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Establishment of novel disease-modifying therapy for synucleinopathy targeting internalization of protein aggregates

Publicly Offered Research

Project AreaPrevention of brain protein aging and dementia
Project/Area Number 17H05683
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTohoku University

Principal Investigator

長谷川 隆文  東北大学, 医学系研究科, 准教授 (70361079)

Project Period (FY) 2017-04-01 – 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 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywordsパーキンソン病 / αシヌクレイン / プリオン仮説 / エンドサイトーシス / DAT / フロチリン / ハイスループット解析 / BLOTCHIP-質量分析法 / シヌクレイノパチー / 異常タンパク伝播 / 進行抑制治療 / PETイメージング / 小胞輸送 / エンドソーム / ドパミントランスポーター / flotillin-1 / 異常タンパク凝集 / 疾患修飾療法 / サロゲートマーカー
Outline of Annual Research Achievements

H30年度はパーキンソン病(PD)におけるαシヌクレイン(αSYN)プリオン様伝播現象に関連して、αSYN細胞内取り込み機序の解明に焦点をおき研究を進めた。まず、脳幹カテコラミン神経細胞に高発現し、PD患者脳で発現が亢進(正常対照の6.25倍)しているラフト関連分子フロチリン-1に着目し細胞生物学的な解析を進めた。その結果、細胞外モノマー・線維化αSYNが、ドパミン神経細胞表面に発現するドパミントランスポータ-(DAT)とフロチリン-1の会合を強化し、細胞表層でのDATのpre-endocytic clustering・endocytic uptakeをを誘導することで、DATトランスポーター活性を低下させることを発見した。さらに、DATのエンドサイトーシスに便乗して細胞外αSYNが細胞内へ侵入し、Rab7陽性後期エンドソームに蓄積すること、またPD患者脳内のレビー小体にDAT、フロチリン-1、Rab7が局在することを確認した(論文投稿中)。
上記課題と併行して、神経・グリア細胞表面に発現するαSYN受容体の網羅的探索も実施した。マウス全脳を出発材料として、膜蛋白質ライブラリー(membrane Protein Library, MPL)を作製し、高速ペプチドーム解析法であるBLOTCHIP-質量分析法(Protosera, Inc)を用いたハイスループット網羅的解析を行った。一次スクリーニングでヒットした106分子から、形質膜に発現しかつ細胞外domainを有し、線維化αSYN受容体となり得る候補分子5つを同定した(特許出願準備中)。これらは過去にαSYN受容体として報告された分子(LAG-3、TLR2/4、Na+/K+-ATPase)とは異なる新規の分子であった。現在、培養細胞を用い線維化αSYNと受容体分子の特異結合ならびにαSYN細胞内取り込みへの影響を確認中である。

Research Progress Status

平成30年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

平成30年度が最終年度であるため、記入しない。

Report

(2 results)
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (27 results)

All 2019 2018 2017 Other

All Int'l Joint Research (2 results) Journal Article (10 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 7 results,  Open Access: 5 results) Presentation (12 results) (of which Int'l Joint Research: 8 results,  Invited: 2 results) Remarks (2 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Int'l Joint Research] University of British Columbia(Canada)

    • Related Report
      2017 Annual Research Report
  • [Int'l Joint Research] Lund University(Sweden)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis.2019

    • Author(s)
      Carballo-Carbajal I, Laguna A, Romero-Gimenez J, Cuadros T, Bove J, Martinez-Vicente M, Parent A, Gonzalez-Sepulveda M, Penuelas N, Torra A, Rodrguez-Galvan B, Ballabio A, Hasegawa T, Bortolozzi A, Gelpi E and Vila M.
    • Journal Title

      Nat Commun

      Volume: 10 Issue: 1 Pages: 973-973

    • DOI

      10.1038/s41467-019-08858-y

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Longitudinal changes in 18F-THK5351 PET in corticobasal syndrome2019

    • Author(s)
      Ezura M, Kikuchi A, Ishiki A, Okamura N, Hasegawa T, Harada R, Watanuki S, Funaki Y, Hiraoka K, Baba T, Sugeno N, Oshima R, Yoshida S, Kobayashi J, Kobayashi M, Tano O, Nakashima I, Mugikura S, Iwata R, Taki Y, Furukawa K, Arai H, Furumoto S, Tashiro M, Yanai K, Kudo Y, Takeda A, Aoki M
    • Journal Title

      Eur J Neurol

      Volume: in press

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] PEG-J tube breakage in a patient with Parkinson's disease receiving levodopa-carbidopa intestinal gel therapy.2018

    • Author(s)
      Soga T, Sugeno N, Baba T, Jin X, Koike T, Hasegawa T, Aoki M.
    • Journal Title

      Neurol Clin Neurosci

      Volume: 6 Issue: 6 Pages: 197-198

    • DOI

      10.1111/ncn3.12220

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] αシヌクレイン細胞間伝播を標的としたシヌクレイノパチー疾患修飾療法の開発2018

    • Author(s)
      長谷川隆文
    • Journal Title

      Brain and Nerve

      Volume: 70 Pages: 551-556

    • NAID

      40021572953

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Zeroing in on membrane trafficking in pathogenesis of PD2018

    • Author(s)
      長谷川隆文
    • Journal Title

      Bio Clinica

      Volume: 7 Pages: 115-117

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Cutting Edge-メンブレントラフィックに着目したパーキンソン病の病態解明2018

    • Author(s)
      長谷川隆文
    • Journal Title

      Medical Science Digest

      Volume: 44 Pages: 5-7

    • Related Report
      2018 Annual Research Report
  • [Journal Article] DnaJ/Hsp40 family and Parkinson’s disease.2018

    • Author(s)
      Hasegawa T, Yoshida S, Sugeno N, Kobayashi J, Aoki M.
    • Journal Title

      Front Neurosci

      Volume: 11 Pages: 743-743

    • DOI

      10.3389/fnins.2017.00743

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Parkinson’s disease-linked DNAJC13 mutation aggravates α-synuclein-induced neurotoxicity through perturbation of endosomal trafficking.2018

    • Author(s)
      Yoshida S, Hasegawa T, Suzuki M, Sugeno N, Kobayashi J, Ueyama M, Fukuda M, Ido-Fujibayashi A, Sekiguchi K, Ezura M, Kikuchi A, Baba T, Takeda A, Mochizuki H, Nagai Y and Aoki M.
    • Journal Title

      Hum Mol Genet.

      Volume: 27 Issue: 5 Pages: 823-836

    • DOI

      10.1093/hmg/ddy003

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Membrane Trafficking Illuminates a Path to Parkinson’s Disease2017

    • Author(s)
      Hasegawa T, Sugeno N, Kikuchi A, Baba T, Aoki M.
    • Journal Title

      The Tohoku Journal of Experimental Medicine

      Volume: 242 Issue: 1 Pages: 63-76

    • DOI

      10.1620/tjem.242.63

    • NAID

      130005679072

    • ISSN
      0040-8727, 1349-3329
    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Aβ accumulation causes MVB enlargement and is modelled by dominant negative VPS4A.2017

    • Author(s)
      Willen K, Edgar JR, Hasegawa T, Tanaka N, Futter CE, Gouras GK.
    • Journal Title

      Mol Neurodeg

      Volume: 12 Issue: 1 Pages: 61-61

    • DOI

      10.1186/s13024-017-0203-y

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Extracellular α-synuclein internalizes into cells by modulating flotillin-1-assisted endocytosis of DAT.2018

    • Author(s)
      Hasegawa T, Kobayashi J, Sugeno N, Yoshida S, Ezura M, Kikuchi A, Takeda A, Aoki M
    • Organizer
      Neuroscience 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Extracellular α-synuclein enters dopaminergic neurons by modulating flotillin-1-assisted dopamine transporter endocytosis.2018

    • Author(s)
      Hasegawa T, Kobayashi J, Sugeno N, Yoshida S, Ezura M, Kikuchi A, Takeda A, Aoki M.
    • Organizer
      Japan-UK Neuroscience Symposium 2019
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Extracellular α-synuclein internalizes into dopaminergic neurons by hijacking flotillin-1-assisted dopamine transporter endocytosis2018

    • Author(s)
      Hasegawa T, Kobayashi J, Sugeno N, Yoshida S, Ezura M, Kikuchi A, Takeda A, Aoki M.
    • Organizer
      AD/PD 2019
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Prion-like phenomenon:from myth to reality:Endosomal pathway: a molecular basis for prion-like phenomenon in synucleinopathy.2018

    • Author(s)
      長谷川隆文
    • Organizer
      第59回日本神経学会学術大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] ランチョンセミナー:パーキンソン病の最新知見-蛋白伝播メカニズムから考えるレビー小体病の多様性2018

    • Author(s)
      長谷川隆文
    • Organizer
      第41回日本神経科学大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 神経化学からみた神経疾患 -ベンチとベットサイドの間:パーキンソン病の共通病態としてのエンドソーム輸送障害2018

    • Author(s)
      長谷川隆文
    • Organizer
      第61回日本神経化学会大会・第40回日本生物学的精神医学会 合同大会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 難病病態解明と新治療法:異常タンパク伝播-分子病態から考えるパーキンソン病の新規治療戦略2018

    • Author(s)
      長谷川隆文
    • Organizer
      第6回日本難病医療ネットワーク学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Mutant DNAJC13 modulates accumulation and toxicity of α-synuclein through altered endosomal trafficking in cell and fly models of Parkinson’s disease.2017

    • Author(s)
      Hasegawa T, Yoshida S, Suzuki M, Sugeno N, Kobayashi J, Ezura M, Kikuchi A, Baba T, Takeda A, Mochizuki H, Nagai Y, Aoki M.
    • Organizer
      The 21th International Congress of Parkinson's Disease and Movement Disorders, 2017, Vancouver, Canada
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Membrane Trafficking Illuminates a Path to Parkinson’s Disease2017

    • Author(s)
      Hasegawa T.
    • Organizer
      JNS2017Satellite Symposium-Protein Misfolding Disease, Sendai, Japan
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Parkinson's disease-linked DNAJC13 mutation aggravates α-synuclein-induced neurotoxicity through alteration of endosomal trafficking.2017

    • Author(s)
      Hasegawa T, Yoshida S, Suzuki M, Sugeno N, Kobayashi J, Ezura M, Kikuchi A, Baba T, Takeda A, Mochizuki H, Nagai Y, Aoki M.
    • Organizer
      XXIII World Congress of Neurology, Kyoto, Japan
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Parkinson’s disease-linked DNAJC13 mutation aggravates α-synuclein-induced neurotoxicity through alteration of endosomal trafficking.2017

    • Author(s)
      Hasegawa T, Yoshida S, Suzuki M, Sugeno N, Kobayashi J, Ezura M, Kikuchi A, Baba T, Takeda A, Mochizuki H, Nagai Y, Aoki M.
    • Organizer
      Neuroscience 2017, Washington DC, USA
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Deciphering the molecular mechanism behind the prion-like spread of α-synuclein.2017

    • Author(s)
      Hasegawa T.
    • Organizer
      The 11th International Conference on Complex Medical Engineering, Shenzhen, China
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Remarks] 脳内の交通渋滞がパーキンソン病を誘発する ~悪玉タンパク蓄積・神経細胞死に至るメカニズムが明らかに

    • URL

      https://www.tohoku.ac.jp/japanese/2018/01/press20180117-01.html

    • Related Report
      2017 Annual Research Report
  • [Remarks] 脳内の交通渋滞がパーキンソン病を誘発する

    • URL

      http://resou.osaka-u.ac.jp/ja/research/2018/20180117_1

    • Related Report
      2017 Annual Research Report
  • [Patent(Industrial Property Rights)] 特許願2019

    • Inventor(s)
      東北大学、プロトセラ(株)
    • Industrial Property Rights Holder
      東北大学、プロトセラ(株)
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2018 Annual Research Report
    • Overseas

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Published: 2017-04-28   Modified: 2019-12-27  

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