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

View ORCID ProfileKeiko Imamura¹,
View ORCID ProfileYuishin Izumi²,
View ORCID ProfileAkira Watanabe¹,
Kayoko Tsukita¹,
Knut Woltjen¹,³,
Takuya Yamamoto¹,⁴,
Akitsu Hotta¹,⁴,⁵,
View ORCID ProfileTakayuki Kondo¹,
Shiho Kitaoka¹,
View ORCID ProfileAkira Ohta¹,
Akito Tanaka¹,
Dai Watanabe⁶,
View ORCID ProfileMitsuya Morita⁷,
Hiroshi Takuma⁸,
Akira Tamaoka⁸,
View ORCID ProfileTilo Kunath⁹,
Selina Wray¹⁰,
View ORCID ProfileHirokazu Furuya¹¹,
Takumi Era¹²,
Kouki Makioka¹³,
Koichi Okamoto¹⁴,
Takao Fujisawa¹⁵,
View ORCID ProfileHideki Nishitoh¹⁶,
View ORCID ProfileKengo Homma¹⁵,
Hidenori Ichijo¹⁵,
Jean-Pierre Julien¹⁷,
Nanako Obata¹⁸,
View ORCID ProfileMasato Hosokawa¹⁸,
Haruhiko Akiyama¹⁸,
Satoshi Kaneko¹⁹,
Takashi Ayaki²⁰,
View ORCID ProfileHidefumi Ito²¹,
View ORCID ProfileRyuji Kaji⁴,
View ORCID ProfileRyosuke Takahashi²⁰,
Shinya Yamanaka¹,²² and
View ORCID ProfileHaruhisa 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

1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

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Yuishin Izumi

2Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.

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Akira Watanabe

1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

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Kayoko Tsukita

1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

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Knut Woltjen

1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

3Hakubi Center for Advanced Research, Kyoto University, Kyoto 606-8501, Japan.

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Takuya Yamamoto

1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

4Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan.

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Akitsu Hotta

1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, 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.

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Takayuki Kondo

1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

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Shiho Kitaoka

1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

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Akira Ohta

1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

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Akito Tanaka

1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

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Dai Watanabe

6Department of Biological Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.

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Mitsuya Morita

7Division of Neurology, Department of Internal Medicine, Jichi Medical University, Tochigi 329-0498, Japan.

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Hiroshi Takuma

8Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.

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Akira Tamaoka

8Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.

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Tilo Kunath

9MRC 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

10Department of Molecular Neuroscience, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.

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Hirokazu Furuya

11Department of Neurology, Kochi Medical School, Kochi University, Kochi 783-8505, Japan.

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Takumi Era

12Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.

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Kouki Makioka

13Department of Neurology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.

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Koichi Okamoto

14Geriatrics Research Institute and Hospital, Maebashi 371-0847, Japan.

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Takao Fujisawa

15Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.

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Hideki Nishitoh

16Department of Medical Sciences, University of Miyazaki, Miyazaki 889-1601, Japan.

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Kengo Homma

15Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.

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Hidenori Ichijo

15Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.

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Jean-Pierre Julien

17Department of Psychiatry and Neurosciences, Research Centre of Mental Health Institute of Quebec (IUSMQ), Laval University, Québec, Canada.

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Nanako Obata

18Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.

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Masato Hosokawa

18Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.

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Haruhiko Akiyama

18Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.

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Satoshi Kaneko

19Department of Neurology, Kansai Medical University, Hirakata 573-1191, Japan.

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Takashi Ayaki

20Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.

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Hidefumi Ito

21Department of Neurology, Wakayama Medical University, Kimiidera, Wakayama 641-8509, Japan.

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Ryuji Kaji

4Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan.

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Ryosuke Takahashi

20Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.

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Shinya Yamanaka

1Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.

22Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.

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Haruhisa Inoue

1Center 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.

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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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