Discovery of novel target and disease modifying therapy for ALS/FTLD using neuro-specific transcriptome analysis

• Project/Area Number: 17K09753
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Neurology
• Research Institution: Nagoya University
• Principal Investigator: IGUCHI YOHEI 名古屋大学, 医学部附属病院, 助教 (80790659)
• Co-Investigator(Kenkyū-buntansha): 勝野 雅央 名古屋大学, 医学系研究科, 教授 (50402566) ; 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: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ALS / FTLD / TDP-43 / TBK1 / 筋萎縮性側索硬化症 / 前頭側頭葉変性症 / polysome解析

Outline of Final Research Achievements

ALS and FTLD are progressive neurodegenerative diseases and the causes are unknown. The genetic and neuropathological studies suggest that loss of functions of TDP-43 or TBK1 are related to the neurodegeneration. We established a novel transgenic mouse, in which GFP-tagged ribosomal protein (RPL10a) and Cre are expressed under synapsin promotor. This mouse allows us to perform neuron-specific polysome (mRNA-ribosome complex) in the conditional TDP-43/TBK1 knockout mice. We validated the expression profile of GFP-RPL10a of the transgenic mouse and analyzed the neuron-specific transcriptome data of the conditional knockout mice.

Academic Significance and Societal Importance of the Research Achievements

ALSとFTLDは上位・下位運動ニューロンや前頭側頭葉皮質のニューロンが選択的に変性する原因不明の神経変性疾患である。これらの疾患における神経変性病態を解明するにはニューロン特異的な解析が必須であるが、モデル動物において変性過程にあるニューロンの単離は非常に困難である。この問題を解決するために、Syn-Ribotag-Creマウスを作成した。このマウスと各floxマウスを交配することで特定の遺伝子をノックアウトしたニューロン特異的な遺伝子発現解析が可能となった。今後多くの神経変性疾患の病態解明に利用することができるため研究を発展させていきたい。

Research Products

• [Journal Article] Characteristic Features of FUS Inclusions in Spinal Motor Neurons of Sporadic Amyotrophic Lateral Sclerosis. (2020)
  • Author(s): Ikenaka K, Ishigaki S, Iguchi Y, Kawai K, Fujioka Y, Yokoi S, Abdelhamid RF, Nagano S, Mochizuki H, Katsuno M, Sobue G.
  • Journal Title: J Neuropathol Exp Neurol Volume: 79 Issue: 4 Pages: 370-377
  • DOI: 10.1093/jnen/nlaa003
  • 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] 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] Preclinical progression of neurodegenerative diseases. (2018)
  • Author(s): Katsuno M, Sahashi K, Iguchi Y, Hashizume A
  • Journal Title: Nagoya J Med Sci Volume: 80 Pages: 289-298
  • NAID: 120006502462
  • Peer Reviewed
• [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凝集におけるエンドソームの関わり (2019)
  • Author(s): 井口洋平、高橋裕平、李佳益、荒木邦彦、井汲一尋、勝野雅央
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Filamin-A as a novel driver for progressive supra nuclear palsy (2019)
  • Author(s): Koyo Tsujikawa, kohei Hamanaka, Mari Yoshida, Kentaro Sahashi, Satoko Miyatake, Satomi Mihashi, Yohei Iguchi, Yuichi Riku, Shinsuke Ishigaki, Gen Sobue, Naomichi Matsumoto, Masahisa Katsuno
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Elevation of serum creatine kinase before the disease onset of amyotrophic lateral sclerosis (2019)
  • Author(s): Daisuke Ito, Atsushi Hashizume, Yasuhiro Hijikata, Shinichiro Yamada, Yoshiyuki Kishimoto, Hideyuki Moriyoshi, Yohei Iguchi, Madoka Iida, Masahisa Katsuno
  • Organizer: 第60回日本神経学会学術大会
• [Presentation] Role of late endosome in the formation of TDP-43 cytoplasmic aggregation (2019)
  • Author(s): Yuhei takahashi, Yohei Iguchi, Masahisa Katsuno
  • Organizer: 第42回日本神経科学大会
• [Presentation] Exosome pathway: a key for clearance of pathological TDP-43 (2018)
  • Author(s): Yohei Iguchi
  • Organizer: 第５９回日本神経学会総会
  • Invited
• [Presentation] Hereditary leukoencephalopathy with brain stem and spinal cord involvement (2018)
  • Author(s): 井口 洋平, 熱田 直樹, 勝野 雅央
  • Organizer: 第５９回日本神経学会総会
• [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
  • Int'l Joint Research
• [Presentation] THE ROLE OF TDP-43 SECRETION IN ASSOCIATION WITH EXOSOMES (2017)
  • Author(s): Yohei Iguchi1, 2, Lara Eid1, Martin Parent1, Yuichi Riku2, Kaori Kawai, Mari Yoshida, Masahisa Katsuno, Gen Sobue, Jean-Pierre Julien
  • Organizer: XXIII World Congress of Neurology
  • Int'l Joint Research