title: Drug screening for ALS using patient-specific induced pluripotent stem cells.
abstract: 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.
authors.affiliation: Center for iPS Cell Research and Application-CiRA, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Egawa
authors.forename: Shiho
authors.initials: S
authors.lastname: Kitaoka
authors.forename: Kayoko
authors.initials: K
authors.lastname: Tsukita
authors.forename: Motoko
authors.initials: M
authors.lastname: Naitoh
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Takahashi
authors.forename: Takuya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Adachi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kondo
authors.forename: Keisuke
authors.initials: K
authors.lastname: Okita
authors.forename: Isao
authors.initials: I
authors.lastname: Asaka
authors.forename: Takashi
authors.initials: T
authors.lastname: Aoi
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamada
authors.forename: Asuka
authors.initials: A
authors.lastname: Morizane
authors.forename: Jun
authors.initials: J
authors.lastname: Takahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Ayaki
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Ito
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Satoko
authors.initials: S
authors.lastname: Yamawaki
authors.forename: Shigehiko
authors.initials: S
authors.lastname: Suzuki
authors.forename: Dai
authors.initials: D
authors.lastname: Watanabe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hioki
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kaneko
authors.forename: Kouki
authors.initials: K
authors.lastname: Makioka
authors.forename: Koichi
authors.initials: K
authors.lastname: Okamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takuma
authors.forename: Akira
authors.initials: A
authors.lastname: Tamaoka
authors.forename: Kazuko
authors.initials: K
authors.lastname: Hasegawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Nonaka
authors.forename: Masato
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kawata
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshida
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Maria C N
authors.initials: MC
authors.lastname: Marchetto
authors.forename: Fred H
authors.initials: FH
authors.lastname: Gage
authors.forename: Shinya
authors.initials: S
authors.lastname: Yamanaka
authors.forename: Haruhisa
authors.initials: H
authors.lastname: Inoue
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D047468:Immunoprecipitation; D057026:Induced Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology* / Q000378:metabolism