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Oxidative stress mechanisms related to ribotoxic stress and endoplasmic reticulum stress

Research Project

Project/Area Number 13470196
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Psychiatric science
Research InstitutionOsaka University

Principal Investigator

TAKEDA Masatoshi  Osaka University Graduate School of Medicine, Professor, 医学系研究科, 教授 (00179649)

Co-Investigator(Kenkyū-buntansha) KUDO Takashi  Osaka University Graduate School of Medicine, Associate Professor, 医学系研究科, 助教授 (10273632)
TANAKA Toshihisa  Osaka University Graduate School of Medicine, Lecturer, 医学系研究科, 講師 (10294068)
中村 祐  奈良県立医科大学, 医学部, 講師 (70291440)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥16,000,000 (Direct Cost: ¥16,000,000)
Fiscal Year 2002: ¥4,200,000 (Direct Cost: ¥4,200,000)
Fiscal Year 2001: ¥11,800,000 (Direct Cost: ¥11,800,000)
KeywordsAlzheimer disease / tau protein / phosphorylation / presenilin / oxidative stress / spoptosis / ribotoxic stress / endoplasmic reticulum stress
Research Abstract

Neurofibliraly tangles (NFTs) and neuronal cell death are hallmark of Alzheimer's disease (AD) and abnormal hyperphospholylated tau protein is the major subunit of NFT. However the mechanisms of phosphorylation of tau in neurodegenerative process of AD is unknown. We investigated the changes of phosphorylation of tau protein and neuronal cell death in SY5Y human neuroblastoma cells treated with peptidyltransferase inhibitors including anisomycin and T2-triol. Western blot analysis revealed that anisomycin and T2-triol induced activation of SAPK and p38 MAPK and hyperphosphorylation of tau protein at the M4 (Thr-231/Ser-235), the PHF-1 (Ser-396/404) and the S422 (Ser-422) site. The inhibitor of p38, SB203580, attenuated the phosphorylation of tau protein in this response, whereas an inhibition of GSK-3, lithium, did not. In this response the number of apoptotic cells visualized by Hoechst33342 was less than *he number of total dead cells visualized by Live/Dead kit (Molecular Probe), suggesting the non-apoptotoc cell death mechanism might be involved. This peptidyltransferase-inhibition is one kind of ribotoxic stresses. Further the cells were treated with rose bengal and light, and singlet oxygen was induced. Under this condition, ribosomal RNA was oxidized and tau protein was phosphorylated, probably through ribotoxic stress. In AD brain hyperphosphorylation of tau protein and neuronal cell death might be explained by this ribotoxic stress mechanism.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Okochi M, et al.: "Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1"EMBO J. 21・20. 5408-5416 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kudo T, et al.: "The unfolded protein response is involved in the pathology of Alzheimer's disease"Ann N Y Acad Sci. 977・11. 349-355 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kamino K, et al.: "Apolipoproteins and β amyloid transport pathway"Psychogeriatrics. 2. 149-155 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 田中稔久 他: "タウ蛋白重合蓄積への結合因子の関与とその阻害剤開発についての研究"精神薬療研究年報. 34. 21-27 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 田中稔久 他: "タウ蛋白の異常と痴呆症-神経変性メカニズムの理解"脳と神経. 54. 777-787 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 田中稔久 他: "アルツハイマー病の診断の新機軸"臨床と研究. 79. 930-933 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Takeda, M., Tanaka, T., Arai, H., Sasaki, H., Shoji, M., Okamoto, K., Urakami, K., Nakashima, K., Matshubayashi, T., Sugita, M., Yoshida, H.: "Basic and clinical studies on the measurement of β-amyloid(1-42) in cerebrospinal fluid as a diagnostic marker for Alzheimer's disease and related disorders: Multi study in Japan."Psychogeriatrics. 1. 56-63 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Pei JJ, Khatoon S, An WL, Nordlinder M, Tanaka T, Braak H, Tsujio I, Takeda M, Alafuzoff I, Winblad B, Cowburn RF, Grundke-Iqbal I, Iqbal K.: "Role of protein kinase B in Alzheimer's neurofibrillary pathology."Acta Neuropathol (Berl). 105. 381-92 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Okochi M, et al.: "Presenilins mediate a dual intramembranous gamma-secretase cleavage of Notch-1"EMBO J. 21・20. 5408-5416 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kudo T, et al.: "The unfolded protein response is involved in the pathology of Alzheimer's disease"Ann N Y Acad Sci. 977・11. 349-355 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kamino K, et al.: "Apolipoproteins and β amyloid transport pathway"Psychogeriatrics. 2. 149-155 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 田中稔久 他: "タウ蛋白重合蓄積への結合因子の関与とその阻害剤開発についての研究"精神薬療研究年報. 34. 21-27 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 田中稔久 他: "タウ蛋白の異常と痴呆症-神経変性メカニズムの理解"脳と神経. 54. 777-787 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 田中稔久 他: "アルツハイマー病の診断の新機軸"臨床と研究. 79. 930-933 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 田中稔久, ほか: "一次変性痴呆治療のためのタウ蛋白重合阻害についての研究"精神薬療研究年報. 33. 2-10 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Takeda, M., Tanaka, T., et al.: "Basic and clinical studies on the measurement of β-amyloid(1-42) in cerebrospinal fluid as a diagnoctic marker for Alzheimer's disease and related disorders : Multi study in Japan"Psychogeriatrics. 1. 56-63 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 田中稔久, 武田雅俊: "タウオパチー"臨床精神医学. 30. 80-82 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] 田中稔久, 武田雅俊: "「タウ蛋白の異常リン酸化機構」 先端医療シリーズ 14 神経・筋疾患"先端医療技術研究所. 190-194/420 (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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