Signaling mechanism for myelin maintenance

• Project/Area Number: 17H03564
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Junji Yamauchi 東京薬科大学, 生命科学部, 教授 (20335483)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2019: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2018: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2017: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
• Keywords: ミエリン / 脱ミエリン / ミエリン維持 / ミエリン再編 / シュワン細胞 / オリゴデンドロサイト / シグナル伝達分子 / 交換因子 / 大脳白質変性症 / 恒常性 / 再ミエリン化 / オリゴデンドログリア細胞 / カプリゾン / ミエリン化 / 再生医療 / ミエリン再生 / 受容体 / アダプター分子 / サイトヘジン / ホメオスタシス / 創薬標的 / シグナル伝達 / 変性疾患 / 創薬標的分子 / インビトロ共培養システム / キナーゼ / 遺伝子改変マウス / 脱ミエリン現象 / 低分子量GTP結合蛋白質 / 髄鞘 / 維持 / 脱髄

Outline of Final Research Achievements

Reorganization of myelin in the peripheral nervous system is essential for maintaining homeostasis of the nervous tissue as a whole; however, the concept that myelin in the peripheral nervous system is a strong structure has been established. Until now, few studies have been directed to the myelin reorganization. The purpose of this study has been to clarify the mechanism of this myelin reorganization. We tried to elucidate the major molecules that control myelin reorganization and maintenance. As a result, we have identified new molecules such as BIG1 and Arf1 that control myelin reorganization and maintenance. By identifying the molecules involved in myelin reorganization and maintenance, it would be expected that the mechanism "inherent in the body" can be induced and the molecular basis for a new therapeutic strategy for demyelinating diseases can be provided.

Academic Significance and Societal Importance of the Research Achievements

本研究では自然状態での再ミエリン化に関与する主要な分子メカニズムの解明を行った。どのような分子がその起点になり、その後のミエリン化過程を維持し制御するのか明らかにした。遺伝性や炎症性の脱ミエリン病が発症すると、初期過程では脱ミエリン現象と再ミエリン化が繰り返され、最終的に脱ミエリン現象が再ミエリン化より優勢を占めることで不可逆的な脱ミエリン状態になる。もし自然状態での再ミエリン化のメカニズムが解明できれば、本来からだに備わっているメカニズムを人為的に操作することで再ミエリン化が達成できるはずである。したがって、当該研究は末梢神経変性疾患の改善研究にも応用できると期待される。

Research Products

• [Journal Article] PP1C and PP2A are p70S6K phosphatases whose inhibition ameliorates HLD12-associated inhibition of oligodendroglial cell morphological differentiation (2020)
  • Author(s): Naoto Matsumoto, Yuki Miyamoto, Kohei Hattori, Akihiro Ito, Hironori Harada, Hiroaki Oizumi, Katsuya Ohbuchi, Kazushige Mizoguchi, and Junji Yamauchi
  • Journal Title: Biomedicines Volume: 8 Issue: 4 Pages: 89-89
  • DOI: 10.3390/biomedicines8040089
  • Peer Reviewed / Open Access
• [Journal Article] Rare Neurologic Disease-Associated Mutations of AIMP1 are Related with Inhibitory Neuronal Differentiation Which is Reversed by Ibuprofen (2020)
  • Author(s): Yu Takeuchi, Marina Tanaka, Nanako Okura, Yasuyuki Fukui, Ko Noguchi, Yoshihiro Hayashi, Tomohiro Torii, Hiroaki Ooizumi, Katsuya Ohbuchi, Kazushige Mizoguchi, Yuki Miyamoto, and Junji Yamauchi
  • Journal Title: Medicines Volume: 7 Issue: 5 Pages: 25-25
  • DOI: 10.3390/medicines7050025
  • Peer Reviewed / Open Access
• [Journal Article] Expression of kinase-deficient MEK2 ameliorates Pelizaeus-Merzbacher disease phenotypes in mice (2020)
  • Author(s): Yuki Miyamoto, Marina Tanaka, Hisanaka Ito, Hiroaki Ooizumi, Katsuya Ohbuchi, Kazushige Mizoguchi, Tomohiro Torii, and Junji Yamauchi
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 531, Issue: 4 Pages: 445-451
  • DOI: 10.1016/j.bbrc.2020.07.131
  • Peer Reviewed / Open Access
• [Journal Article] CMT type 2N disease-associated AARS mutant inhibits neurite growth that can be reversed by valproic acid (2019)
  • Author(s): Tatsumi Yuriko、Matsumoto Naoto、Iibe Noriko、Watanabe Natsumi、Torii Tomohiro、Sango Kazunori、Homma Keiichi、Miyamoto Yuki、Sakagami Hiroyuki、Yamauchi Junji
  • Journal Title: Neuroscience Research Volume: 139 Pages: 69-78
  • DOI: 10.1016/j.neures.2018.09.016
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Defective neuronal and oligodendroglial differentiation by FTD3- and ALS17-associated Ile29-to-Val mutation of CHMP2B. (2019)
  • Author(s): Yamawaki M, Akiba M, Matsumoto N, Watanabe N, Hattori K, Takeuchi Y, Morimoto T, Oizumi H, Ohbuchi K, Miyamoto Y, Yamauchi J.
  • Journal Title: Mol Genet Metab Rep. Volume: 19 Pages: 100458-100458
  • Peer Reviewed / Open Access
• [Journal Article] Data on the effects of Charcot-Marie-Tooth disease type 2N-associated AARS missense mutation (Arg329-to-His) on the cell biological properties. (2019)
  • Author(s): Imaizumi N, Takeuchi Y, Hirano H, Torii T, Seki Y, Morimoto T, Miyamoto Y, Sakagami H, Yamauchi J.
  • Journal Title: Data Brief Volume: 25 Pages: 104029-104029
  • DOI: 10.1016/j.dib.2019.104029
  • Peer Reviewed / Open Access
• [Journal Article] Hypomyelinating leukodystrophy-associated mutation of RARS leads it to the lysosome, inhibiting oligodendroglial morphological differentiation. (2019)
  • Author(s): Matsumoto N, Watanabe N, Iibe N, Tatsumi Y, Hattori K, Takeuchi Y, Oizumi H, Ohbuchi K, Torii T, Miyamoto Y, Yamauchi J.
  • Journal Title: Biochem Biophys Rep. Volume: 20 Pages: 100705-100705
  • DOI: 10.1016/j.bbrep.2019.100705
  • Peer Reviewed / Open Access
• [Journal Article] Effects of HLD-associated POLR1C mutant proteins on cellular localization and differentiation. (2018)
  • Author(s): Hiraoka Y, Hattori K, Takeuchi Y, Yamawaki M, Watanabe N, Matsumoto N, Homma K, Miyamoto Y, Yamauchi J
  • Journal Title: Mol. Genet. Metab. Rep. Volume: 17 Pages: 80-82
  • DOI: 10.1016/j.ymgmr.2018.11.002
  • Peer Reviewed / Open Access
• [Journal Article] BIG1/Arfgef1 and Arf1 regulate the initiation of myelination by Schwann cells in mice. (2018)
  • Author(s): Miyamoto Y, Torii T, Tago K, Tanoue A, Takashima S, Yamauchi J
  • Journal Title: Sci Adv. Volume: 4 Issue: 4
  • DOI: 10.1126/sciadv.aar4471
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The promoter region of 46-kDa CNPase is sufficient for its expression in corpus callosum. (2018)
  • Author(s): Miyamoto Y, Torii T, Tanoue A, Yamamoto M, Yamauchi J
  • Journal Title: Mol. Genet. Metab. Rep. Volume: 15 Pages: 78-79
  • DOI: 10.1016/j.ymgmr.2018.03.003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pull down assay for GTP-bound form of Sar1a reveals its activation during morphological differentiation. (2018)
  • Author(s): Urai Y, Yamawaki M, Watanabe N, Seki Y, Morimoto T, Tago K, Homma K, Sakagami H, Miyamoto Y, Yamauchi J
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 503 Issue: 3 Pages: 2047-2053
  • DOI: 10.1016/j.bbrc.2018.07.157
  • Peer Reviewed
• [Journal Article] Treacher Collins syndrome 3 (TCS3)-associated POLR1C mutants are localized in the lysosome and inhibits chondrogenic differentiation. (2018)
  • Author(s): Matsumoto N, Kaneko M, Watanabe N, Itaoka M, Seki Y, Morimoto T, Torii T, Miyamoto Y, Keiichi Homma, Yamauchi J
  • Journal Title: Biochem. Biophys. Res. Commun. Volume: 499 Issue: 1 Pages: 78-85
  • DOI: 10.1016/j.bbrc.2018.03.136
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Neuregulin-1 type III knockout mice exhibit delayed migration of Schwann cell precursors. (2017)
  • Author(s): Miyamoto Y, Torii T, Tanoue A, Kawahara K, Arai M, Tsumura H, Ogata T, Nagao M, Terada N, Yamamoto M, Takashima S, Yamauchi J
  • Journal Title: Biochemical and Biophysical Research Communication, Volume: 486 Issue: 2 Pages: 506-513
  • DOI: 10.1016/j.bbrc.2017.03.074
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Data on the effect of knockout of cytohesin-1 in myelination-related protein kinase signaling. (2017)
  • Author(s): Ruri Tsuneishi, Naoto Matsumoto, Misa Itaoka, Yuki Urai, Minami Kaneko, Natsumi Watanabe, Shou Takashima, Yoichi Seki, Takako Morimoto, Hiroyuki Sakagami, Yuki Miyamoto, and Junji Yamauchi
  • Journal Title: Data Brief. Volume: 15 Pages: 234-239
  • DOI: 10.1016/j.dib.2017.09.024
  • Peer Reviewed / Open Access
• [Journal Article] Data on the effect of in vivo knockdown using artificial ErbB3 miRNA on Remak bundle structure. (2017)
  • Author(s): Yuki Miyamoto, Tomohiro Torii, Kazuko Kawahara, Masashi Inoue, Takako Morimoto, Masahiro Yamamoto, and Junji Yamauchi
  • Journal Title: Data Brief. Volume: 12 Pages: 313-319
  • DOI: 10.1016/j.dib.2017.04.014
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Data supporting the role of Fyn in embryonic sciatic nerve fasciculation. (2017)
  • Author(s): Tomohiro Torii, Yuki Miyamoto, Kazuko Kawahara, Akito Tanoue, Yoichi Seki, Takako Morimoto, Masahiro Yamamoto, and Junji Yamauchi
  • Journal Title: Data Brief. Volume: 11 Pages: 358-363
  • DOI: 10.1016/j.dib.2017.02.042
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Data on the effect of hypomyelinating leukodystrophy 6 (HLD6)-associated mutations on the TUBB4A properties. (2017)
  • Author(s): Yuki Miyamoto, Tomohiro Torii, Kazuko Kawahara, Nanami Hasegawa, Akito Tanoue, Yoichi Seki, Takako Morimoto, Megumi Funakoshi-Tago, Hiroomi Tamura, Keiichi Homma, Masahiro Yamamoto, and Junji Yamauchi
  • Journal Title: Data Brief. Volume: 11 Pages: 284-289
  • DOI: 10.1016/j.dib.2017.02.024
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Intercellular molecules whose primary role is in the immune system can also play an unexpected role in the CNS (2018)
  • Author(s): 宮本 幸、山内淳司
  • Organizer: 日本神経科学会（シンポジウム）
• [Presentation] α4β1インテグリンリガンドとVCAM1受容体による中枢神経系のミエリン形成機構 (2017)
  • Author(s): 宮本 幸、山内淳司
  • Organizer: 生命科学系学会合同年次大会
• [Presentation] VCAM1 regulates oligodendrocyte myelination (2017)
  • Author(s): 宮本 幸、山内淳司
  • Organizer: 日本神経化学会大会
• [Remarks] 分子神経科学研究室TOP
  • URL: http://www.ls.toyaku.ac.jp/~noshinkei/
• [Remarks] 東京薬科大学生命科学部分子生命科学科TOP
  • URL: https://www.ls.toyaku.ac.jp/ls_molbio