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The aggregation mechanism of TDP-43 protein

Research Project

Project/Area Number 16K21650
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Neurophysiology / General neuroscience
Cell biology
Research InstitutionTokyo Metropolitan Institute of Medical Science

Principal Investigator

SUZUKI Genjiro  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, 主席研究員 (60466034)

Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
KeywordsALS / TDP-43 / プリオン / 神経変性疾患 / 筋委縮性側索硬化症
Outline of Final Research Achievements

In neurodegenerative diseases, accumulation of abnormal proteins in cells in the brain is a widespread phenomenon and is considered to be the cause of neuronal degeneration. Abnormal aggregations of TDP-43 are observed in neurons of amyotrophic lateral sclerosis (ALS) patients and frontotemporal lobar degeneration (FTLD) patients, thus, these aggregations may be the cause of these diseases. In this study, abnormal aggregates were made from TDP-43 monomer synthesized in vitro, and the accumulation process of abnormal TDP-43 aggregates could be observed in detail in the human neurofibroblast SH-SY5Y cell line. We also found that accumulated TDP-43 is aberrantly phosphorylated in the same way as the patient's brain.

Academic Significance and Societal Importance of the Research Achievements

筋萎縮性側索硬化症(ALS)や前頭側頭葉変性症(FTLD)などの神経変性疾患ではTDP-43というタンパク質が神経細胞において異常に凝集していることが観察されており、これらの疾患の原因であると考えられる。本研究により試験管内で合成したTDP-43タンパク質の異常凝集によりヒト神経線維芽細胞において異常TDP-43凝集体の蓄積を誘導することができた点は、これらの疾患の細胞モデルの確立へとつながり、学術的かつ社会的に意義が高いものであると考えられる。今後、マウスなどの動物モデルに応用することにより、有効な動物モデルの確立や、治療薬の開発への応用も期待できる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (13 results)

All 2019 2018 2017 2016 Other

All Journal Article (7 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 5 results,  Acknowledgement Compliant: 3 results) Presentation (3 results) (of which Int'l Joint Research: 2 results,  Invited: 2 results) Remarks (3 results)

  • [Journal Article] The effect of truncation on prion-like properties of α-synuclein.2018

    • Author(s)
      Terada T, Suzuki G, Nonaka T, Kametani F, Tamaoka A, and Hasegawa M.
    • Journal Title

      J Biol Chem

      Volume: 293 Issue: 36 Pages: 13910-13920

    • DOI

      10.1074/jbc.ra118.001862

    • NAID

      120007133755

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Following the fate of endocytosed fibrils2017

    • Author(s)
      Hasegawa Masato、Suzuki Genjiro
    • Journal Title

      Journal of Biological Chemistry

      Volume: 292 Issue: 32 Pages: 13498-13499

    • DOI

      10.1074/jbc.h117.780296

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Progranulin regulates lysosomal function and biogenesis through acidification of lysosomes.2017

    • Author(s)
      Tanaka Y, Suzuki G, Matsuwaki T, Hosokawa M, Serrano G, Beach TG, Yamanouchi K, Hasegawa M, Nishihara M.
    • Journal Title

      Human Molecular Genetics

      Volume: 26 Pages: 969-988

    • DOI

      10.1093/hmg/ddx011

    • Related Report
      2017 Research-status Report 2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Phosphorylation of TAR DNA-binding Protein of 43 kDa (TDP-43) by Truncated Casein Kinase 1δ Triggers Mislocalization and Accumulation of TDP-43.2016

    • Author(s)
      Nonaka T, Suzuki G, Tanaka Y, Kametani F, Hirai S, Okado H, Miyashita T, Saitoe M, Akiyama H, Masai H, Hasegawa M.
    • Journal Title

      J Biol Chem

      Volume: 291 Issue: 17 Pages: 8896-907

    • DOI

      10.1074/jbc.m115.713552

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Gain-of-function profilin 1 mutations linked to familial amyotrophic lateral sclerosis cause seed-dependent intracellular TDP-43 aggregation.2016

    • Author(s)
      Tanaka Y, Nonaka T, Suzuki G, Kametani F, Hasegawa M.
    • Journal Title

      Human Molecular Genetics

      Volume: 25 Issue: 7 Pages: 1420-33

    • DOI

      10.1093/hmg/ddw024

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] The proceeding of drug development based on the propagation of tau protein2016

    • Author(s)
      Suzuki G, Hasegawa M.
    • Journal Title

      Nihon Rinsho

      Volume: 74 Pages: 432-7

    • NAID

      40020797303

    • Related Report
      2016 Research-status Report
  • [Journal Article] Effect of Fragmented Pathogenic α-Synuclein Seeds on Prion-like Propagation.2016

    • Author(s)
      Tarutani A, Suzuki G, Shimozawa A, Nonaka T, Akiyama H, Hisanaga S, and Hasegawa M.
    • Journal Title

      J. Biol. Chem., J. Biol. Chem.

      Volume: 291 Issue: 36 Pages: 18675-18688

    • DOI

      10.1074/jbc.m116.734707

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Different properties of α-synuclein conformational strains2019

    • Author(s)
      Genjiro Suzuki, Masato Hasegawa
    • Organizer
      The 14th International Conference on Alzheimer's and Parkinson's Diseases and related neurological disorders
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Different properties of α-synuclein conformational strains2018

    • Author(s)
      Genjiro Suzuki, Masato Hasegawa
    • Organizer
      日本神経科学大会
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] プリオンひろがる ―タンパク質構造変化による機能獲得―2016

    • Author(s)
      鈴木元治郎
    • Organizer
      明治薬科大学認知症創薬資源研究開発センター 公開セミナー
    • Place of Presentation
      明治薬科大学 (東京都清瀬市)
    • Year and Date
      2016-05-31
    • Related Report
      2016 Research-status Report
    • Invited
  • [Remarks] 東京都医学総合研究所認知症プロジェクト

    • URL

      http://www.igakuken.or.jp/dementia/

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
  • [Remarks] 東京都医学総合研究所 認知症プロジェクト

    • URL

      http://www.igakuken.or.jp/dementia/

    • Related Report
      2016 Research-status Report
  • [Remarks] 東京都医学総合研究所 トピックス リソソームにおけるプログラニュリンの機能的役割を解明

    • URL

      http://www.igakuken.or.jp/topics/2017/0110.html

    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2020-03-30  

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