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

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.

journal_name

Sci Transl Med

journal_title

Science translational medicine

authors

Imamura K,Izumi Y,Watanabe A,Tsukita K,Woltjen K,Yamamoto T,Hotta A,Kondo T,Kitaoka S,Ohta A,Tanaka A,Watanabe D,Morita M,Takuma H,Tamaoka A,Kunath T,Wray S,Furuya H,Era T,Makioka K,Okamoto K,Fujisawa T,Nishit

doi

10.1126/scitranslmed.aaf3962

subject

Has Abstract

pub_date

2017-05-24 00:00:00

issue

391

eissn

1946-6234

issn

1946-6242

pii

9/391/eaaf3962

journal_volume

9

pub_type

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