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2013 Fiscal Year Final Research Report

Molecular mechanisms of pathological protein propagation and its regulation

Research Project

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Project/Area Number 23240050
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Nerve anatomy/Neuropathology
Research InstitutionTokyo Metropolitan Institute of Medical Science

Principal Investigator

HASEGAWA Masato  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, 分野長 (10251232)

Project Period (FY) 2011-04-01 – 2014-03-31
Keywords神経変性疾患 / 伝播 / シヌクレイン / TDP-43 / タウ / プリオン
Research Abstract

Progressive neurodegeneration with accumulation of abnormal proteins is the defining neuropathological feature of many neurodegenerative diseases, including Lewy body disease (LBD) and ALS/FTLD. We revealed that injections of recombinant alpha-synuclein (aS) fibrils efficiently induced hyperphosphorylated aS pathology in wild-type mice. Biochemical analyses demonstrated that endogenous mouse aS started to accumulate 3 months after inoculation. Furthermore, injections of Sarkosyl-insoluble aS from LBD patients induced similar aS pathology, indicating that aS fibrils show prion-like infectivity. We also demonstrated that insoluble TDP-43 has prion-like properties. These results indicate that pathological proteins may play a role in the progression of neurodegenerative diseases with protein pathologies. These cellular and mouse models should be useful for elucidating progression mechanisms and evaluating disease-modifying therapy.

  • Research Products

    (24 results)

All 2014 2013 2012 2011 Other

All Journal Article (10 results) (of which Peer Reviewed: 10 results) Presentation (4 results) Book (4 results) Remarks (1 results) Patent(Industrial Property Rights) (5 results) (of which Overseas: 3 results)

  • [Journal Article] 3R and 4R tau isoforms in paired helical filaments in Alzheimer's disease2014

    • Author(s)
      Hasegawa M, Watanabe S, Kondo H, Akiyama H, Mann DMA, Saito Y and Murayama S
    • Journal Title

      Acta Neuropathol

      Volume: 127(2) Pages: 303-5

    • Peer Reviewed
  • [Journal Article] Prion-like Properties of Pathological TDP-43 Aggregates from Diseased Brains2013

    • Author(s)
      Nonaka T, Masuda-Suzukake M, Arai T, Hasegawa Y, Akatsu H, Obi T, Yoshida M, Murayama S, Mann DM, Akiyama H, Hasegawa
    • Journal Title

      Cell Rep

      Volume: 4(1) Pages: 124-34

    • Peer Reviewed
  • [Journal Article] Dipeptide repeat proteins are present in the p62 positive inclusions in patients with Frontotemporal Lobar Degeneration and Motor Neuron Disease associated with expansions in C9ORF722013

    • Author(s)
      Mann DMA, Rollinson S, Robinson AC, Callister J, Snowden JS, Gendron T, Petrucelli L, Masuda- Suzukake M, Hasegawa M, Davidson YS and Pickering-Brown S
    • Journal Title

      Acta Neuropathol. Commun

      Volume: 1 (1) Pages: 68

    • Peer Reviewed
  • [Journal Article] Extensive deamidation at asparagine residue 279 accounts for weak immunoreactivity of tau with RD4 antibody in Alzheimer's disease brain2013

    • Author(s)
      Dan A, Takahashi M, Masuda-Suzukake M, Kametani F, Nonaka T, Kondo H, Akiyama H, Arai T, Mann DMA, Saito Y, Hatsuta H, Murayama S, Hasegawa M
    • Journal Title

      Acta Neuropathol. Commun

      Volume: 1 (1) Pages: 54

    • Peer Reviewed
  • [Journal Article] Prion-like spreading of pathological alpha-synuclein in brain2013

    • Author(s)
      Masuda-Suzukake M, Nonaka T, Hosokawa M., Oikawa T, Arai T, Akiyama H, Mann D, Hasegawa M
    • Journal Title

      Brain

      Volume: 136 (Pt 4) Pages: 1128-38

    • Peer Reviewed
  • [Journal Article] Pin1 stimulates dephosphorylation of tau at Cdk5- dependent Alzheimer phosphorylation sites2013

    • Author(s)
      Kimura T, Tsutsumi K, Taoka M, Saito T, Masuda-Suzukake M, Ishiguro K, Plattner F, Uchida T, Ishobe T, Hasegawa M, Hisanaga SI
    • Journal Title

      J. Biol. Chem

      Volume: 288(11) Pages: 7968 -77

    • Peer Reviewed
  • [Journal Article] A longitudinal study on alpha-synuclein in blood plasma as a biomarker for Parkinson's disease2013

    • Author(s)
      Foulds PG, Diggle P, Mitchell D, Parker A, Hasegawa M, Masuda-Suzukake M, Mann DMA, Allsop D
    • Journal Title

      Sci. Rep

      Volume: 3 Pages: 2540

    • Peer Reviewed
  • [Journal Article] Molecular analysis and biochemical classification of TDP-43 proteinopathy2012

    • Author(s)
      Tsuji1 H, Arai T, Kametani F, Nonaka T, Yamashita M, Suzukake M, Hosokawa M, Yoshida M, Hatsuta H, Takao M, Saito Y, Murayama M, Akiyama H, Hasegawa M, Mann DMA, Tamaoka A
    • Journal Title

      Brain

      Volume: 135 Pages: 3380-3391

    • 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 degeneration2012

    • Author(s)
      Tsuji H, Nonaka T, Yamashita M, Suzukake M, Kametani F, Akiyama H, Mann DM, Tamaoka A and Hasegawa M
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 417 Pages: 116-121

    • Peer Reviewed
  • [Journal Article] Molecular Dissection of TDP-43 Proteinopathies2011

    • 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
  • [Presentation] 3R and 4R tau isoforms in paired helical filaments in Alzheimer's disease. International symposium2014

    • Author(s)
      Hasegawa M, Dan A, Watanabe S, Kondo H, Akiyama H, Mann DM, Saito Y, Murayama S
    • Organizer
      New Frontier of Molecular Neuropathology 2014
    • Place of Presentation
      Tokyo, Japan
    • Year and Date
      2014-03-17
  • [Presentation] Insoluble TDP-43 prepared from diseased brains has prion-like properties2013

    • Author(s)
      Nonaka T, Masuda-Suzukake M, Arai T, Hasegawa Y, Akatsu H, Obi T, Yoshida M, Murayama S, Mann DM, Akiyama H and Hasegawa M
    • Organizer
      Alzheimer's Association International Conference (AAIC2013)
    • Place of Presentation
      Boston, USA
    • Year and Date
      2013-07-18
  • [Presentation] Prion-like spreading of pathological alpha-synuclein in brain2013

    • Author(s)
      Masuda-Suzukake M, Nonaka T, Hosokawa M, Oikawa T, Arai T, Akiyama H and Hasegawa M
    • Organizer
      The 11th International Conference on Alzheimer's & Parkinson's Diseases
    • Place of Presentation
      Florence, Italy
    • Year and Date
      2013-03-09
  • [Presentation] Prion-like properties of pathological TDP-43 aggregates in diseased brains2013

    • Author(s)
      Nonaka T, Masuda-Suzukake M, Arai T, Yoshida M, Murayama S, Mann D, Akiyama H and Hasegawa M
    • Organizer
      The 11th International Conference on Alzheimer's & Parkinson's Diseases
    • Place of Presentation
      Florence, Italy
    • Year and Date
      2013-03-07
  • [Book] 細胞内異常タンパク質の伝播の可能性2013

    • Author(s)
      長谷川成人
    • Total Pages
      45-53
    • Publisher
      Dementia Japan
  • [Book] 脳内に蓄積したTDP-43 凝集体のプリオン様性質2013

    • Author(s)
      野中隆, 長谷川成人
    • Total Pages
      1076-1078
    • Publisher
      細胞工学
  • [Book] Braak 仮説をαシヌクレインの細胞間伝播で説明できるか?2013

    • Author(s)
      長谷川成人
    • Total Pages
      13-16
    • Publisher
      Frontiers in Parkinson's Disease
  • [Book] 細胞内異常タンパク質凝集体の細胞間伝播 : 神経変性疾患の病態進行に関する新たなメカニズム2013

    • Author(s)
      野中隆, 長谷川成人
    • Total Pages
      7-10
    • Publisher
      基礎老化研究
  • [Remarks]

    • URL

      http://www.igakuken.or.jp/dementia/Neuropathol/toppage.html

  • [Patent(Industrial Property Rights)] 新規タウオパチーモデルマウスの作製方法2013

    • Inventor(s)
      鈴掛雅美、長谷川成人
    • Industrial Property Rights Holder
      東京都医学総合研究所
    • Industrial Property Number
      2013-268257
    • Filing Date
      2013-12-26
    • Overseas
  • [Patent(Industrial Property Rights)] 新規タウオパチーモデルマウスの作製方法2013

    • Inventor(s)
      鈴掛雅美、長谷川成人
    • Industrial Property Rights Holder
      京都医学総合研究所
    • Industrial Property Number
      2013-268257
    • Filing Date
      2013-12-26
  • [Patent(Industrial Property Rights)] 神経変性疾患関連タンパク質の不溶性凝集体の増幅方法2011

    • Inventor(s)
      野中隆、増田雅美、山下万喜子、秋山治彦、長谷川成人
    • Industrial Property Rights Holder
      東京都医学総合研究所
    • Industrial Property Number
      2011-252522
    • Filing Date
      2011-11-18
    • Overseas
  • [Patent(Industrial Property Rights)] 神経変性疾患関連タンパク質の不溶性凝集体の増幅方法2011

    • Inventor(s)
      野中隆、増田雅美、山下万喜子、秋山治彦、長谷川成人
    • Industrial Property Rights Holder
      東京都医学総合研究所
    • Industrial Property Number
      2011-252522
    • Filing Date
      2011-11-18
  • [Patent(Industrial Property Rights)] タンパク質重合体の重合核となりうるタンパク質又はその重合体が導入された細胞及びその製造法2011

    • Inventor(s)
      野中隆、渡辺小百合、増田雅美、長谷川成人
    • Industrial Property Rights Holder
      東京都医学総合研究所
    • Industrial Property Number
      EP 出願番号:06834541.2
    • Acquisition Date
      2011-10-05
    • Overseas

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Published: 2015-06-25  

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