Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells

報告日期: 2012/11/27
報告時間: 16:00~16:50
報告學生: 梁詠喻
講評老師: 顏孟畿
附件下載: 下載[1259-1351777511-1.pdf] 


Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells

Naohiro Egawa, Shiho Kitaoka, Kayoko Tsukita,Motoko Naitoh,Kazutoshi Takahashi,Takuya Yamamoto,Fumihiko Adachi,Takayuki Kondo,Keisuke Okita,Isao Asaka,Takashi Aoi,Akira Watanabe,Yasuhiro Yamada,Asuka Morizane,Jun Takahashi,Takashi Ayaki,Hidefumi Ito,Katsuhiro Yoshikawa,Satoko Yamawaki,Shigehiko Suzuki,Dai Watanabe,Hiroyuki Hioki,Takeshi Kaneko,Kouki Makioka,Koichi Okamoto,Hiroshi Takuma,Akira Tamaoka,Kazuko Hasegawa,Takashi Nonaka,Masato Hasegawa,Akihiro Kawata,Minoru Yoshida,Tatsutoshi Nakahata,Ryosuke Takahashi,Maria C. N. Marchetto,Fred H. Gage,Shinya Yamanaka,Haruhisa Inoue

Sci Transl Med 4, 145ra104 (2012)                                                 


                                            Date: 2012.11.27

Speaker: Yung-Yu Liang

Commentator: Meng-Chi Yen, Ph.D.  



Amyotrophic lateral sclerosis (ALS) is a late-onset, fatal disorder in which the motor neurons degenerate (1, 2). 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. In this study, the authors 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 (3). 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. The author 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.


1. L. I. Bruijn, T. M. Miller, D. W. Cleveland, Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu. Rev. Neurosci. 27, 723–749 (2004).

2. J. D. Rothstein, Current hypotheses for the underlying biology of amyotrophic lateral sclerosis. Ann. Neurol. 65 (Suppl. 1), S3–S9 (2009).

3. E. Kabashi, L. Lin, M. L. Tradewell, P. A. Dion, V. Bercier, P. Bourgouin, D. Rochefort, S. Bel Hadj, H. D. Durham, C. Vande Velde, G. A. Rouleau, P. Drapeau, Gain and loss of function of ALSrelated mutations of TARDBP (TDP-43) cause motor deficits in vivo. Hum. Mol. Genet. 19, 671–683 (2010).