Elucidation of defective neural communication in motor neuron diseases

• Project/Area Number: 17H04195
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: Katsuno Masahisa 名古屋大学, 医学系研究科, 教授 (50402566)
• Co-Investigator(Kenkyū-buntansha): 橋詰 淳 名古屋大学, 医学部附属病院, 病院助教 (00637689) ; 井口 洋平 名古屋大学, 医学部附属病院, 助教 (80790659) ; 佐橋 健太郎 名古屋大学, 医学部附属病院, 病院助教 (90710103)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2019: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
• Keywords: 運動ニューロン疾患 / エクソサイトーシス / インスリン / DNAメチル化 / Src / TDP-43 / アンドロゲン受容体 / カルシウムチャンネル / エクソサイト-シス / 運動ニューロン / 神経変性疾患 / 神経活動 / DREADD / エクソソーム / 後根神経節

Outline of Final Research Achievements

Nuclear depletion of TDP-43 is the histopathological hallmark of amyotrophic lateral sclerosis. In this research, we showed that loss of TDP-43 inhibited exocytosis by down-regulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion. Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a CAG repeat expansion in the androgen receptor (AR) gene. In this research, we showed that DNA methyltransferase 1 is highly expressed in the motor neurons of an SBMA mouse model, and in patients with SBMA. Treatment with RG108, a DNA methylation inhibitor, ameliorated the viability of SBMA model cells and s the motor function of SBMA mice. We also found that the level of phosphorylated Src was markedly increased in the spinal cords and skeletal muscles of SBMA mice prior to the onset, by utilizing a phosphoprotein assay. Intraperitoneal administration of a Src kinase inhibitor improved the behavioral and histopathological phenotypes of SBMA mice.

Academic Significance and Societal Importance of the Research Achievements

本研究は、ニューロンが細胞外分泌などを介して行っている他の細胞との情報・分子伝達の異常が運動ニューロン疾患における神経・筋システム変性の基盤であるとの仮説に基づき、従来にはない画期的な視点で運動ニューロン疾患の病態の本質を明らかにした。この成果は運動ニューロン疾患の進行メカニズムの解明と、それに基づく予後予測や治療法の開発に直結するだけでなく、認知症を含む他の多くの神経変性疾患や筋疾患などの病態メカニズム研究に応用が可能である。

Research Products

• [Int'l Joint Research] Michigan State University(米国)
• [Journal Article] Unveiling synapse pathology in spinal bulbar muscular atrophy by genome-wide transcriptome analysis of purified motor neurons derived from disease specific iPSCs (2020)
  • Author(s): Onodera K, Shimojo D, Ishihara Y, Yano M, Miya F, Banno H, Kuzumaki N, Ito T, Okada R, Ohyama M, Yoshida M, Tsunoda T, Katsuno M, Doyu M, Sobue G, Okano H, Okada Y
  • Journal Title: Mol. Brain Volume: 13 Issue: 1 Pages: 18-18
  • DOI: 10.1186/s13041-020-0561-1
  • Peer Reviewed / Open Access
• [Journal Article] Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy (2019)
  • Author(s): Iida Madoka、Sahashi Kentaro、Kondo Naohide、Nakatsuji Hideaki、Tohnai Genki、Tsutsumi Yutaka、Noda Seiya、Murakami Ayuka、Onodera Kazunari、Okada Yohei、Nakatochi Masahiro、Tsukagoshi Okabe Yuka、Shimizu Shinobu、Mizuno Masaaki、Adachi Hiroaki、Okano Hideyuki、Sobue Gen、Katsuno Masahisa
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 4262-4262
  • DOI: 10.1038/s41467-019-12282-7
  • Peer Reviewed / Open Access
• [Journal Article] Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis. (2019)
  • Author(s): Ito D, Hashizume A, Hijikata Y, Yamada S, Iguchi Y, Iida M, Kishimoto Y, Moriyoshi H, Hirakawa A, Katsuno M.
  • Journal Title: J Neurol. Volume: 266 Issue: 12 Pages: 2952-2961
  • DOI: 10.1007/s00415-019-09507-6
  • NAID: 120006786260
  • Peer Reviewed
• [Journal Article] TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets (2019)
  • Author(s): Araki Kunihiko、(他10名）、Ishigaki Shinsuke、Nakamichi Yoko、Tsunekawa Shin、Seino Yusuke、Yamamoto Akiko、Takayama Yasunori、Hidaka Shihomi、Tominaga Makoto、Ohara-Imaizumi Mica、Suzuki Atsushi、Ishiguro Hiroshi、Enomoto Atsushi、Yoshida Mari、Arima Hiroshi、Muramatsu Shin-ichi、Sobue Gen、Katsuno Masahisa
  • Journal Title: Journal of Clinical Investigation Volume: 129 Issue: 9 Pages: 3578-3593
  • DOI: 10.1172/jci124481
  • Peer Reviewed / Open Access
• [Journal Article] DNA methylation inhibitor attenuates polyglutamine-induced neurodegeneration by regulating Hes5 (2019)
  • Author(s): Kondo N, Tohnai G, Sahashi K, Iida M, Kataoka M, Nakatsuji H, Tsutsumi Y, Hashizume A, Adachi H, Koike H, Shinjo K, Kondo Y, Sobue G, Katsuno M.
  • Journal Title: EMBO Mol Med Volume: none Issue: 5
  • DOI: 10.15252/emmm.201708547
  • Peer Reviewed / Open Access
• [Journal Article] Disease Affects Bdnf Expression in Synaptic and Extrasynaptic Regions of Skeletal Muscle of Three SBMA Mouse Models (2019)
  • Author(s): Halievski K, Nath SR, Katsuno M, Adachi H, Sobue G, Breedlove SM, Lieberman AP, Jordan CL.
  • Journal Title: Int J Mol Sci Volume: 20 Issue: 6 Pages: 1314-1314
  • DOI: 10.3390/ijms20061314
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IGF-1 for spinal and bulbar muscular atrophy: hope and challenges. (2018)
  • Author(s): Hashizume A, Katsuno M.
  • Journal Title: Lancet Neurol. Volume: 17 Issue: 12 Pages: 1026-1027
  • DOI: 10.1016/s1474-4422(18)30359-4
• [Journal Article] Pre-clinical symptoms of SBMA may not be androgen-dependent: Implications from two SBMA mouse models. (2018)
  • Author(s): Xu Y, Halievski K, Katsuno M, Adachi H, Sobue G, Breedlove M, Jordan CL.
  • Journal Title: Hum Mol Genet in press Volume: 未 Issue: 14 Pages: 2425-2442
  • DOI: 10.1093/hmg/ddy142
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Biomarker-based analysis of preclinical progression in spinal and bulbar muscular atrophy. (2018)
  • Author(s): Hijikata Y, Hashizume A, Yamada S, Inagaki T, Ito D, Hirakawa A, Suzuki K, Atsuta N, Tsuboi T, Hattori M, Hori A, Banno H, Sobue G, Katsuno M.
  • Journal Title: Neurology Volume: 90 Issue: 17 Pages: 1501-1509
  • DOI: 10.1212/wnl.0000000000005360
  • Peer Reviewed
• [Journal Article] 3'UTR Length-Dependent Control of SynGAP Isoform α2 mRNA by FUS and ELAV-like Proteins Promotes Dendritic Spine Maturation and Cognitive Function. (2017)
  • Author(s): Yokoi S, Udagawa T, Fujioka Y, Honda D, Okado H, Watanabe H, Katsuno M.
  • Journal Title: Cell Rep Volume: 20(13) Issue: 13 Pages: 3071-3084
  • DOI: 10.1016/j.celrep.2017.08.100
  • Peer Reviewed / Open Access
• [Journal Article] Altered tau isoform ratio caused by loss of Fus and Sfpq function leads to FTLD-like phenotypes (2017)
  • Author(s): Ishigaki S, Fujioka Y, Okada Y, Riku Y, Udagawa T, Honda D, Yokoi S, Endo K, Ikenaka K, Takagi S, Iguchi Y, Sahara N, Takashima A, Okano H, Yoshida M, Warita H, Aoki M, Watanabe H, Okado H, Katsuno H, Sobue G.
  • Journal Title: Cell Reports Volume: 18 Issue: 5 Pages: 1118-1131
  • DOI: 10.1016/j.celrep.2017.01.013
  • Peer Reviewed / Open Access
• [Presentation] TDP-43 facilitates exocytosis: unexpected link between ALS and diabetes. (2019)
  • Author(s): Katsuno M.
  • Organizer: Australia-Japan Joint Neurodegenerative Disease Symposium.
  • Int'l Joint Research / Invited
• [Presentation] TDP-43 regulates early-phase insulin secretion from pancreatic beta cells. (2019)
  • Author(s): Katsuno M.
  • Organizer: The 22nd US-Japan Cellular and Gene Therapy Conference “Adeno-associated Virus-Mediated Gene Therapy Gene Therapy”.
  • Int'l Joint Research / Invited
• [Presentation] リバーストランスレーションによるTDP-43の機能解明. (2018)
  • Author(s): 勝野雅央
  • Organizer: 第6回日本難病医療ネットワーク学会
  • Invited
• [Presentation] 球脊髄性筋萎縮症における神経筋システム変性病態 (2018)
  • Author(s): 勝野雅央
  • Organizer: 第63回日本人類遺伝学会
  • Invited
• [Presentation] Emerging roles of exosomes in TDP-43 proteinopathy (2017)
  • Author(s): Yohei Iguchi
  • Organizer: 第60回日本神経化学会大会
  • Int'l Joint Research / Invited
• [Presentation] Exosome secretion is a key pathway for clearance of pathological TDP-43 (2017)
  • Author(s): Yohei Iguchi
  • Organizer: 第40回日本神経科学大会
• [Presentation] THE ROLE OF TDP-43 SECRETION IN ASSOCIATION WITH EXOSOMES. (2017)
  • Author(s): Yohei Iguchi, Lara Eid, Martin Parent, Yuichi Riku, Kaori Kawai, Mari Yoshida, Masahisa Katsuno, Gen Sobue, Jean-Pierre Julien
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research
• [Presentation] Akt signaling pathway is dysregulated in polyglutamine diseases. (2017)
  • Author(s): Madoka Iida, Kentaro Sahashi, Naohide Kondo, Hideaki Nakatsuji, Genki Tohnai, Yutaka Tsutsumi, Hiroaki Adachi, Gen Sobue, Masahisa Katsuno
  • Organizer: 第58回日本神経学会学術大会
• [Presentation] Akt signaling pathway is dysregulated in polyglutamine diseases. (2017)
  • Author(s): Madoka Iida, Kentaro Sahashi, Naohide Kondo, Hideaki Nakatsuji, Genki Tohnai, Yutaka Tsutsumi, Hiroaki Adachi, Gen Sobue, Masahisa Katsuno
  • Organizer: 第40回日本神経科学大会
• [Presentation] Biomarker-based analysis of preclinical progression in motor neuron disease. (2017)
  • Author(s): Masahisa Katsuno
  • Organizer: The 8th East Asia Neurological Forum (8th EANF).
  • Int'l Joint Research / Invited