In vivo differentiation control of endogenous neural cells in ALS

• Project/Area Number: 17K09773
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Tohoku University
• Principal Investigator: Warita Hitoshi 東北大学, 大学病院, 助教 (30400245)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 神経再生 / 運動ニューロン / アストロサイト / 神経炎症 / 神経変性 / 神経科学 / 再生医学 / 脳神経疾患

Outline of Final Research Achievements

Amyotrophic lateral sclerosis (ALS) is an adult-onset, devastating neurodegenerative syndrome characterized by systemic loss of motor neurons with prominent gliogenesis in the central nervous system. We focused on bone morphogenetic proteins (BMP) as a major soluble protein that promotes astrocytogenesis and its activation in the adult spinal cord. In a transgenic rat model with ALS-linked mutant Cu/Zn superoxide dismutase gene, BMP-4 was progressively up-regulated in spinal ventral horn reactive astrocytes, whereas noggin, a BMP-antagonist, was decreased. Continuous intrathecal infusion of either noggin or Bmp4-targeted antisense oligonucleotides after disease onset significantly ameliorated motor dysfunction and neurogenic muscle atrophy, and also extended survival of ALS model rats, by reducing astrocytogenesis, astrocytic activation, and neuroinflammation. The BMP-4 and its downstream signaling may be a novel therapeutic target for disease-modifying therapies in ALS.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、成人発症の難治性・進行性疾患の代表である筋萎縮性側索硬化症（ALS）において骨形成蛋白質（BMP）とその下流シグナルが新たな進行抑制治療の標的となり得ることを初めて明らかにしたものである。ALS同様に神経炎症を伴う他の神経変性疾患への応用も期待され、人口の高齢化とともに増加しつつある神経変性疾患の新しい進行抑制療法の開発につながると期待される。

Research Products

• [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
• [Presentation] hnRNPA1変異によるMSP3型の病態解明研究 (2019)
  • Author(s): 割田 仁
  • Organizer: 第60回日本神経学会学術大会
  • Invited
• [Presentation] Microvasculature as a pro-inflammatory component in a rat model of ALS. (2019)
  • Author(s): 割田 仁，四條友望，池田謙輔，秋山徹也，光澤志緒，中村尚子，小野洋也，西山亜由美，鈴木直輝，青木正志
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] BMP4, a bone morphogenetic protein, accelerates disease progression of amyotrophic lateral sclerosis. (2019)
  • Author(s): 四條友望，割田 仁，鈴木直輝，池田謙輔，光澤志緒，秋山徹也，小野洋也，西山亜由美，井泉瑠美子，青木正志
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Elucidating axonal pathophysiology under fused in sarcoma (FUS)-mutant ALS motor neurons. (2019)
  • Author(s): 秋山徹也，鈴木直輝，石川 充，川田治良，藤井輝夫，藤島史喜，舟山 亮，中山啓子，三橋弘明，割田 仁，岡野栄之，青木正志
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Cytoplasmic aggregation involving RNA-binding proteins in spinal cord of ALS model rats (2018)
  • Author(s): 割田 仁，四條友望，池田謙輔，秋山徹也，小野洋也，光澤志緒，西山亜由美，井泉瑠美子，鈴木直輝，青木正志
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] 神経疾患の新薬開発・医師主導治験の最前線：ALSに対する肝細胞増殖因子（HGF） (2018)
  • Author(s): 割田 仁
  • Organizer: 第59回日本神経学会学術大会
  • Invited
• [Presentation] Genotype-phenotype analysis of Japanese familial ALS pedigrees with SOD1 mutations (2018)
  • Author(s): 西山亜由美，鈴木直輝，割田 仁，井泉瑠美子，島倉奈緒子，秋山徹也，長名シオン，加藤 昌昭，新堀哲也，青木洋子，青木正志
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] ALS-associated C21ORF2 mutation enhances the autoregulation mechanism of NEK1 (2018)
  • Author(s): 渡辺靖章，中川 直，鈴木直輝，割田 仁，中山啓子，青木正志
  • Organizer: 第59回日本神経学会学術大会
• [Presentation] 筋萎縮性側索硬化症モデル脊髄のアストロサイトにおける骨形成蛋白質の過剰発現 (2018)
  • Author(s): 四條 友望，割田 仁，鈴木直輝，池田謙輔，小野洋也，秋山徹也，光澤志緒，西山亜由美，井泉瑠美子，青木正志
  • Organizer: 第17回日本再生医療学会総会
• [Presentation] Bone morphogenetic protein 4 is up-regulated in a rat model of amyotrophic lateral sclerosis (2017)
  • Author(s): Shijo T, Warita H, Suzuki N, Ikeda K, Akiyama T, Ono H, Mitsuzawa S, Nishiyama A, Izumi R, Aoki M
  • Organizer: XXIII World Congress of Neurology, Kyoto, Japan (INTERNATIONAL CONFERENCE CENTER KYOTO)
  • Int'l Joint Research
• [Presentation] Targeted next-generation sequencing in Japanese familial amyotrophic lateral sclerosis reveals differences in the genetic variations across populations (2017)
  • Author(s): Nishiyama A, Niihori T, Warita H, Izumi R, Akiyama T, Kato M, Suzuki N, Aoki Y, Aoki M
  • Organizer: XXIII World Congress of Neurology, Kyoto, Japan (INTERNATIONAL CONFERENCE CENTER KYOTO)
  • Int'l Joint Research
• [Presentation] Novel binding partner of dysferlin is required for plasma-membrane repair (2017)
  • Author(s): Ono H, Suzuki N, Kanno S, Izumi R, Takahashi T, Kitajima Y, Osana S, Akiyama T, Ikeda K, Shijo T, Mitsuzawa S, Warita H, Nagatomi R, Araki N, Yasui A Miyake K, Aoki M
  • Organizer: 22th International Annual Congress of the World Muscle Society, Saint Malo, France (Palais du Grand LArge)
  • Int'l Joint Research
• [Remarks] 東北大学医学部神経内科
  • URL: http://www.neurol.med.tohoku.ac.jp/index.html
• [Remarks] 東北大学研究者紹介
  • URL: http://db.tohoku.ac.jp/whois/detail/37acc23a2ceeffbecab9d8569a61a9f2.html
• [Remarks] Researchmap
  • URL: https://researchmap.jp/warita_2012
• [Remarks] ResearchGate
  • URL: https://www.researchgate.net/profile/Hitoshi_Warita
• [Remarks] Researchmap
  • URL: https://researchmap.jp/warita_2012/