Analysis of axonal pathomechanism in amyotrophic lateral sclerosis using human iPS cell-derived nerve organoid.

• Project/Area Number: 18K07519
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Tohoku University
• Principal Investigator: Suzuki Naoki 東北大学, 大学病院, 助教 (70451599)
• Co-Investigator(Kenkyū-buntansha): 割田 仁 東北大学, 大学病院, 助教 (30400245) ; 青木 正志 東北大学, 医学系研究科, 教授 (70302148)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 筋萎縮性側索硬化症 / iPS細胞 / 軸索 / ALS / 運動ニューロン軸索 / 軸索レジリエンス / オミックス解析 / FUS / RNA代謝 / 軸索病態 / マイクロ流体デバイス / RNAシークエンス

Outline of Final Research Achievements

RNA sequencing analysis of axonal fraction of nerve organoid revealed a gene, Fos-B, associated with the pathogenesis of FUS mutations. We demonstrated that Fos-B is involved in the formation of abnormal axon branching associated with FUS mutations in motor neurons using overexpression and inhibition experiments. Furthermore, using zebrafish overexpression of Fos-B and human autopsy spinal cord, we clarified the relationship between Fos-B and ALS pathology. These results were reported in EBioMedicine in 2019. We wrote a review on omics analysis of axons, which was published in Frontiers in Neuroscience in 2020. In 2021, we found decreased expression of Phox2B using TARDBP mutant iPS cells, the causative gene of ALS, and it was accepted by Stem Cell Reports. We will continue to investigate the axonal pathology underlying motor neuron vulnerability.

Academic Significance and Societal Importance of the Research Achievements

ALS患者は日本で約1万人、世界で約35万人と想定され、高齢化に伴い増加傾向にある。人工呼吸器を使用しなければ2-5年で呼吸不全により死亡する予後不良の難病である。根本的な治療法が確立されていない。本研究はALSの初期から病変がみとめられる軸索の病態にフォーカスすることで早期治療介入が可能となると考えた。ALS軸索病態の鍵分子を明らかにすることで、新規治療法開発への道筋がつけられたと考えている。

Research Products

• [Journal Article] A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis. (2020)
  • Author(s): Nakamura R, Misawa K, Tohnai G, Nakatochi M, Furuhashi S, Atsuta N, Hayashi N, Yokoi D, Watanabe H, Watanabe H, Katsuno M, Izumi Y, Kanai K, Hattori N, Morita M, Taniguchi A, Kano O, Oda M, Shibuya K, Kuwabara S, Suzuki N, Aoki M, Ohta Y, Yamashita T, Abe K, Hashimoto R, Aiba I, Okada Y, Nagasaki M, Sobue G. et al.,
  • Journal Title: Commun Biol. Volume: 23 Issue: 1 Pages: 526-526
  • DOI: 10.1038/s42003-020-01251-2
  • NAID: 120007178464
  • Peer Reviewed / Open Access
• [Journal Article] Generation of an ALS human iPSC line KEIOi001-A from peripheral blood of a Charcot disease-affected patient carrying TARDBP p.N345K heterozygous SNP mutation (2020)
  • Author(s): Leventoux Nicolas、Morimoto Satoru、Hara Kenju、Nakamura Shiho、Ozawa Fumiko、Mitsuzawa Shio、Akiyama Tetsuya、Nishiyama Ayumi、Suzuki Naoki、Warita Hitoshi、Aoki Masashi、Okano Hideyuki
  • Journal Title: Stem Cell Research Volume: 47 Pages: 101896-101896
  • DOI: 10.1016/j.scr.2020.101896
  • Peer Reviewed / Open Access
• [Journal Article] AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy (2020)
  • Author(s): Ono Hiroya、Suzuki Naoki、Kanno Shin-ichiro、Kawahara Genri、Izumi Rumiko、Takahashi Toshiaki、Kitajima Yasuo、Osana Shion、Nakamura Naoko、Akiyama Tetsuya、Ikeda Kensuke、Shijo Tomomi、Mitsuzawa Shio、Nagatomi Ryoichi、Araki Nobukazu、Yasui Akira、Warita Hitoshi、Hayashi Yukiko K.、Miyake Katsuya、Aoki Masashi
  • Journal Title: Molecular Therapy Volume: 28 Issue: 4 Pages: 1133-1153
  • DOI: 10.1016/j.ymthe.2020.02.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Omics Approach to Axonal Dysfunction of Motor Neurons in Amyotrophic Lateral Sclerosis (ALS) (2020)
  • Author(s): Suzuki Naoki、Akiyama Tetsuya、Warita Hitoshi、Aoki Masashi
  • Journal Title: Frontiers in Neuroscience Volume: 14
  • DOI: 10.3389/fnins.2020.00194
  • Peer Reviewed / Open Access
• [Journal Article] Prognosis of amyotrophic lateral sclerosis patients undergoing tracheostomy invasive ventilation therapy in Japan (2020)
  • Author(s): Hayashi Naoki、Atsuta Naoki、Yokoi Daichi、Nakamura Ryoichi、Nakatochi Masahiro、Katsuno Masahisa、Izumi Yuishin、Kanai Kazuaki、Hattori Nobutaka、Taniguchi Akira、Morita Mitsuya、Kano Osamu、Shibuya Kazumoto、Kuwabara Satoshi、Suzuki Naoki、Aoki Masashi、Aiba Ikuko、Mizoguchi Kouichi、Oda Masaya、Kaji Ryuji、Sobue Gen
  • Journal Title: Journal of Neurology, Neurosurgery & Psychiatry Volume: 91 Issue: 3 Pages: 285-290
  • DOI: 10.1136/jnnp-2019-322213
  • Peer Reviewed / Open Access
• [Journal Article] 増大特集 ALS2019 家族性ALS (2019)
  • Author(s): 鈴木 直輝、西山 亜由美、加藤 昌昭、割田 仁、青木 正志
  • Journal Title: BRAIN and NERVE Volume: 71 Issue: 11 Pages: 1169-1181
  • DOI: 10.11477/mf.1416201427
  • ISSN: 1344-8129, 1881-6096
  • Year and Date: 2019-11-01
• [Journal Article] Pathogenic mutations in the ALS gene CCNF cause cytoplasmic mislocalization of Cyclin F and elevated VCP ATPase activity. (2019)
  • Author(s): Yu Y, Nakagawa T, Morohoshi A, Nakagawa M, Ishida N, Suzuki N, Aoki M, Nakayama K.
  • Journal Title: Hum Mol Genet Volume: 28 Issue: 20 Pages: 3486-3497
  • DOI: 10.1093/hmg/ddz119
  • Peer Reviewed
• [Journal Article] Aberrant axon branching via Fos-B dysregulation in FUS-ALS motor neurons. (2019)
  • Author(s): Akiyama T, Suzuki N, Ishikawa M, Fujimori K, Sone T, Kawada J, Funayama R, Fujishima F, Mitsuzawa S, Ikeda K, Ono H, Shijo T, Osana S, Shirota M, Nakagawa T, et al.
  • Journal Title: EBioMedicine Volume: 45 Pages: 362-378
  • DOI: 10.1016/j.ebiom.2019.06.013
  • Peer Reviewed / Open Access
• [Journal Article] p.N345K mutation in TARDBP in a patient with familial amyotrophic lateral sclerosis: An autopsy case (2019)
  • Author(s): Takeda Takahiro、Iijima Mutsumi、Shimizu Yuko、Yoshizawa Hiroshi、Miyashiro Mayu、Onizuka Hiromi、Yamamoto Tomoko、Nishiyama Ayumi、Suzuki Naoki、Aoki Masashi、Shibata Noriyuki、Kitagawa Kazuo
  • Journal Title: Neuropathology Volume: 39 Issue: 4 Pages: 286-293
  • DOI: 10.1111/neup.12559
  • Peer Reviewed
• [Journal Article] Interstitial pneumonia and other adverse events in riluzole-administered amyotrophic lateral sclerosis patients: a retrospective observational study (2019)
  • Author(s): Inoue-Shibui Aya、Kato Masaaki、Suzuki Naoki、Kobayashi Junpei、Takai Yoshiki、Izumi Rumiko、Kawauchi Yuuko、Kuroda Hiroshi、Warita Hitoshi、Aoki Masashi
  • Journal Title: BMC Neurology Volume: 19 Issue: 1 Pages: 72-78
  • DOI: 10.1186/s12883-019-1299-1
  • Peer Reviewed / Open Access
• [Journal Article] A juvenile sporadic amyotrophic lateral sclerosis case with P525L mutation in the FUS gene: A rare co-occurrence of autism spectrum disorder and tremor (2019)
  • Author(s): Eura Nobuyuki、Sugie Kazuma、Suzuki Naoki、Kiriyama Takao、Izumi Tesseki、Shimakura Naoko、Kato Masaaki、Aoki Masashi
  • Journal Title: Journal of the Neurological Sciences Volume: 398 Pages: 67-68
  • DOI: 10.1016/j.jns.2019.01.032
  • Peer Reviewed
• [Journal Article] Antagonizing bone morphogenetic protein 4 attenuates disease progression in a rat model of amyotrophic lateral sclerosis (2018)
  • Author(s): Shijo Tomomi、Warita Hitoshi、Suzuki Naoki、Ikeda Kensuke、Mitsuzawa Shio、Akiyama Tetsuya、Ono Hiroya、Nishiyama Ayumi、Izumi Rumiko、Kitajima Yasuo、Aoki Masashi
  • Journal Title: Experimental Neurology Volume: 307 Pages: 164-179
  • DOI: 10.1016/j.expneurol.2018.06.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TARDBP p.G376D mutation, found in rapid progressive familial ALS, induces mislocalization of TDP-43 (2018)
  • Author(s): Mitsuzawa Shio、Akiyama Tetsuya、Nishiyama Ayumi、Suzuki Naoki、Kato Masaaki、Warita Hitoshi、Izumi Rumiko、Osana Shion、Koyama Shingo、Kato Takeo、Suzuki Yoshihiro、Aoki Masashi
  • Journal Title: eNeurologicalSci Volume: 11 Pages: 20-22
  • DOI: 10.1016/j.ensci.2018.04.001
• [Remarks] 東北大学神経内科
  • URL: http://www.neurol.med.tohoku.ac.jp/
• [Patent(Industrial Property Rights)] 神経軸索分岐異常の改善剤 (2019)
  • Inventor(s): 国立大学法人東北大学等
  • Industrial Property Rights Holder: 国立大学法人東北大学等
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-060876
  • Filing Date: 2019
• [Patent(Industrial Property Rights)] 神経軸索分岐異常の改善 (2019)
  • Inventor(s): 秋山徹也、鈴木直輝、割田仁、青木正志ら。
  • Industrial Property Rights Holder: 秋山徹也、鈴木直輝、割田仁、青木正志ら。
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-060876
  • Filing Date: 2019