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Molecular mechanism underlying propagation of pathogenic protein aggregates in neurodegenerative disorders

Research Project

Project/Area Number 15H06588
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeSingle-year Grants
Research Field Functional biochemistry
Research InstitutionKeio University

Principal Investigator

Eiichi Tokuda  慶應義塾大学, 理工学部(矢上), 助教 (00757510)

Project Period (FY) 2015-08-28 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords筋萎縮性側索硬化症 / タンパク質凝集体 / シーディング / 線虫 / スーパーオキサイド ディスムターゼ / 神経変性疾患 / タンパク質線維
Outline of Final Research Achievements

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease. The disease begins focally and spreads contiguously, resulting in progressive paralysis. The pathological hallmark of ALS is the accumulation of insoluble protein aggregates containing Cu/Zn-superoxide dismutase (SOD1) in motor neurons. The aim of this project was to clarify a molecular mechanism underlying the spread of lesion sites in the disease from the viewpoint of seeding activity of insoluble SOD1 aggregates. I first established two different methods: oral intake of E.coli forming the aggregates by thermoregulation, and exposure of the purified aggregates. Although transgenic C.elegans harboring human SOD1 were fed with the aggregates, feeding with either E.coli forming the aggregates or the purified aggregates did not induce the aggregation of human SOD1 in C.elegans. Furthermore, these aggregates did not affect overall lifespan and motor function of C.elegans.

Report

(3 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Annual Research Report
  • Research Products

    (12 results)

All 2017 2016 Other

All Journal Article (5 results) (of which Int'l Joint Research: 5 results,  Peer Reviewed: 5 results,  Open Access: 4 results,  Acknowledgement Compliant: 2 results) Presentation (3 results) (of which Int'l Joint Research: 1 results) Book (2 results) Remarks (2 results)

  • [Journal Article] Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA312017

    • Author(s)
      Taro Ishiguro, Nozomu Sato, Morio Ueyama, Nobuhiro Fujikake, Chantal Sellier, Akemi Kanegami, Eiichi Tokuda, Bita Zamiri, Terence Gall-Duncan, Mila Mirceta, Yoshiaki Furukawa, 他8名
    • Journal Title

      Neuron

      Volume: 94 Issue: 1 Pages: 108-124

    • DOI

      10.1016/j.neuron.2017.02.046

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Immunochemical characterization on pathological oligomers of mutant Cu/Zn-superoxide dismutase in amyotrophic lateral sclerosis2017

    • Author(s)
      Tokuda E, Anzai I, Nomura T, Toichi K, Watanabe M, Ohara S, Watanabe S, Yamanaka K, Morisaki Y, Misawa H, and Furukawa Y.
    • Journal Title

      Molecular Neurodegeneration

      Volume: 12 Pages: 2-2

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A misfolded dimer of Cu/Zn-superoxide dismutase leading to pathological oligomerization in amyotrophic lateral sclerosis2017

    • Author(s)
      Itsuki Anzai, Eiichi Tokuda, Atsushi Mukaiyama, Shuji Akiyama, Fumito Endo, Koji Yamanaka, Hidemi Misawa, and Yoshiaki Furukawa
    • Journal Title

      Protein Science

      Volume: 26 Issue: 3 Pages: 484-496

    • DOI

      10.1002/pro.3094

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Screening of Drugs Inhibiting In vitro Oligomerization of Cu/Zn-Superoxide Dismutase with a Mutation Causing Amyotrophic Lateral Sclerosis2016

    • Author(s)
      Itsuki Anzai, Keisuke Toichi, Eiichi Tokuda, Atsushi Mukaiyama, Shuji Akiyama, and Yoshiaki Furukawa
    • Journal Title

      Frontiers in Molecular Biosciences

      Volume: 3 Pages: 40-40

    • DOI

      10.3389/fmolb.2016.00040

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Low autophagy capacity implicated in motor system vulnerability to mutant superoxide dismutase2016

    • Author(s)
      Eiichi Tokuda, Thomas Brannstrom, Peter M. Andersen, and Stefan L. Marklund
    • Journal Title

      Acta Neuropathologica Communications

      Volume: 4 Issue: 1 Pages: 6-6

    • DOI

      10.1186/s40478-016-0274-y

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 筋萎縮性側索硬化症における変異SOD1オリゴマーの免疫化学的な検出2017

    • Author(s)
      徳田栄一、森崎祐太、三澤日出巳、渡邊征爾、山中宏二、大原慎司、古川良明
    • Organizer
      日本薬学会第137年会
    • Place of Presentation
      仙台国際センター(宮城県・仙台市)
    • Year and Date
      2017-03-25
    • Related Report
      2016 Annual Research Report
  • [Presentation] In vivo and in vitro characterization of SOD1 in early stages of ALS as a precursor to insoluble aggregates2016

    • Author(s)
      Eiichi Tokuda, Itsuki Anzai, Takao Nomura, Shinji Ohara, Seiji Watanabe, Koji Yamanaka, Yuta Morisaki, Hidemi Misawa, and Yoshiaki Furukawa
    • Organizer
      27th International Symposium on ALS/MND
    • Place of Presentation
      Dublin (Ireland)
    • Year and Date
      2016-12-07
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 銅・亜鉛スーパーオキサイドディスムターゼの金属イオン結合状態を識別できる新規抗体の開発と筋萎縮性側索硬化症の病理解明への応用2016

    • Author(s)
      徳田栄一、森崎祐太、三澤日出巳、渡邊征爾、山中宏二、古川良明
    • Organizer
      日本薬学会第136年会
    • Place of Presentation
      パシフィコ横浜(神奈川県・横浜)
    • Year and Date
      2016-03-26
    • Related Report
      2015 Annual Research Report
  • [Book] Aggregation of FET proteins as a pathological change in amyotrophic lateral sclerosis.2017

    • Author(s)
      Furukawa Y and Tokuda E.
    • Total Pages
      161
    • Publisher
      Springer US
    • Related Report
      2016 Annual Research Report
  • [Book] Protein Reviews2016

    • Author(s)
      Yoshiaki Furukawa and Eiichi Tokuda
    • Publisher
      Springer Link
    • Related Report
      2015 Annual Research Report
  • [Remarks] 研究室ホームページ

    • URL

      http://www.chem.keio.ac.jp/~furukawa/

    • Related Report
      2016 Annual Research Report
  • [Remarks] 慶應義塾大学 理工学部 化学科 生命機構化学研究室 (古川研究室)

    • URL

      http://www.chem.keio.ac.jp/~furukawa/History2014.html

    • Related Report
      2015 Annual Research Report

URL: 

Published: 2015-08-26   Modified: 2018-03-22  

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