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Analysis of AGE modification of CRMP2 by carbonyl stress

Research Project

Project/Area Number 18K07616
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 52030:Psychiatry-related
Research InstitutionInstitute of Physical and Chemical Research

Principal Investigator

Toyoshima Manabu  国立研究開発法人理化学研究所, 脳神経科学研究センター, 研究員 (90582750)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords統合失調症 / CRMP2 / カルボニルストレス / 神経発達 / iPS細胞 / 神経発達障害 / AGE修飾
Outline of Final Research Achievements

Impairments in neurodevelopmental process are thought to play a pivotal role in the pathogenesis of schizophrenia. To date, carbonyl stress have been identified as pathophysiological factors for schizophrenia, but it is unclear by molecular mechanism underlying carbonyl stress affects neural differentiation and development. Here, we elucidated the molecular mechanism underlying the effects of carbonyl stress in GLO I KO iPS cells. The GLO I KO iPS cells exhibited significant cellular and developmental deficits, and hyper-AGE modification of CRMP2. Structural and biochemical analyses revealed that AGE modificated CRMP2 was stacked in the multimer conformation by irreversible cross-linking, resulting in loss of function to bundle microtubules. Thus the current study revealed that the enhanced carbonyl stress stemmed from the genetic aberrations results in neurodevelopmental deficits through the formation of irreversible dysfunctional multimer of AGE modificated CRMP2.

Academic Significance and Societal Importance of the Research Achievements

カルボニルストレスを伴う統合失調症において、AGE修飾を受けたCRMP2タンパク質が多量体化して細胞骨格の制御機能を失うことが疾患病態の基盤にある可能性を初めて示した。
これまでカルボニルストレスがどのように統合失調症の病態を引き起こすのか不明であったが、患者由来iPS細胞と原子レベルの構造解析によって新しい分子経路が明らかになった。カルボニルストレスを伴う統合失調症の詳細な分子病態が明らかになったことにより、統合失調症における分子標的治療・創薬、及び発症予防法開発を促進する基盤となる。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (7 results)

All 2020 2019 2018

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (6 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Enhanced carbonyl stress induces irreversible multimerization of CRMP2 in schizophrenia pathogenesis2019

    • Author(s)
      Toyoshima M, Jiang X, Ogawa T, Ohnishi T, Yoshihara S, Balan S, Yoshikawa T, Hirokawa N.
    • Journal Title

      Life Sci Alliance

      Volume: 2 Issue: 5 Pages: e201900478-e201900478

    • DOI

      10.26508/lsa.201900478

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] カルボニルストレスによる神経発達異常のタンパク質分子病態解析2020

    • Author(s)
      豊島学, 蒋緒光, 小川覚之,大西哲生, Shabeesh Balan, 吉原壯悟, 廣川信隆, 吉川武男
    • Organizer
      50回日本神経精神薬理学会年会・42回日本生物学的精神医学会年会・第4回日本精神薬学会総会・学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] カルボニルストレスによる神経発達異常の分子メカニズムの解明2019

    • Author(s)
      豊島学, 大西 哲生, 新井誠, 糸川昌成, 岡野栄之, 吉川武男
    • Organizer
      第41回日本生物学的精神医学会
    • Related Report
      2019 Research-status Report
  • [Presentation] iPS細胞を用いた神経発達障害の分子病態の解明2019

    • Author(s)
      豊島学, 大西 哲生, 吉川武男
    • Organizer
      第49回日本神経精神薬理学会
    • Related Report
      2019 Research-status Report
  • [Presentation] カルボニルストレス性統合失調症におけるタンパク質分子病態解析2019

    • Author(s)
      豊島学, 蒋緒光, 小川覚之, 大西 哲生, 吉原壯悟, Shabeesh Balan, 吉川武男, 廣川信隆
    • Organizer
      第42回日本分子生物学会
    • Related Report
      2019 Research-status Report
  • [Presentation] 神経分化・発達におけるカルボニルストレスの影響2018

    • Author(s)
      豊島学, 大西哲生, 新井誠, 糸川昌成, 岡野栄之, 吉川武男,
    • Organizer
      第40回日本生物学的精神医学会
    • Related Report
      2018 Research-status Report
  • [Presentation] Examination of the effects of carbonyl stress elicited by GLO1 gene knockout in human iPS cells2018

    • Author(s)
      Manabu Toyoshima, Wado Akamatsu, Tetsuo Ohnishi, Makoto Arai, Masanari Itokawa, Hideyuki Okano, Takeo Yoshikawa
    • Organizer
      CINP 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2022-01-27  

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