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The development of new diagnostic and therapeutic tools for AD based on regulation of the gamma-secretase complex assembly.

Research Project

Project/Area Number 23590110
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Biological pharmacy
Research InstitutionIwate Medical University

Principal Investigator

MAEDA Tomoji  岩手医科大学, 薬学部, 准教授 (60303294)

Co-Investigator(Renkei-kenkyūsha) KOMANO Chiaki  岩手医科大学, 薬学部, 教授 (40170378)
TANABE Chiaki  岩手医科大学, 薬学部, 助教 (00552902)
Project Period (FY) 2011 – 2013
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsプレセニリン複合体 / ニカストリン / シノビオリン / Rer1 / アルツハイマー / アミロイドベータ / 小胞体 / 小胞体関連分解 / OS-9 / アルツハイマー病 / amyloid beta / ユビキチン化
Research Abstract

Alzheimer disease is characterized by the deposition of amyloid beta, which is generated from the amyloid precursor protein (APP) through its cleavage by beta- and gamma-secretases. The gamma-secretases complex component nicastrin (NCT) plays significant roles in the assembly and proper trafficking of the gamma-secretases complex and in the recognition of APP. Unassembled NCT is retrieved or retained in the ER by the protein Retention in endoplasmic reticulum 1 (Rer1). We hypothesized, therefore, that Synoviolin (Syvn), an E3 ubiquitin ligase, regulates the assembly or localization of the gamma-secretases complex by ubiquitinating Rer1 resulting in its subsequent degradation. Our findings that the level of Rer1 was increased in Syvn-knockout fibroblasts due to inhibition of its degradation support this hypothesis. Thus, it is likely that Syvn regulates the assembly of the gamma-secretases complex via the degradation of Rer1, which results in the generation of amyloid beta.

Report

(4 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Research-status Report
  • 2011 Research-status Report
  • Research Products

    (9 results)

All 2013 2012 2011 Other

All Journal Article (2 results) (of which Peer Reviewed: 2 results) Presentation (6 results) Remarks (1 results)

  • [Journal Article] The ubiquitin ligase synoviolin up-regulates amyloid β production by targeting a negative regulator of γ-secretase, Rer1, for degradation.2012

    • Author(s)
      Tanabe C, Maeda T, Zou K, Liu J, Liu S, Nakajima T, Komano H.
    • Journal Title

      J Biol Chem.

      Volume: 287 Issue: 53 Pages: 44203-44211

    • DOI

      10.1074/jbc.m112.365296

    • Related Report
      2013 Final Research Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] ER-stress-inducible Herp, facilitates the degradation of immature nicastrin.2011

    • Author(s)
      Toshihiro Marutani, Tomoji Maeda, Chiaki Tanabe, Kun Zou, Wataru Araki, Koichi Kokame, Makoto Michikawa, and Hiroto Komano.
    • Journal Title

      Biochim. Biophys. Acta-General Subjects

      Volume: 1810 Issue: 8 Pages: 790-798

    • DOI

      10.1016/j.bbagen.2011.04.017

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Presentation] The stability of endoplasmic stress-inducible Herp is regulated by synoviolin-mediated and ubiquitin-independent proteasomal degradation2013

    • Author(s)
      前田智司、田邉千晶、鄒鶤、鈴木ひとみ、稲垣学人、劉俊俊、劉しゅ余、駒野宏人
    • Organizer
      第86回日本生化学会大会
    • Place of Presentation
      横浜
    • Related Report
      2013 Annual Research Report 2013 Final Research Report
  • [Presentation] 小胞体ストレス誘導タンパク質Herpの分解機構の解析2012

    • Author(s)
      鈴木ひとみ、稲垣学人、田邉千晶、鄒鶤、Junjun Liu、Shuyu Liu、小亀浩一、前田智司、駒野宏人
    • Organizer
      日本生化学会東北支部第78回例会・シンポジウム
    • Place of Presentation
      山形
    • Related Report
      2013 Final Research Report
  • [Presentation] 小胞体ストレス誘導タンパク質Herp の分解機構の解析2012

    • Author(s)
      鈴木ひとみ, 稲垣学人, 田邉千晶, 鄒鶤, 劉俊俊, 劉姝余, 小亀浩市, 前田智司, 駒野宏人
    • Organizer
      日本生化学会東北支部 第78回 例会・シンポジウム
    • Place of Presentation
      山形
    • Related Report
      2012 Research-status Report
  • [Presentation] Synoviolin facilitates the degradation of an ER-stress-inducible protein, Herp2011

    • Author(s)
      前田智司、田邉千晶、鄒鶤、劉俊俊、劉しゅ余、小亀浩市、駒野宏人
    • Organizer
      第84回日本生化学会大会
    • Place of Presentation
      京都
    • Related Report
      2013 Final Research Report
  • [Presentation] Synoviolin is involved in the degradation of Rer1, thereby modulating Amyloid beta2011

    • Author(s)
      田邉千晶、前田智司、鄒鶤、劉俊俊、劉しゅ余、駒野宏人
    • Organizer
      第84回日本生化学会大会
    • Place of Presentation
      京都
    • Related Report
      2013 Final Research Report
  • [Presentation] Synoviolin facilitates the degradation of an ER-stress-inducible protein, Herp.2011

    • Author(s)
      前田智司、田邉千晶、鄒鶤、小亀浩市、駒野宏人
    • Organizer
      第84回日本生化学会大会
    • Place of Presentation
      京都
    • Related Report
      2011 Research-status Report
  • [Remarks] 田邉千晶、前 田智司、駒 野宏人 アルツハイ マー病にかかわるプロテアーゼ活性調節機 構の解明を目指して、臨床検査57号110、医学書院(2013)

    • Related Report
      2013 Final Research Report

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Published: 2011-08-05   Modified: 2019-07-29  

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