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Role of cross-seeding in the pathogenesis of neurodegenerative disorders

Research Project

Project/Area Number 17K15077
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeMulti-year Fund
Research Field Structural biochemistry
Research InstitutionTokushima Bunri University (2018)
Keio University (2017)

Principal Investigator

Eiichi Tokuda  徳島文理大学, 薬学部, 講師 (00757510)

Project Period (FY) 2017-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2017: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Keywordsクロスシーディング / タンパク質凝集体 / ミスフォールドタンパク質 / 神経変性疾患 / 筋萎縮性側索硬化症 / マウスモデル / プリオン様特性
Outline of Final Research Achievements

Mutations in the gene encoding superoxide dismutase-1 (SOD1) is causative for amyotrophic lateral sclerosis (ALS). Accumulation of conformational disordered SOD1 protein (i.e. misfolded SOD1) in motor neurons is a hallmark of ALS with SOD1 mutations. Several lines of evidence suggest that misfolded proteins observed in neurodegenerative diseases have prion-like properties: namely, misfolded proteins act as conformational templates that convert normal proteins into a pathogenic form.
To clarify whether the prion paradigm could be applicable for the misfolding of SOD1 in vivo, I investigated double transgenic mice expressing both mutant and wild-type SOD1. I found that misfolding of wild-type SOD1 was induced by the expression of mutant SOD1 even at an early stage of the disease and exaggerated ALS-like motor neuron symptoms.

Academic Significance and Societal Importance of the Research Achievements

SOD1変異を伴うALS患者は、約98%が優性遺伝であるため、変異型と野生型SOD1が共発現している。本課題では、マウスに変異型と野生型SOD1を共発現させると、変異型SOD1が野生型SOD1のミスフォールディングを誘発し、マウスの運動マヒ発症を早めることを明らかにした。本成果は動物実験ではあるが、SOD1変異を伴うALS患者の遺伝形式を再現している。野生型SOD1のミスフォールディングはALS発症に関与していることから、将来、野生型SOD1のミスフォード状態を測定することで、ALSの発症時期が予測できるようになるかもしれない。

Report

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

    (19 results)

All 2019 2018 2017

All Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 3 results) Presentation (14 results) (of which Int'l Joint Research: 5 results,  Invited: 5 results)

  • [Journal Article] Cu/Zn-superoxide dismutase forms fibrillar hydrogels in a pH-dependent manner via a water-rich extended intermediate state2018

    • Author(s)
      Fujiwara Noriko、Wagatsuma Michiru、Oba Naoto、Yoshihara Daisaku、Tokuda Eiichi、Sakiyama Haruhiko、Eguchi Hironobu、Ichihashi Motoko、Furukawa Yoshiaki、Inoue Tadashi、Suzuki Keiichiro
    • Journal Title

      PLOS ONE

      Volume: 13 Issue: 10 Pages: e0205090-e0205090

    • DOI

      10.1371/journal.pone.0205090

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A copper-deficient form of mutant cu/Zn-superoxide dismutase as an early pathological species in amyotrophic lateral sclerosis2018

    • Author(s)
      Tokuda Eiichi、Nomura Takao、Ohara Shinji、Watanabe Seiji、Yamanaka Koji、Morisaki Yuta、Misawa Hidemi、Furukawa Yoshiaki
    • Journal Title

      Biochimica et Biophysica Acta - Molecular Basis of Disease

      Volume: 印刷中 Issue: 6 Pages: 2119-2130

    • DOI

      10.1016/j.bbadis.2018.03.015

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] An essential role of N-terminal domain of copper chaperone in the enzymatic activation of Cu/Zn-superoxide dismutase2017

    • Author(s)
      Fukuoka Mami、Tokuda Eiichi、Nakagome Kenta、Wu Zhiliang、Nagano Isao、Furukawa Yoshiaki
    • Journal Title

      Journal of Inorganic Biochemistry

      Volume: 175 Pages: 208-216

    • DOI

      10.1016/j.jinorgbio.2017.07.036

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Abnormal protein oligomers for neurodegeneration2017

    • Author(s)
      Tokuda Eiichi、Furukawa Yoshiaki
    • Journal Title

      Oncotarget

      Volume: 8 Issue: 25 Pages: 39943-39944

    • DOI

      10.18632/oncotarget.18030

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [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
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Neuroprotection of metallothionein in ALS-SOD1 is mediated via an endocytic receptor Megalin2019

    • Author(s)
      Tokuda Eiichi
    • Organizer
      1st International Mini Symposium on Metal in ALS
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Wild-type SOD1 is misfolded in cerebrospinal fluid of sporadic ALS2018

    • Author(s)
      Furukawa Yoshiaki, Tokuda Eiichi, Ohara Shinji, Fujiwara Noriko
    • Organizer
      29th International Symposium on ALS/MND
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 筋萎縮性側索硬化症 (Amyotrophic Lateral Sclerosis; ALS) と Cu、Zn、そして misfolding2018

    • Author(s)
      小野真一、徳田栄一
    • Organizer
      メタルバイオサイエンス研究会2018
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] A misfolding mechanism of Cu/Zn-superoxide dismutase under oxidative conditions of amyotrophic lateral sclerosis2018

    • Author(s)
      Anzai Itsuki, Tokuda Eiichi, Mukaiyama Atsushi, Akiyama Shuji, Furukawa Yoshiaki
    • Organizer
      9th Asian Biological Inorganic Chemistry Conference
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Conformational dependent toxicity of Cu/Zn-superoxide dismutase in Caenortabditis elegans2018

    • Author(s)
      Toba Ayano, Tokuda Eiichi, Furukawa Yoshiaki
    • Organizer
      9th Asian Biological Inorganic Chemistry Conference
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 筋萎縮性側索硬化症に見られるSOD1タンパク質の凝集を抑制するメカニズム2018

    • Author(s)
      松本響佳, 中村滉平, 徳田栄一, 古川良明
    • Organizer
      第18回日本蛋白質科学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] システイン残基の酸化が促進するSOD1タンパク質のミスフォールディング2018

    • Author(s)
      安齋樹, 徳田栄一, 古川良明
    • Organizer
      第18回日本蛋白質科学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] SOD1タンパク質への銅イオン供給に金属シャペロンCCSが果たす役割2018

    • Author(s)
      羽飼友昭, 福岡真実, 徳田栄一, 古川良明
    • Organizer
      第18回日本蛋白質科学会年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 運動ニューロン疾患ALSにおけるミスフォールドタンパク質のプリオン様特性:現状と今後の展望2018

    • Author(s)
      徳田栄一, Marklund Stefan, 古川良明
    • Organizer
      日本薬学会138年会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 運動ニューロン疾患ALSにおけるミスフォールドタンパク質のプリオン様特性:現状と今後の展望2018

    • Author(s)
      徳田栄一、Stefan Marklund、 古川良明
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Development of peptides that specifically recognize misfolded SOD1 proteins in amyotrophic lateral sclerosis2017

    • Author(s)
      Eiichi Tokuda、Kenichi Nagasawa、Takao Nomura、Hidemi Misawa、Shinji Ohara、Koji Yamanaka、Yoshiaki Furukawa
    • Organizer
      第40回日本神経科学大会
    • Related Report
      2017 Research-status Report
  • [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、三澤日出巳、山中宏二、 大原慎司、古川良明
    • Organizer
      慶應ライフサイエンスシンポジウム
    • Related Report
      2017 Research-status Report
  • [Presentation] 神経変性疾患ALSの病初期に現れる銅イオン欠乏型SOD12017

    • Author(s)
      徳田栄一、大原慎司、山中宏二、三澤日出巳、 古川良明
    • Organizer
      メタルバイオサイエンス研究会2017
    • Related Report
      2017 Research-status Report
    • Invited
  • [Presentation] Development of peptides that specifically recognize misfolded SOD1 proteins in amyotrophic lateral sclerosis2017

    • Author(s)
      Eiichi Tokuda、Kenichi Nagasawa、Takao Nomura、Hidemi Misawa、Shinji Ohara、Koji Yamanaka、Yoshiaki Furukawa
    • Organizer
      28th International Symposium on ALS/MND
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research

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Published: 2017-04-28   Modified: 2020-03-30  

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