Common pathogenesis in a wide-range of FTLD spectrum including ALS/FTLD and tauopathies

• Project/Area Number: 18K07367
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 51030:Pathophysiologic neuroscience-related
• Research Institution: Nagoya University
• Principal Investigator: Ishigaki Shinsuke 名古屋大学, 医学系研究科, 特任准教授 (40378170)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 前頭側頭葉変性症 / 筋萎縮性側索硬化症 / FUS / SFPQ / タウ / タウオパチー / 進行性核上性麻痺 / 大脳皮質基底核変性症 / FTLD / ALS / PSP / 認知症 / CBD

Outline of Final Research Achievements

Immunofluorescent imaging showed impaired intranuclear colocalization of FUS and SFPQ in neurons of ALS/FTLD-FUS, ALS/FTLD-TDP, PSP, and CBD patients, but not in AD and PiD patients. Immunoprecipitation analyses of FUS and SFPQ revealed reduced interactions between the two proteins in ALS/FTLD-TDP and PSP patients, but not in those with AD. Furthermore, the mRNA ratio of 4R/3R-tau was elevated in patients with ALS/FTLD-TDP and PSP, but was largely unaffected in patients with AD. Lastly, considerable variation was observed in the expression of FUS and SFPQ within the neuronal nuclei of patients with ALS/FTLD-FUS, ALS/FTLD-TDP, PSP, and CBD, but was absent in those with AD or PiD.

Academic Significance and Societal Importance of the Research Achievements

FUS・SFPQの神経細胞核内における微小局在は広義のFTLD疾患スペクトラムにおいて障害されていることが明らかになったことから、これまでスペクトラムを形成するものの病態機序が不明であったALS, FTLD, PSP, CBDといった疾患に共通のメカニズムが存在していることが示唆され、こうした知見をもとに疾患修飾薬の開発を進めることを可能にした。

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] Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD?spectrum diseases (2020)
  • Author(s): Ishigaki Shinsuke、Riku Yuichi、Fujioka Yusuke、Endo Kuniyuki、Iwade Nobuyuki、Kawai Kaori、Ishibashi Minaka、Yokoi Satoshi、Katsuno Masahisa、Watanabe Hirohisa、Mori Keiko、Akagi Akio、Yokota Osamu、Terada Seishi、Kawakami Ito、Suzuki Naoki、Warita Hitoshi、Aoki Masashi、Yoshida Mari、Sobue Gen
  • Journal Title: Brain Volume: 143 Issue: 8 Pages: 2398-2405
  • DOI: 10.1093/brain/awaa196
  • NAID: 40022684971
  • 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] Tau isoform expression and phosphorylation in marmoset brains (2019)
  • Author(s): Sharma Govinda、Huo Anni、Kimura Taeko、Shiozawa Seiji、Kobayashi Reona、Sahara Naruhiko、Ishibashi Minaka、Ishigaki Shinsuke、Saito Taro、Ando Kanae、Murayama Shigeo、Hasegawa Masato、Sobue Gen、Okano Hideyuki、Hisanaga Shin-ichi
  • Journal Title: Journal of Biological Chemistry Volume: 294 Issue: 30 Pages: 11433-11444
  • DOI: 10.1074/jbc.ra119.008415
  • Peer Reviewed / Open Access
• [Journal Article] Tau Accumulation and Network Breakdown in Alzheimer’s Disease (2019)
  • Author(s): Watanabe Hirohisa、Bagarinao Epifanio、Yokoi Takamasa、Yamaguchi Hiroshi、Ishigaki Shinsuke、Mausuda Michihito、Katsuno Masahisa、Sobue Gen
  • Journal Title: Adv Exp Med Biol Volume: 1184 Pages: 231-240
  • DOI: 10.1007/978-981-32-9358-8_19
  • ISBN: 9789813293571, 9789813293588
  • Peer Reviewed / Open Access
• [Journal Article] Importance of Functional Loss of FUS in FTLD/ALS (2018)
  • Author(s): Ishigaki Shinsuke、Sobue Gen
  • Journal Title: Frontiers in Molecular Biosciences Volume: 5 Pages: 44-44
  • DOI: 10.3389/fmolb.2018.00044
  • Peer Reviewed / Open Access
• [Journal Article] Pathogenesis of Frontotemporal Lobar Degeneration: Insights From Loss of Function Theory and Early Involvement of the Caudate Nucleus (2018)
  • Author(s): Sobue Gen、Ishigaki Shinsuke、Watanabe Hirohisa
  • Journal Title: Frontiers in Neuroscience Volume: 12 Pages: 473-473
  • DOI: 10.3389/fnins.2018.00473
  • Peer Reviewed / Open Access
• [Journal Article] Involvement of the Precuneus/Posterior Cingulate Cortex Is Significant for the Development of Alzheimer’s Disease: A PET (THK5351, PiB) and Resting fMRI Study (2018)
  • Author(s): Yokoi Takamasa、Watanabe Hirohisa、Ishigaki Shinsuke、Katsuno Masahisa、Miyao Shinichi、Kato Katsuhiko、Naganawa Shinji、Harada Ryuichi、Okamura Nobuyuki、Yanai Kazuhiko、Yoshida Mari、Sobue Gen （ほか9名）
  • Journal Title: Frontiers in Aging Neuroscience Volume: 10 Pages: 304-304
  • DOI: 10.3389/fnagi.2018.00304
  • Peer Reviewed / Open Access
• [Journal Article] Silencing of FUS in the common marmoset (Callithrix jacchus) brainvia stereotaxic injection of an adeno-associated virus encoding shRNA. (2018)
  • Author(s): Endo K, Ishigaki S, Masamizu Y, Fujioka Y, Watakabe A, Yamamori T, Hatanaka N, Nambu A, Okado H, Katsuno M, Watanabe H, Matsuzaki M, Sobue G
  • Journal Title: Neurosci Res Volume: in press Pages: 30183-9
  • DOI: 10.1016/j.neures.2017.08.006
  • Peer Reviewed
• [Presentation] Functional loss of RNA binding proteins in tauopathies (2020)
  • Author(s): 石垣診祐
  • Organizer: 第61回神経学会学術大会 シンポジウム
  • Invited
• [Presentation] Impaired dopamine release response in the NAcc is in the center of “binge-like eating” mechanism. -Attempt to detect “Binge like eating” as the early sign of neurodegenerative disease - (2020)
  • Author(s): Fujioka Y, Kawai K, Endo K, Ishibashi M, Yokoi S, Iwade N, Katsuno M, Watanabe H, Ishigaki S, Sobue G.
  • Organizer: 第61回神経学会学術大会
• [Presentation] Tau plays a key role in adult hippocampal neurogenesis alteration caused by environmental changes (2020)
  • Author(s): Iwade N, Ishigaki S, Fujioka Y, Endo K, Kawai K, Miyasaka T, Katsuno M, Watanabe H, Sobue G.
  • Organizer: 第61回神経学会学術大会
• [Presentation] Aberrant FUS-SFPQ interaction in a wide-range of FTLD spectrum diseases (2020)
  • Author(s): Ishigaki S, Riku Y, Yoshida M, Sobue G.
  • Organizer: 第39回日本認知症学会学術集会
• [Presentation] A novel State-of-the-art System for the single cell transcriptome analysis based on planar patch clamp. (2019)
  • Author(s): Ishigaki S, Uno H, Wang Z-H, Ukita Y, Bhardwaj R, Tue PT, Iwabuchi S, Hashimoto S, Oka T, Kawahara K, Takamura Y, Urisu T, Sobue G.
  • Organizer: The 49th Society for Neuroscience annual meeting
  • Int'l Joint Research
• [Presentation] Real-time monitoring and quantification of binge-like eating behaviors in animal models. (2019)
  • Author(s): Fujioka Y, Kawai K, Endo K, Ishibashi M, Yokoi S, Iwade N, Katsuno M, Watanabe H, Ishigaki S, Sobue G.
  • Organizer: The 49th Society for Neuroscience annual meeting
  • Int'l Joint Research
• [Presentation] Aberrant interaction between FUS and SFPQ in a wide-ranged FTLD spectrum including ALS and PSP (2019)
  • Author(s): Shinsuke Ishigaki, Yuichi Riku, Yusuke Fujioka, Satoshi Yokoi, Kuniyuki Endo, Nobuyuki Iwade, Kaori Kawai, Minaka Ishibashi, Masahisa Katsuno, Hirohisa Watanabe, Keiko Mori, Mari Yoshida, Gen Sobue
  • Organizer: 第60回神経学会学術大会
• [Presentation] The roles of tau isoforms in adult hippocampal neurogenesis (2019)
  • Author(s): Nobuyuki Iwade, Shinsuke Ishigaki, Yusuke Fujioka, Kaori Kawai, Tomohiro Miyasaka, Hirohisa Watanabe, Masahisa Katsuno, Gen Sobue
  • Organizer: 第60回神経学会学術大会
• [Presentation] Aberrant interaction between FUS and SFPQ in the brain of a wide-ranged FTLD spectrum including amyotrophic lateral sclerosis (ALS) and progressive supranuclear palsy (PSP) (2019)
  • Author(s): Shinsuke Ishigaki, Yuichi Riku, Mari Yoshida, Gen Sobue
  • Organizer: 第60回神経病理学会総会学術研究会
• [Presentation] Involvement of SFPQ in the pathogenesis of a wide-ranged FTLD spectrum (2019)
  • Author(s): Shinsuke Ishigaki, Yuichi Riku, Yusuke Fujioka, Minaka Ishibashi, Satoshi Yokoi, Kuniyuki Endo, Nobuyuki Iwade, Kaori Kawai, Hirohisa Watanabe, Masahisa Katsuno, Mari Yoshida, Gen Sobue
  • Organizer: The 42nd annual Meeting of the Japan Neuroscience Society
• [Presentation] Tau Phosphorylation at AT8 Pathological Site during Brain Development (2019)
  • Author(s): Dilina Tuerde, Kotaro Furusawa, Toshiyuki Takasugi, Taeko Kimura, Shinsuke Ishigaki, Kanae Ando, Shin-ichi Hisanaga, Gen Sobue
  • Organizer: The 42nd annual Meeting of the Japan Neuroscience Society
• [Presentation] RNA結合タンパク質FUSの機能と神経変性疾患への関わり (2018)
  • Author(s): Ishigaki S, Sobue G
  • Organizer: 第41回日本分子生物学会年会 ワークショップ
• [Presentation] FUS/TLSに関連するALS/FTLDの分子病態 (2018)
  • Author(s): 石垣診祐
  • Organizer: 第59神経学会学術大会 シンポジウム
  • Invited
• [Presentation] Functional Loss of FUS in neurodegenerative diseases (2018)
  • Author(s): Ishigaki,S, Sobue,G
  • Organizer: The 41st annual Meeting of the Japan Neuroscience Society Symposium
  • Invited
• [Presentation] Development of a single cell analysis tool for neurological disorders on 2D planar-patch-clamp plate with positional information (2018)
  • Author(s): Ishigaki S, Uno H, Wang Z-H, Ukita Y, Bhardwaj R, Tue PT, Hashimoto S, Oka T, Kawahara K, Takamura Y, Urisu T, Sobue G.
  • Organizer: The 48th Society for Neuroscience annual meeting, Nano symposium
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] タウのスプライシングを制御するアンチセンスオリゴヌクレオチド及びその用途 (2019)
  • Inventor(s): 石垣診祐、祖父江元、佐橋健太郎、遠藤邦幸、他3名
  • Industrial Property Rights Holder: 国立大学法人名古屋大学、神戸天然物化学株式会社
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Overseas
• [Patent(Industrial Property Rights)] タウのスプライシングを制御するアンチセンスオリゴヌクレオチド及びその用途 (2018)
  • Inventor(s): 祖父江元、石垣診祐、他5名
  • Industrial Property Rights Holder: 名古屋大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
• [Patent(Industrial Property Rights)] TDP-43の発現量を調節するアンチセンスオリゴヌクレオチド及びその用途 (2018)
  • Inventor(s): 祖父江元、石垣診祐、他7名
  • Industrial Property Rights Holder: 名古屋大学
  • Industrial Property Rights Type: 特許
  • Filing Date: 2018
  • Overseas