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Aberrant Axon Branching Via Fos-B Dysregulation in FUS-ALS Motor Neurons

79 Pages Posted: 6 Dec 2018

See all articles by Tetsuya Akiyama

Tetsuya Akiyama

Tohoku University - Graduate School of Medicine

Naoki Suzuki

Tohoku University - Graduate School of Medicine

Mitsuru Ishikawa

Keio University

Koki Fujimori

Keio University

Takefumi Sone

Keio University

Jiro Kawada

University of Tokyo

Ryo Funayama

Tohoku University

Fumiyoshi Fujishima

Tohoku University

Shio Mitsuzawa

Tohoku University - Graduate School of Medicine

Kensuke Ikeda

Tohoku University - Graduate School of Medicine

Hiroya Ono

Tohoku University - Graduate School of Medicine

Tomomi Shijo

Tohoku University - Graduate School of Medicine

Shion Osana

Tohoku University

Matsuyuki Shirota

Tohoku University - Graduate School of Medicine

Tadashi Nakagawa

Tohoku University - Graduate School of Medicine

Yasuo Kitajima

Tohoku University - Graduate School of Medicine

Ayumi Nishiyama

Tohoku University - Graduate School of Medicine

Rumiko Izumi

Tohoku University - Graduate School of Medicine

Yohei Okada

Keio University

Shohei Kaneda

University of Tokyo

Yoshiho Ikeuchi

University of Tokyo

Hiroaki Mitsuhashi

Tokai University

Keiko Nakayama

Tohoku University - Graduate School of Medicine

Teruo Fujii

University of Tokyo

Hitoshi Warita

Tohoku University - Graduate School of Medicine

Hideyuki Okano

Keio University

Masashi Aoki

Tohoku University - Department of Neurology

More...

Abstract

The characteristic structure of motor neurons (MNs), particularly of the long axons, becomes damaged in the early stages of amyotrophic lateral sclerosis (ALS). However, the molecular pathophysiology of axonal degeneration remains to be fully elucidated. In the present study, two sets of isogenic human-induced pluripotent stem cell (hiPSCs)-derived MNs were compared, and we found an abnormal increase in axon branching in the ALS-causative FUS-mutant lines. Moreover, we applied microfluidic devices that enable axon bundles to be produced for omics analysis and conducted RNA profiling of isolated axons. Thus, we identified increased level of Fos-B mRNA, the binding target of FUS, in FUS-mutant MNs. While Fos-B reduction using si-RNA or an inhibitor ameliorated the observed aberrant axon branching, Fos-B overexpression resulted in aberrant axon branching even in vivo. Analyzing the axonal fraction of hiPSC-derived MNs using microfluidic devices revealed that Fos-B is a key regulator of FUS-mutant axon branching.

Funding Statement: This work was supported by Research and Study Project of Tokai University Educational System General Research Organization [to H.M].

Declaration of Interests: H.Ok. is a paid Scientific Advisor of SanBio Co.Ltd and K Pharma Inc. Y.O. is a scientific advisor for Kohjin Bio Co., Ltd. Other authors declare no competing financial interests.

Ethics Approval Statement: All protocols were approved by the ethics committees of Tohoku University School of Medicine (No. 2010–306) and the Keio University School of Medicine (N0. 20080016).

Keywords: amyotrophic lateral sclerosis (ALS); fused in sarcoma (FUS); axon branching; Fos-B; nerve organoid; human-induced pluripotent stem cells (hiPSCs)-derived motor neuron

Suggested Citation

Akiyama, Tetsuya and Suzuki, Naoki and Ishikawa, Mitsuru and Fujimori, Koki and Sone, Takefumi and Kawada, Jiro and Funayama, Ryo and Fujishima, Fumiyoshi and Mitsuzawa, Shio and Ikeda, Kensuke and Ono, Hiroya and Shijo, Tomomi and Osana, Shion and Shirota, Matsuyuki and Nakagawa, Tadashi and Kitajima, Yasuo and Nishiyama, Ayumi and Izumi, Rumiko and Okada, Yohei and Kaneda, Shohei and Ikeuchi, Yoshiho and Mitsuhashi, Hiroaki and Nakayama, Keiko and Fujii, Teruo and Warita, Hitoshi and Okano, Hideyuki and Aoki, Masashi, Aberrant Axon Branching Via Fos-B Dysregulation in FUS-ALS Motor Neurons (November 30, 2018). 10.1016/j.ebiom.2019.06.013. Available at SSRN: https://ssrn.com/abstract=3294755

Tetsuya Akiyama

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Naoki Suzuki

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Mitsuru Ishikawa

Keio University

2-15-45 Mita
Minato-ku
Tokyo, 108-8345
Japan

Koki Fujimori

Keio University

2-15-45 Mita
Minato-ku
Tokyo, 108-8345
Japan

Takefumi Sone

Keio University

2-15-45 Mita
Minato-ku
Tokyo, 108-8345
Japan

Jiro Kawada

University of Tokyo

Yayoi 1-1-1
Bunkyo-ku
Tokyo, Tokyo 113-8657
Japan

Ryo Funayama

Tohoku University

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Fumiyoshi Fujishima

Tohoku University

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Shio Mitsuzawa

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Kensuke Ikeda

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Hiroya Ono

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Tomomi Shijo

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Shion Osana

Tohoku University

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Matsuyuki Shirota

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Tadashi Nakagawa

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Yasuo Kitajima

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Ayumi Nishiyama

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Rumiko Izumi

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Yohei Okada

Keio University

2-15-45 Mita
Minato-ku
Tokyo, 108-8345
Japan

Shohei Kaneda

University of Tokyo

Yayoi 1-1-1
Bunkyo-ku
Tokyo, Tokyo 113-8657
Japan

Yoshiho Ikeuchi

University of Tokyo

Yayoi 1-1-1
Bunkyo-ku
Tokyo, Tokyo 113-8657
Japan

Hiroaki Mitsuhashi

Tokai University

3-20-1 Orido
Shimizu-ku
Shizuoka, 424-8610
Japan

Keiko Nakayama

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Teruo Fujii

University of Tokyo

Yayoi 1-1-1
Bunkyo-ku
Tokyo, Tokyo 113-8657
Japan

Hitoshi Warita

Tohoku University - Graduate School of Medicine

SKK Building, Katahira 2
Aoba-ku, Sendai, Miyagi 980-8577
Japan

Hideyuki Okano

Keio University

2-15-45 Mita
Minato-ku
Tokyo, 108-8345
Japan

Masashi Aoki (Contact Author)

Tohoku University - Department of Neurology ( email )

1-1 Seiryo-machi
Sendai, 980-8574
Japan

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