Molecular mechanisms of conformational changes of proteins and neurodegeneration in neurodegenerative diseases.

2008 Fiscal Year Final Research Report

• Project/Area Number: 18300117
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Nerve anatomy/Neuropathology
• Research Institution: Tokyo Metropolitan Organization for Medical Research
• Principal Investigator: HASEGAWA Masato Tokyo Metropolitan Organization for Medical Research, 東京都精神医学総合研究所, 副参事研究員 (10251232)
• Project Period (FY): 2006 – 2008
• Keywords: タウ / αシヌクレイン / TDP-43 / アルツハイマー / パーキンソン

Research Abstract

神経変性の共通の分子メカニズムを明らかにすることを目的として、患者脳に蓄積する蛋白質の解析、リコンビナント蛋白質を用いた解析を行った。その結果、同じ4リピートタウが蓄積するPSPとCBDにおいて、蓄積するタウの線維構造が異なっている可能性が示唆された。また、FTLD、ALSに蓄積するユビキチン陽性封入体の構成タンパク質としてリン酸化TDP-43を同定した。さらにαシヌクレインの部位特異抗体を用いて、αシヌクレインのモノマーから線維化への構造変化をとらえることに成功した。

Research Products

• [Journal Article] TDP-43 in ubiquitinated inclusions in the inferior olives in frontotemporal lobar degeneration and in other neurodegenerative diseases: a degenerative process distinct from normal ageing. (2009)
  • Author(s): Davidson Y, Amin H, Kelley T, Shi J, Tian J, Kumaran R, Lashley T, Lees AJ, Duplessis D, Neary D, Snowden J, Akiyama H, Arai T, Hasegawa M, et al.
  • Journal Title: Acta Neuropathol. [Epub ahead of print] Pages: 0
  • Peer Reviewed
• [Journal Article] Identification of casein kinase-1 phosphorylation sites on TDP-43. (2009)
  • Author(s): Kametani F, Nonaka T, Suzuki T, Arai T, Dohmae N, Akiyama H, Hasegawa M.
  • Journal Title: Biochem Biophys Res Commun. 382 Pages: 405-9
  • Peer Reviewed
• [Journal Article] TDP-43 pathology in familial British dementia. (2009)
  • Author(s): Schwab C, Arai T, Hasegawa M, Akiyama H, Yu S, McGeer PL.
  • Journal Title: Acta Neuropathol. [Epub ahead of print] Pages: 0
  • Peer Reviewed
• [Journal Article] Conversion of wild-type α-synuclein into mutant-type fibrils and its propagation in the presence of A30P mutant. (2009)
  • Author(s): Yonetani M, Nonaka T, Masuda M, Inukai Y, Oikawa T, Hisanaga S, Hasegawa M.
  • Journal Title: J Biol Chem 284 Pages: 7940-50
  • Peer Reviewed
• [Journal Article] Inhibition of α-synuclein fibril assembly by small molecules: analysis using epitope-specific antibodies. (2009)
  • Author(s): Masuda M, Hasegawa M, Nonaka T, Oikawa T, Yonetani M, Yamaguchi Y, Kato K, Hisanaga S, Goedert M.
  • Journal Title: FEBS Lett 583 Pages: 787-91
  • Peer Reviewed
• [Journal Article] Phosphorylated and ubiquitinated TDP-43 pathological inclusions in ALS and FTLD-U are recapitulated in SH-SY5Y cells. (2009)
  • Author(s): Nonaka T, Arai T, Buratti E, Baralle FE, Akiyama H, Hasegawa M.
  • Journal Title: FEBS Lett 583 Pages: 394-400
  • Peer Reviewed
• [Journal Article] Phosphorylated TDP-43 in Alzheimer's disease and dementia with Lewy bodies (2009)
  • Author(s): Arai T Mackenzie IR, Hasegawa M, Nonaka T, Niizato K, Tsuchiya K, Iritani S, Onaya M, Akiyama H
  • Journal Title: Acta Neuropathol. 117 Pages: 125-36
  • Peer Reviewed
• [Journal Article] Accumulation of phosphorylated TDP-43 in brains of patients with argyrophilic grain disease. (2008)
  • Author(s): Fujishiro H, Uchikado H, Arai T, Hasegawa M, Akiyama H, Yokota O, Tsuchiya K, Togo T, Iseki E.
  • Journal Title: Acta Neuropathol. 117 Pages: 151-8
  • Peer Reviewed
• [Journal Article] Colocalization of TDP-43 and Huntingtin in inclusions of Huntington's disease (2008)
  • Author(s): Schwab C, Arai T, Hasegawa M, Yu S McGeer PL
  • Journal Title: J Neurolpathol Exp Neurol 67 Pages: 1159-65
  • Peer Reviewed
• [Journal Article] Abnormal phosphorylation of Ser409/410 of TDP-43 in FTLD-U and ALS. (2008)
  • Author(s): Inukai Y, Nonaka T, Arai T, Yoshida M, Hashizume Y, Beach TG, Buratti E, Baralle FE, Akiyama H, Hisanaga SI, Hasegawa M,
  • Journal Title: FEBS Lett 582 Pages: 2289-2904
  • Peer Reviewed
• [Journal Article] Phosphorylated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. (2008)
  • Author(s): Hasegawa M, Arai T, Nonaka T, Kametani F, Yoshida M, Hashizume Y, Beach TG, Buratti E, Baralle F, Morita M, Nakano I, Oda T, Tsuchiya K, Akiyama H
  • Journal Title: Ann Neurol 64 Pages: 60-70
  • Peer Reviewed
• [Journal Article] Relationship of phosphorylated alpha-synuclein and tau accumulation to Abeta deposition in the cerebral cortex of dementia with Lewy bodies. (2008)
  • Author(s): Obi K, Akiyama H, Kondo H, Shimomura Y, Hasegawa M, Iwatsubo T, Mizuno Y, Mochizuki H.
  • Journal Title: Exp Neurol 210 Pages: 409-20
  • Peer Reviewed
• [Journal Article] Casein kinase 2 is the major enzyme in brain that phosphorylates Ser129 of human alpha-synuclein: Implication for alpha-synucleinopathies. (2007)
  • Author(s): Ishii A, Nonaka T, Taniguchi S, Saito T, Arai T, Mann D, Iwatsubo T, Hisanaga SI, Goedert M, Hasegawa M
  • Journal Title: FEBS Lett 581 Pages: 4711-4717
  • Peer Reviewed
• [Journal Article] Ultra-high field NMR studies of antibody binding and site-specific phosphorylation of alpha-synuclein. (2007)
  • Author(s): Sasakawa H, Sakata E, Yamaguchi Y, Masuda M, Mori T, Kurimoto E, Iguchi T, Hisanaga SI, Iwatsubo T, Hasegawa M, Kato K
  • Journal Title: Biochem Biophys Res Commun 363 Pages: 795-799
  • Peer Reviewed
• [Journal Article] Fibrillogenic nuclei composed of P301L mutant tau induce elongation of P301L tau, but not wild-type tau. (2007)
  • Author(s): Aoyagi H, Hasegawa M, Tamaoka A
  • Journal Title: J Biol Chem 282 Pages: 20309-20318
  • Peer Reviewed
• [Journal Article] TDP-43 is deposited in the Guam parkinsonism-dementia complex brains. (2007)
  • Author(s): Hasegawa M, Arai T, Akiyama H, Nonaka T, Mori H, Hashimoto T, Yamazaki M, Oyanagi K.
  • Journal Title: Brain 130 Pages: 1386-1394
  • Peer Reviewed
• [Journal Article] Regulation of membrane association and kinase activity of Cdk5-p35 by phosphorylation of p35. (2007)
  • Author(s): Sato K, Zhu YS, Saito T, Yotsumoto K, Asada A, Hasegawa M, Hisanaga S.
  • Journal Title: J Neurosci Res. 85 Pages: 3071-8
  • Peer Reviewed
• [Journal Article] TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. (2006)
  • Author(s): Arai T*, Hasegawa M*, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T
  • Journal Title: Biochem Biophys Res Commun 351 Pages: 602-611
  • Peer Reviewed
• [Journal Article] Dyrk1A phosphorylates alpha-synuclein and enhances intracellular inclusion formation. (2006)
  • Author(s): Kim EJ, Sung JY, Lee HJ, Rhim H, Hasegawa M, Iwatsubo T, Min DS, Kim J, Paik SR, Chung KC
  • Journal Title: J Biol Chem 281 Pages: 33250-33257
  • Peer Reviewed
• [Journal Article] Small molecule inhibitors of alpha-synuclein filament assembly. (2006)
  • Author(s): Masuda M, Suzuki N, Taniguchi S, Oikawa T, Nonaka T, Iwatsubo T, Hisanaga SI, Goedert M, Hasegawa M
  • Journal Title: Biochemistry 45 Pages: 6085-6094
  • Peer Reviewed
• [Journal Article] Cysteine misincorporation in bacterially expressed human alpha-synuclein. (2006)
  • Author(s): Masuda M, Dohmae N, Nonaka T, Oikawa T, Hisanaga S, Goedert M, Hasegawa M
  • Journal Title: FEBS Lett 580 Pages: 1775-1779
  • Peer Reviewed
• [Journal Article] Pathological and biochemical studies on a case of Pick disease with severe white matter atrophy. (2006)
  • Author(s): Yamakawa K, Takanashi M, Watanabe M, Nakamura N, Kobayashi T, Hasegawa M, Mizuno Y, Tanaka S, Mori H.
  • Journal Title: Neuropathology 26 Pages: 586-591
  • Peer Reviewed
• [Journal Article] Biochemistry and molecular biology of tauopathies. (2006)
  • Author(s): Hasegawa M
  • Journal Title: Neuropathology 26 Pages: 484-490
  • Peer Reviewed
• [Journal Article] Corticobasal degeneration with focal, massive tau accumulation in the subcortical white matter astrocytes. (2006)
  • Author(s): Sakai K, Piao YS, Kikugawa K, Ohara S, Hasegawa M, Takano H, Fukase M, Nishizawa M, Kakita A, Takahashi H
  • Journal Title: Acta Neuropathol 112 Pages: 341-348
  • Peer Reviewed
• [Journal Article] Co-localization of beta-peptide and phosphorylated tau in astrocytes in a patient with corticobasal degeneration. (2006)
  • Author(s): Wakabayashi K, Mori F, Hasegawa M, Kusumi T, Yoshimura I, Takahashi H, Kaneko S
  • Journal Title: Neuropathology 26 Pages: 66-71
  • Peer Reviewed
• [Presentation] ALS、FTLDにおけるリン酸化TDP-43の蓄積 (2008)
  • Author(s): 長谷川成人, 野中隆, 新井哲明, 犬飼有紀, 亀谷富由樹, 久永眞市, 秋山治彦
  • Organizer: 第81回日本生化学会大会, シンポジウム「神経変性疾患関連遺伝子探索と機能解析」
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-11
• [Presentation] FTLD、ALSに蓄積する異常TDP-43 の解析 (2008)
  • Author(s): 長谷川成人, 新井哲明, 野中隆, 亀谷富由樹, 吉田眞理, 橋詰良夫, Beach T, 森田光哉, 中野今治, 織田辰郎, 土谷邦秋, 秋山治彦
  • Organizer: 第27回日本認知症学会
  • Place of Presentation: 前橋
  • Year and Date: 2008-10-11
• [Presentation] TDP-43の細胞内封入体モデルの作製 (2008)
  • Author(s): 野中隆, 新井哲明, 秋山治彦, 長谷川成人
  • Organizer: 第27回日本認知症学会
  • Place of Presentation: 前橋
  • Year and Date: 2008-10-11
• [Presentation] αシヌクレインの線維形成におけるA30P凝集核の効果 (2008)
  • Author(s): 米谷元邦, 犬飼有紀, 野中隆, 久永眞市, 長谷川成人
  • Organizer: 第27回日本認知症学会
  • Place of Presentation: 前橋
  • Year and Date: 2008-10-10
• [Presentation] TDP-43におけるSer409/410の異常リン酸化 (2008)
  • Author(s): 犬飼有紀, 野中隆, 新井哲明, 吉田眞理,橋詰良夫, 秋山治彦, 久永眞市, 長谷川成人
  • Organizer: 第27回日本認知症学会
  • Place of Presentation: 前橋
  • Year and Date: 2008-10-10
• [Presentation] Accumulation of phosphorylated TDP-43 in neurodegenerative disorders. (2008)
  • Author(s): Arai T, Hasegawa M, Nonaka T, Kametani F, Ikeda K, Yoshida M, Hashizume Y, Beach TG, Buratti E, Baralle F, Morita M, Nakano I, Oda T, Tsuchiya K, Akiyama H
  • Organizer: International Conference on Alzheimer's Disease 2008
  • Place of Presentation: Chicago, USA
  • Year and Date: 2008-07-28
• [Presentation] Intracellular aggregation of phosphorylated and ubiquitinated TDP-43 in SH-SY5Y cells. (2008)
  • Author(s): Nonaka T, Arai T, Akiyama H, Buratti E, Baralle F E, and Hasegawa M
  • Organizer: International Conference on Alzheimer's Disease 2008
  • Place of Presentation: Chicago, USA
  • Year and Date: 2008-07-27
• [Presentation] FTDにおけるTDP-43蓄積の意義 (2008)
  • Author(s): 長谷川成人, 新井哲明, 野中隆, 亀谷富由樹, 吉田眞理, 橋詰良夫, Thomas Beach, 森田光哉, 中野今治, 織田辰郎, 土谷邦秋, 秋山治彦
  • Organizer: 第49回日本神経学会総会
  • Place of Presentation: 横浜
  • Year and Date: 2008-05-17
• [Presentation] 前頭側頭葉変性症、筋萎縮性側索硬化症に出現するユビキチン陽性封入体のプロテオミクス解析とTDP-43の同定 (2007)
  • Author(s): 長谷川成人, 新井哲明
  • Organizer: 日本ヒトプロテオーム機構第5回大会
  • Place of Presentation: 東京
  • Year and Date: 2007-07-31
• [Presentation] グアムPDC患者脳におけるTDP-43の蓄積 (2007)
  • Author(s): 長谷川成人, 新井哲明, 秋山治彦, 橋本智代, 山崎峰雄, 小柳清光
  • Organizer: 第48回日本神経学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2007-05-17
• [Presentation] シヌクレイノパチーの基礎研究 (2006)
  • Author(s): 長谷川成人
  • Organizer: 第25 回日本認知症学会, シンポジウム3 「シヌクレイノパチーの臨床と基礎研究」
  • Place of Presentation: 広島
  • Year and Date: 2006-10-07
• [Presentation] CK2 is the major enxyme in brain that generates PSer129 epitope of alpha-synuclein. (2006)
  • Author(s): Hasegawa M, Ishii A, Nonaka T, Saito T, Arai T, Hisanaga S, Iwatsubo T
  • Organizer: The 6th Annual Meeting of International College of Geriatric Psychoneuropharmacology (ICGP)
  • Place of Presentation: Hiroshima, Japan
  • Year and Date: 2006-10-05
• [Presentation] Proteasome inhibition by alpha-synuclein in living cells. (2006)
  • Author(s): Nonaka T, Hasegawa M
  • Organizer: The 10th International Conference on Alzheimer's Disease and Related Disorders
  • Place of Presentation: Madrid, Spain
  • Year and Date: 2006-07-19
• [Presentation] Small molecule inhibitors of alpha-synuclein filament assembly. (2006)
  • Author(s): Masuda M, Suzuki N, Taniguchi S, Oikawa T, Nonaka T, Iwatsubo T, Hisanaga S, Goedert M, Hasegawa M
  • Organizer: The 10th International Conference on Alzheimer's Disease and Related Disorders
  • Place of Presentation: Madrid, Spain
  • Year and Date: 2006-07-19
• [Book] タウ:老年期認知症ナビゲーター(平井俊策監修) (2006)
  • Author(s): 長谷川成人
  • Total Pages: 218-219
  • Publisher: 東京 : メディカルレビュー社
• [Book] 神経原線維変化: 老年期認知症ナビゲーター( 平井俊策監修) (2006)
  • Author(s): 長谷川成人
  • Total Pages: 214-215
  • Publisher: 東京 : メディカルレビュー社
• [Patent(Industrial Property Rights)] TDP-43蓄積細胞モデル (2008)
  • Inventor(s): 野中隆、新井哲明、秋山治彦、長谷川成人
  • Industrial Property Rights Holder: 財団法人東京都医学研究機構
  • Industrial Property Number: 特許, 特願2008-101899
  • Filing Date: 2008-04-09
• [Patent(Industrial Property Rights)] 遺伝子変異を用いた筋萎縮性側索硬化症の予測法 (2008)
  • Inventor(s): 糸川昌成、新井誠、長谷川成人、野中隆, 秋山治彦、新井哲明
  • Industrial Property Rights Holder: 財団法人東京都医学研究機構
  • Industrial Property Number: 特許, 特願2008-095035
  • Filing Date: 2008-04-01
• [Patent(Industrial Property Rights)] TDP-43凝集物に特異的に結合する抗体 (2007)
  • Inventor(s): 長谷川成人、新井哲明、野中隆、亀谷富由樹、秋山治彦
  • Industrial Property Rights Holder: 財団法人東京都医学研究機構
  • Industrial Property Number: 特許, 特願2007-178583
  • Filing Date: 2007-07-06
• [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 (2006)
  • Inventor(s): 野中隆、増田雅美、長谷川成人
  • Industrial Property Rights Holder: 財団法人東京都医学研究機構
  • Industrial Property Number: 特許, 特願2006-030530
  • Filing Date: 2006-02-08