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Sci Transl Med. 2017 May 24;9(391). pii: eaaf3962. doi: 10.1126/scitranslmed.aaf3962.

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

Author information

1
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
2
Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.
3
Hakubi Center for Advanced Research, Kyoto University, Kyoto 606-8501, Japan.
4
Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto 606-8507, Japan.
5
Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency, Saitama 332-0012, Japan.
6
Department of Biological Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
7
Division of Neurology, Department of Internal Medicine, Jichi Medical University, Tochigi 329-0498, Japan.
8
Department of Neurology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
9
MRC Centre for Regenerative Medicine, School of Biological Sciences, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK.
10
Department of Molecular Neuroscience, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.
11
Department of Neurology, Kochi Medical School, Kochi University, Kochi 783-8505, Japan.
12
Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
13
Department of Neurology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.
14
Geriatrics Research Institute and Hospital, Maebashi 371-0847, Japan.
15
Cell Signaling, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
16
Department of Medical Sciences, University of Miyazaki, Miyazaki 889-1601, Japan.
17
Department of Psychiatry and Neurosciences, Research Centre of Mental Health Institute of Quebec (IUSMQ), Laval University, Qu├ębec, Canada.
18
Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan.
19
Department of Neurology, Kansai Medical University, Hirakata 573-1191, Japan.
20
Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
21
Department of Neurology, Wakayama Medical University, Kimiidera, Wakayama 641-8509, Japan.
22
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
23
Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. haruhisa@cira.kyoto-u.ac.jp.

Abstract

Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro. Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration. One of the hits, bosutinib, boosted autophagy, reduced the amount of misfolded mutant SOD1 protein, and attenuated altered expression of mitochondrial genes. Bosutinib also increased survival in vitro of ALS iPSC-derived motor neurons from patients with sporadic ALS or other forms of familial ALS caused by mutations in TAR DNA binding protein (TDP-43) or repeat expansions in C9orf72 Furthermore, bosutinib treatment modestly extended survival of a mouse model of ALS with an SOD1 mutation, suggesting that Src/c-Abl may be a potentially useful target for developing new drugs to treat ALS.

PMID:
28539470
DOI:
10.1126/scitranslmed.aaf3962
[Indexed for MEDLINE]

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