating ALS disease pathogenesis and for screening drug candidates.