Cellular and animal models for intracellular TDP-43 aggregates

2012 Fiscal Year Final Research Report

• Project/Area Number: 22500345
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: 公益財団法人東京都医学総合研究所 (2012); Tokyo Metropolitan Organization for Medical Research (2010-2011)
• Principal Investigator: NONAKA Takashi 公益財団法人東京都医学総合研究所, 認知症・高次脳機能研究分野, 副参事研究員 (30356258)
• Project Period (FY): 2010 – 2012
• Keywords: 筋萎縮性側索硬化症 / TDP-43

Research Abstract

We established a new cellular model for intracellular TDP-43 aggregate formation and screened small molecules which inhibit the formation of TDP-43 aggregates using this model. These compounds may be possible new drugs for the treatment of ALS and FTLD-TDP.

Research Products

• [Journal Article] Methylene Blue Reduced Abnormal Tau Accumulation in P301L Tau Transgenic Mice (2012)
  • Author(s): Masato Hosokawa, Tetsuaki Arai, Masami Masuda-Suzukake, Takashi Nonaka, Makiko Yamashita, Haruhiko Akiyama, Masato Hasegawa
  • Journal Title: PLoS ONE Pages: e52389
  • Peer Reviewed
• [Journal Article] Molecular analysis and biochemical classification of TDP-43 proteinopathy (2012)
  • Author(s): Tsuji H, Arai T, Kametani F, Nonaka T, Yamashita M, Suzukake M, Hosokawa M, Yoshida M, Hatsuta H, Takao M, Saito Y, Murayama S, Akiyama H, Hasegawa M, Mann DM, Tamaoka A
  • Journal Title: Brain Volume: 135 Pages: 3380-3391
  • Peer Reviewed
• [Journal Article] Inhibition of TDP-43 Accumulation by Bis(thiosemicarbazonato)-Copper Complexes (2012)
  • Author(s): Parker SJ, Meyerowitz J, James JL, Liddell JR, Nonaka T, Hasegawa M, Kanninen KM, Lim S, Paterson BM, Donnelly PS, Crouch PJ, White AR
  • Journal Title: PLoS One Volume: 7(8) Pages: e42277
  • Peer Reviewed
• [Journal Article] Drug Screening for ALS Using Patient-Specific Induced Pluripotent Stem Cells (2012)
  • Author(s): Egawa N, Kitaoka S, Tsukita K, Naitoh M, Takahashi K, Yamamoto T, Adachi F, Kondo T, Okita K, Asaka I, Aoi T, Watanabe A, Yamada Y, Morizane A, Takahashi J, Ayaki T, Ito H, Yoshikawa K, Yamawaki S, Suzuki S, Watanabe D, Hioki H, Kaneko T, Makioka K, Okamoto K, Takuma H, Tamaoka A, Hasegawa K, Nonaka T, Hasegawa M, Kawata A, Yoshida M, Nakahata T, Takahashi R, Marchetto MC, Gage FH, Yamanaka S, Inoue H
  • Journal Title: Sci. Transl. Med Volume: 4(145) Pages: 145ra104
  • Peer Reviewed
• [Journal Article] Prolonged nitric oxide treatment induces tau aggregation in SH-SY5Y cells (2012)
  • Author(s): Takahashi M, Tin Y, Nonaka T, Hasegawa M, Watanabe N, and Arai T
  • Journal Title: Neurosci. Lett Volume: 510 Pages: 48-52
  • Peer Reviewed
• [Journal Article] Epitope mapping of antibodies against TDP-43 and detection of protease-resistant fragments of pathological TDP-43 in amyotrophic lateral sclerosis and frontotemporal lobar degeneration (2012)
  • Author(s): Tsuji H, Nonaka T, Yamashita M, Suzukake M, Kametani F, Akiyama H, Mann DM, Tamaoka A, Hasegawa M
  • Journal Title: Biochem. Biophys. Res. Comm Volume: 417 Pages: 116-121
  • Peer Reviewed
• [Journal Article] C-Jun N-terminal kinase controls TDP-43 accumulation in stress granules induced by oxidative stress (2011)
  • Author(s): Meyerowitz J, Parker SJ, Vella LJ, Ng DC, Price KA, Liddell JR, Caragounis A, Li QX, Masters CL, Nonaka T, Hasegawa M, Bogoyevitch MA, Kanninen KM, Crouch PJ, White AR
  • Journal Title: Mol. Neurodegener Volume: 6 Pages: 57
  • Peer Reviewed
• [Journal Article] Molecular Dissection of TDP-43 Proteinopathies (2011)
  • Author(s): Hasegawa M, Nonaka T, Tsuji H, Tamaoka A, Yamashita M, Kametani F, Yoshida M, Arai T, Akiyama H
  • Journal Title: J Mol Neurosci Volume: 45 Pages: 480-485
  • Peer Reviewed
• [Journal Article] In vitro recapitulation of aberrant protein inclusions in neurodegenerative diseases: New cellular models of neurodegenerative diseases (2011)
  • Author(s): Nonaka T* and Hasegawa M*
  • Journal Title: Communicative & Integrative Biology Volume: 4 Pages: 501-502
  • Peer Reviewed
• [Journal Article] Transcriptional regulation of the hypocretin/orexin gene by NR6A1 (2010)
  • Author(s): Tanaka S, Kodama T, Nonaka T, Toyoda H, Arai M, Fukazawa M, Honda Y, Honda M, Mignot E
  • Journal Title: Biochem. Biophys. Res. Commun Volume: 403 Pages: 178-183
  • Peer Reviewed
• [Journal Article] Seeded aggregation and toxicity of alpha-synuclein and tau: cellular models of neurodegenerative diseases (2010)
  • Author(s): Nonaka T, Watanabe ST, Iwatsubo T, Hasegawa M
  • Journal Title: J. Biol. Chem Volume: 285 Pages: 34885-34898
  • Peer Reviewed
• [Journal Article] Phosphorylated and cleaved TDP-43 in ALS, FTLD and other neurodegenerative disorders and in cellular models of TDP-43 proteinopathy (2010)
  • Author(s): Arai T, Hasegawa M, Nonaka T, Kametani F, Yamashita M, Hosokawa M, Niizato K, Tsuchiya K, Kobayashi Z, Ikeda K, Yoshida M, Onaya M, Fujishiro H and Akiyama H
  • Journal Title: Neuropathol Volume: 30 Pages: 372-380
  • Peer Reviewed
• [Journal Article] Characterization of Inhibitor-Bound alpha-Synuclein Dimer: Role of alpha-Synuclein N-Terminal Region in Dimerization and Inhibitor Binding (2010)
  • Author(s): Yamaguchi Y, Masuda M, Sasakawa H, Nonaka T, Hanashima S, Hisanaga S, Kato K, Hasegawa M
  • Journal Title: J. Mol. Biol Volume: 395 Pages: 445-456
  • Peer Reviewed
• [Presentation] Intracellular seeding model reproduces characteristic features of affected neurons in TDP-43 proteinopathy (2012)
  • Author(s): Takashi Nonaka, Masami Masuda-Suzukake, Yoko Hasegawa,Mari Yoshida, Shigeo Murayama,David Mann, Haruhiko Akiyama and Masato Hasegawa
  • Organizer: The 8th International Conference on Fronttemporal Dementias
  • Place of Presentation: Manchester, UK
  • Year and Date: 20120905-07
• [Presentation] 患者脳に蓄積したTDP-43のプリオン様性質 (2012)
  • Author(s): 野中隆,鈴掛(増田)雅美,新井哲明,吉田眞理,村山繁雄,Mann David,秋山治彦,長谷川成人
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡
  • Year and Date: 2012-12-15
• [Presentation] シード依存的な細胞内TDP-43蓄積による細胞死の誘導 (2012)
  • Author(s): 野中隆,鈴掛(増田)雅美,新井哲明,吉田眞理,村山繁雄,Mann David,秋山治彦,長谷川成人
  • Organizer: 第31回日本認知症学会学術集会
  • Place of Presentation: 筑波
  • Year and Date: 2012-10-27
• [Presentation] Intracellular seeded aggregation and cytotoxic model of TDP-43 (2012)
  • Author(s): Takashi Nonaka, Masami Masuda-Suzukake, Makiko Yamashita, Masato Hosokawa, Haruhiko Akiyama and Masato Hasegawa
  • Organizer: Alzheimer's Association International Conference (AAIC)2012
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2012-07-16
• [Presentation] TDP-43のシード依存的細胞内凝集体形成 (2012)
  • Author(s): 野中隆、長谷川成人
  • Organizer: 第53回日本神経学会学術大会、シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2012-05-24
• [Presentation] メチレンブルーによるリン酸化タウ蓄積抑制効果の検討 (2012)
  • Author(s): 細川雅人,新井哲明,野中隆,山下万貴子,鈴掛雅美,辻浩史,長谷川成人,秋山治彦
  • Organizer: 第132回 日本薬学会
  • Place of Presentation: 札幌
  • Year and Date: 2012-03-29
• [Presentation] Prolonged nitric oxide treatment induces tau aggregation in SH-SY5Y cells (2011)
  • Author(s): Muneaki Takahashi, Takashi Nonaka, Masato Hasegawa, Nobuo Watanabe, Takao Arai
  • Organizer: SOCIETY FOR FREE RADICAL BIOLOGY AND MEDICINE SFRBM's 18th Annual Meeting
  • Place of Presentation: Atlanta, USA
  • Year and Date: 20111116-20
• [Presentation] Prolonged nitric oxide treatment induces tau aggregation in SH-SY5Y cells (2011)
  • Author(s): Muneaki Takahashi, Takashi Nonaka, Masato Hasegawa, Nobuo Watanabea, Takao Araia
  • Organizer: 5th Biennial Meeting of Society for Free Radical Research-Asia (SFRR-Asia) 2011
  • Place of Presentation: Kagoshima, Japan
  • Year and Date: 20110831-0904
• [Presentation] Progranulin reduction affects tau phosphorylation in P301L tau transgenic mice (2011)
  • Author(s): M. HOSOKAWA; T. ARAI; T. NONAKA; M. YAMASHITA; M. SUZUKAKE; T. MATSUWAKI; M. NISHIHARA; M. HASEGAWA; H. AKIYAMA
  • Organizer: Neuroscience 2011
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2011-11-13
• [Presentation] Heat shock protein 90 (HSP90) suppresses cell death induced by cytoplasmic TDP-43 and inositol hexakisphosphate kinase 2 (2011)
  • Author(s): E. NAGATA; T. NONAKA; Y. MORIYA; A. SAIARDI; Y. OKADA; H. TSUKAMOTO; J. ITOH; T. SATOH; T. ARAI; S. TAKIZAWA; F. YOSHII; M. HASEGAWA; S. TAKAGI
  • Organizer: Neuroscience 2011
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2011-11-13
• [Presentation] FTLD-TDPおよびALSに蓄積するTDP-43蛋白の凝集体構造に関する解析 (2011)
  • Author(s): 辻浩史、野中隆、新井哲明、山下万喜子、亀谷富由樹、細川雅人、初田裕幸、高尾昌樹、村山繁雄、斉藤祐子、長谷川成人、秋山治彦、David Mann、詫間浩、玉岡晃
  • Organizer: 第30回日本認知症学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2011-11-12
• [Presentation] 細胞内異常蛋白質の伝播の可能性 (2011)
  • Author(s): 長谷川成人、野中隆、辻浩史、山下万喜子、増田雅美、玉岡晃、Mann David,村山繁雄、新井哲明、秋山治彦
  • Organizer: 第30回日本認知症学会学術集会、シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2011-11-11
• [Presentation] メチレンブルーによるリン酸化タウ蓄積抑制効果の検討 (2011)
  • Author(s): 細川雅人、新井哲明、野中隆、山下万喜子、鈴掛雅美、辻浩史、長谷川成人、秋山治彦
  • Organizer: 第30回日本認知症学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2011-11-11
• [Presentation] FTDP-17が疑われた日本人患者75症例におけるPGRNとMAPT 遺伝子解析 (2011)
  • Author(s): 大垣光太郎、李元哲、高梨雅史、石川景一、小林智則、中西淳、野中隆、長谷川成人、岸 雅彦、吉野浩代、舩山学、塩屋敬一、横地正之、佐々木良元、小久保康昌、葛原茂樹、本井ゆみ子、富山弘幸、服部信孝
  • Organizer: 第5回パーキンソン病・運動障害疾患コングレス
  • Place of Presentation: 東京
  • Year and Date: 2011-10-07
• [Presentation] Cellular models of seeded aggregation of alpha-synuclein and tau (2011)
  • Author(s): Takashi Nonaka, Sayuri T. Watanabe, Takeshi Iwatsubo, Masato Hasegawa
  • Organizer: International conference on Alzheimer's disease and related disorders (ICAD) 2011
  • Place of Presentation: Paris, France
  • Year and Date: 2011-07-17
• [Presentation] Histopathological Analysis of Progranulin Knockout Mice (2011)
  • Author(s): Tetsuaki Arai, Katsuyoshi Mizukami, Masugi Nishihara, Masato Hosokawa, Takashi Nonaka, Masato Hasegawa, Haruhiko Akiyama, Takashi Matsuwaki, Sho Takahashi, Takashi Asada
  • Organizer: International conference on Alzheimer's disease and related disorders (ICAD) 2011
  • Place of Presentation: Paris, France
  • Year and Date: 2011-07-17
• [Presentation] C-terminal TDP-43 Inclusion Suppress Proliferation Mediated by Transcriptional Dysregulation (2011)
  • Author(s): Makiko Yamashita, Takashi Nonaka, Masato Hasegawa, Haruhiko Akiyama
  • Organizer: International conference on Alzheimer's disease and related disorders (ICAD) 2011
  • Place of Presentation: Paris, France
  • Year and Date: 2011-07-17
• [Presentation] Quantitative Determination of TDP-43 in Cerebrospinal Fluid of Patients With Amyotrophic Lateral Sclerosis and Other Neurodegenerative Disorders (2011)
  • Author(s): Masato Hosokawa, Haruhiko Akiyama, Tetsuaki Arai, Hiroshi Tsuji, Takashi Nonaka, Makiko Yamashita, Masato Hasegawa
  • Organizer: International conference on Alzheimer's disease and related disorders (ICAD) 2011
  • Place of Presentation: Paris, France
  • Year and Date: 2011-07-17
• [Presentation] TDP-43による運動ニューロン変性の分子病態 (2011)
  • Author(s): 野中隆、長谷川成人
  • Organizer: 第52回日本神経学会学術大会、シンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-20
• [Presentation] 神経変性疾患における蛋白癌仮説 (2011)
  • Author(s): 長谷川成人、野中隆、辻浩史、山下万喜子、増田雅美、玉岡晃、村山繁雄、新井哲明、秋山治彦
  • Organizer: 第52回日本神経学会学術大会、シンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-20
• [Presentation] ALSおよびFTLD-TDPに蓄積するリン酸化TDP-43蛋白コンフォメーションに関する解析 (2011)
  • Author(s): 辻浩史、長谷川成人、野中隆、亀谷富由樹、山下万喜子、増田雅美、細川雅人、秋山治彦、David Mann、初田裕幸、高尾昌樹、村山繁雄、斉藤祐子、詫間浩、冨所康志、中馬越清隆、石井亜紀子、石井一弘、渡邉雅彦、新井哲明、玉岡晃
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-19
• [Presentation] 細胞質内TDP-43凝集体形成細胞でのイノシトール6リン酸キナーゼ2の役割 (2011)
  • Author(s): 永田栄一郎、野中隆、森谷祐介、岡田義則、佐藤忠之、塚本秀雄、新井哲明、長谷川成人、瀧澤俊也、高木繁治
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-19
• [Presentation] FTDP-17が疑われた日本人75症例におけるPGRNとMAPT遺伝子解析 (2011)
  • Author(s): 大垣光太郎、李元哲、高梨雅史、石川景一、小林智則、中西淳、野中隆、長谷川成人、岸雅彦、吉野浩代、舩山学、塩谷敬一、横地正之、佐々木良元、小久保康昌、葛原茂樹、本井ゆみ子、富山弘幸、服部信孝
  • Organizer: 第52回日本神経学会学術大会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-05-18
• [Patent(Industrial Property Rights)] フルベストラントを含む神経変性疾患の治療又は予防のための医薬組成物 (2013)
  • Inventor(s): 山下 万貴子; 長谷川 成人; 秋山 治彦; 野中 隆
  • Industrial Property Rights Holder: 公益財団法人東京都医学総合研究所
  • Industrial Property Number: 特許、2013- 72977
  • Filing Date: 2013-03-29
• [Patent(Industrial Property Rights)] アモジアキンを含む神経変性疾患の治療又は予防のための医薬組成物 (2013)
  • Inventor(s): 山下 万貴子; 長谷川 成人; 秋山 治彦; 野中 隆
  • Industrial Property Rights Holder: 公益財団法人東京都医学総合研究所
  • Industrial Property Number: 特許、2013- 72983
  • Filing Date: 2013-03-29
• [Patent(Industrial Property Rights)] ミトタンを含む神経変性疾患の治療又は予防のための医薬組成物 (2013)
  • Inventor(s): 山下 万貴子; 長谷川 成人; 秋山 治彦; 野中 隆
  • Industrial Property Rights Holder: 公益財団法人東京都医学総合研究所
  • Industrial Property Number: 特許、2013- 72989
  • Filing Date: 2013-03-29
• [Patent(Industrial Property Rights)] レチノイン酸等を含む神経変性疾患の治療及び/又は予防用医薬組成物 (2013)
  • Inventor(s): 山下 万貴子; 長谷川 成人; 秋山 治彦; 野中 隆
  • Industrial Property Rights Holder: 公益財団法人東京都医学総合研究所
  • Industrial Property Number: 特許、2013- 74114
  • Filing Date: 2013-03-29
• [Patent(Industrial Property Rights)] ブロムヘキシン塩酸塩等を含む神経変性疾患の治療及び/又は予防用医薬組成物 (2013)
  • Inventor(s): 山下 万貴子; 長谷川 成人; 秋山 治彦; 野中 隆
  • Industrial Property Rights Holder: 公益財団法人東京都医学総合研究所
  • Industrial Property Number: 特許、2013- 74155
  • Filing Date: 2013-03-29
• [Patent(Industrial Property Rights)] ニフェジピン等を含む神経変性疾患の治療及び/又は予防用医薬組成物 (2013)
  • Inventor(s): 山下 万貴子; 長谷川 成人; 秋山 治彦; 野中 隆
  • Industrial Property Rights Holder: 公益財団法人東京都医学総合研究所
  • Industrial Property Number: 特許、2013- 74065
  • Filing Date: 2013-03-29
• [Patent(Industrial Property Rights)] 神経変性疾患治療用物質のスクリーニング方法 (2012)
  • Inventor(s): 野中 隆,長谷川成人,増田雅美
  • Industrial Property Rights Holder: 財団法人東京都医学総合研究所
  • Industrial Property Number: 特許、特許第4948845号
  • Acquisition Date: 2012-03-16