Center for iPS Cell Research and Application-CiRA, Kyoto University, Kyoto 606-8507, Japan.
Sci Transl Med. 2012 Aug 1;4(145):145ra104. doi: 10.1126/scitranslmed.3004052.
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.
肌萎缩性侧索硬化症（ALS）是一种迟发性致命疾病，其运动神经元退化。由于缺乏来自 ALS 患者的运动神经元和适当的疾病模型，新的 ALS 治疗药物的发现一直受到阻碍。我们从携带 TDP-43（Tar DNA 结合蛋白-43）突变的家族性 ALS 患者的诱导多能干细胞（iPSC）中产生运动神经元。ALS 患者特异性 iPSC 衍生的运动神经元形成类似于在 ALS 患者死后组织中观察到的细胞质聚集体，并表现出与 ALS 斑马鱼模型中所见相似的较短神经突。ALS 运动神经元的特征是与剪接体因子 SNRPB2 结合的不溶性去污剂形式的突变 TDP-43 蛋白增加。表达谱分析检测到参与 RNA 代谢的基因表达略有增加，编码细胞骨架蛋白的基因表达减少。我们检查了四种化学化合物，发现一种称为漆树酸的组蛋白乙酰转移酶抑制剂可挽救异常的 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。
