Sci Transl Med：患者特异性iPS细胞ALS药物筛选现曙光

肌萎缩性脊髓侧索硬化症（ALS）是一种迟发性的，致命疾病，患者的运动神经元严重退化。难以获得ALS患者的运动神经元和缺乏相应的疾病模型，严重阻碍着发现新的ALS治疗药物。

研究者从携带TDP-43蛋白突变的家族性ALS患者的运动神经元细胞，成功诱导出多能干细胞（iPS细胞）。ALS患者特异性IPSC衍生出的运动神经元，可形成类似ALS患者死后组织中出现的细胞内的聚集，并展示出ALS斑马鱼模型中观察到短突起。

ALS的运动神经元特征是，突变TDP-43蛋白的增加，这些突变蛋白以去垢剂不溶性的形式绑定到剪接因子SNRPB2上。表达阵列分析发现，RNA代谢相关基因表达的小幅度增加，以及在细胞骨架蛋白编码基因的表达降低。研究者同时检查了4个化合物，并发现称为漆树酸（anacardic acid）的组蛋白乙酰转移酶抑制剂，可挽救ALS运动神经元异常表型。

这些结果表明，从ALS患者衍生的iPS细胞生成运动神经元，可为阐明ALS疾病的发病机制和筛选候选药物提供有用的工具。

doi:10.1016/j.cell.2011.10.017
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Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells

Naohiro Egawa1,2,*,Shiho Kitaoka1,2,*,Kayoko Tsukita1,2,Motoko Naitoh3,Kazutoshi Takahashi1,Takuya Yamamoto1,4,Fumihiko Adachi1,Takayuki Kondo1,5,Keisuke Okita1,Isao Asaka1,Takashi Aoi1,Akira Watanabe1,4,Yasuhiro Yamada1,4,Asuka Morizane1,6,Jun Takahashi1,6,Takashi Ayaki5,Hidefumi Ito5,Katsuhiro Yoshikawa3,Satoko Yamawaki3,Shigehiko Suzuki3,Dai Watanabe7,Hiroyuki Hioki8,Takeshi Kaneko8,Kouki Makioka9,Koichi Okamoto9,Hiroshi Takuma10,Akira Tamaoka10,Kazuko Hasegawa11,Takashi Nonaka12,Masato Hasegawa12,Akihiro Kawata13,Minoru Yoshida14,Tatsutoshi Nakahata1,Ryosuke Takahashi5,Maria C. N. Marchetto15,Fred H. Gage15,Shinya Yamanaka1,4,16 andHaruhisa Inoue1,2,16,?

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.