The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis

Keiko Imamura; Yuishin Izumi; Akira Watanabe; Kayoko Tsukita; Knut Woltjen; Takuya Yamamoto; Akitsu Hotta; Takayuki Kondo; Shiho Kitaoka; Akira Ohta; Akito Tanaka; Dai Watanabe; Mitsuya Morita; Hiroshi Takuma; Akira Tamaoka; Tilo Kunath; Selina Wray; Hirokazu Furuya; Takumi Era; Kouki Makioka; Koichi Okamoto; Takao Fujisawa; Hideki Nishitoh; Kengo Homma; Hidenori Ichijo; Jean-Pierre Julien; Nanako Obata; Masato Hosokawa; Haruhiko Akiyama; Satoshi Kaneko; Takashi Ayaki; Hidefumi Ito; Ryuji Kaji; Ryosuke Takahashi; Shinya Yamanaka; Haruhisa Inoue

doi:10.1126/scitranslmed.aaf3962

ReportsAmyotrophic Lateral Sclerosis

The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis

Keiko Imamura¹,
Yuishin Izumi²,
Akira Watanabe¹,
Kayoko Tsukita¹,
Knut Woltjen¹,³,
Takuya Yamamoto¹,⁴,
Akitsu Hotta¹,⁴,⁵,
Takayuki Kondo¹,
Shiho Kitaoka¹,
Akira Ohta¹,
Akito Tanaka¹,
Dai Watanabe⁶,
Mitsuya Morita⁷,
Hiroshi Takuma⁸,
Akira Tamaoka⁸,
Tilo Kunath⁹,
Selina Wray¹⁰,
Hirokazu Furuya¹¹,
Takumi Era¹²,
Kouki Makioka¹³,
Koichi Okamoto¹⁴,
Takao Fujisawa¹⁵,
Hideki Nishitoh¹⁶,
Kengo Homma¹⁵,
Hidenori Ichijo¹⁵,
Jean-Pierre Julien¹⁷,
Nanako Obata¹⁸,
Masato Hosokawa¹⁸,
Haruhiko Akiyama¹⁸,
Satoshi Kaneko¹⁹,
Takashi Ayaki²⁰,
Hidefumi Ito²¹,
Ryuji Kaji⁴,
Ryosuke Takahashi²⁰,
Shinya Yamanaka¹,²² and
Haruhisa Inoue¹,*

¹Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
²Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
³Hakubi Center for Advanced Research, Kyoto University, Kyoto 606-8501, Japan.
⁴Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan.
⁵Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitama 332-0012, Japan.
⁶Department of Biological Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
⁷Division of Neurology, Department of Internal Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
⁸Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
⁹MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK.
¹⁰Department of Molecular Neuroscience, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.
¹¹Department of Neurology, Kochi Medical School, Kochi University, Kochi 783-8505, Japan.
¹²Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
¹³Department of Neurology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.
¹⁴Geriatrics Research Institute and Hospital, Maebashi 371-0847, Japan.
¹⁵Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
¹⁶Department of Medical Sciences, University of Miyazaki, Miyazaki 889-1601, Japan.
¹⁷Department of Psychiatry and Neurosciences, Research Centre of Mental Health Institute of Quebec (IUSMQ), Laval University, Québec, Canada.
¹⁸Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
¹⁹Department of Neurology, Kansai Medical University, Hirakata 573-1191, Japan.
²⁰Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
²¹Department of Neurology, Wakayama Medical University, Kimiidera, Wakayama 641-8509, Japan.
²²Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.

↵*Corresponding author. Email: haruhisa{at}cira.kyoto-u.ac.jp

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Science Translational Medicine 24 May 2017:
Vol. 9, Issue 391, eaaf3962
DOI: 10.1126/scitranslmed.aaf3962

Keiko Imamura

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

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Yuishin Izumi

Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.

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Akira Watanabe

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

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Kayoko Tsukita

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

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Knut Woltjen

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.Hakubi Center for Advanced Research, Kyoto University, Kyoto 606-8501, Japan.

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Takuya Yamamoto

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan.

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Akitsu Hotta

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan.Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitama 332-0012, Japan.

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Takayuki Kondo

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

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Shiho Kitaoka

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

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Akira Ohta

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

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Akito Tanaka

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

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Dai Watanabe

Department of Biological Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.

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Mitsuya Morita

Division of Neurology, Department of Internal Medicine, Jichi Medical University, Tochigi 329-0498, Japan.

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Hiroshi Takuma

Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.

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Akira Tamaoka

Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.

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Tilo Kunath

MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK.

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Selina Wray

Department of Molecular Neuroscience, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.

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Hirokazu Furuya

Department of Neurology, Kochi Medical School, Kochi University, Kochi 783-8505, Japan.

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Takumi Era

Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.

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Kouki Makioka

Department of Neurology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.

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Koichi Okamoto

Geriatrics Research Institute and Hospital, Maebashi 371-0847, Japan.

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Takao Fujisawa

Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.

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Hideki Nishitoh

Department of Medical Sciences, University of Miyazaki, Miyazaki 889-1601, Japan.

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Kengo Homma

Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.

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Hidenori Ichijo

Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.

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Jean-Pierre Julien

Department of Psychiatry and Neurosciences, Research Centre of Mental Health Institute of Quebec (IUSMQ), Laval University, Québec, Canada.

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Nanako Obata

Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.

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Masato Hosokawa

Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.

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Haruhiko Akiyama

Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.

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Satoshi Kaneko

Department of Neurology, Kansai Medical University, Hirakata 573-1191, Japan.

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Takashi Ayaki

Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.

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Hidefumi Ito

Department of Neurology, Wakayama Medical University, Kimiidera, Wakayama 641-8509, Japan.

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Ryuji Kaji

Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan.

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Ryosuke Takahashi

Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.

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Shinya Yamanaka

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.

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Haruhisa Inoue

Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

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For correspondence: haruhisa@cira.kyoto-u.ac.jp

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A stepping stone to ALS drug discovery

ALS is a heterogeneous motor neuron disease for which there is no treatment and for which a common therapeutic target has yet to be identified. In a new study, Imamura et al. developed a drug screen using motor neurons generated from ALS patient induced pluripotent stem cells (iPSCs). They screened existing drugs and showed that inhibitors of Src/c-Abl kinases promoted autophagy and rescued ALS motor neurons from degeneration. One of the drugs was effective for promoting survival of motor neurons derived from ALS patients with different genetic mutations. The Src/c-Abl pathway may be a potential therapeutic target for developing new drugs to treat ALS.

The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis

A stepping stone to ALS drug discovery

Science Translational Medicine

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