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Rescue of Neuronal Cell Death by ER-stress protein over expression

Research Project

Project/Area Number 14580725
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Nerve anatomy/Neuropathology
Research InstitutionKanazawa University

Principal Investigator

KITAO Yasuko  Kanazawa University, Graduate School of Medical Science, Assistant Professor, 医学系研究科, 助手 (00019613)

Co-Investigator(Kenkyū-buntansha) OGAWA Satoshi  Kanazawa University, Graduate School of Medical Science, Professor, 医学系研究科, 教授 (90283746)
HORI Osamu  Kanazawa University, Graduate School of Medical Science, Associate Professor, 医学系研究科, 助教授 (60303947)
Project Period (FY) 2002 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsAstrocytes / Brain ischemia / ER-stress / Gene Therapy / Glutamic acid / Ischemic tolerance / 興奮性アミノ酸 / 神経細胞死
Research Abstract

ORP150 is a novel stress protein localized in the endoplasmic reticulum (ER). To investigate the role of ORP150 in delayed neuronal cell death, we have examined its expression in the gerbil brain after the ischemic insult. The expression of ORP150 antigen, as well as its transcripts, was observed in the CA1 region after the occlusion of the common carotid altety, and this was enhanced by the preconditioning. In cultured neurons, exposure to either hypoxia or glutamate induced the expression of ORP150, and this was also observed by treating the culture with either thapsigargin or breferdin-A, indicating that both glutamate and hypoxia can cause shess in the ER (ER stress). Neurons became more vulnerable to these stresses following treatment of either cyclcheximide or the infection with an adenovirus carrying ORP150 antisense structure. In cantrast, the overexpression of ORP150 by adenovinus suppressed the neuronal cell death, and this was accompanied by the suppression of the Ca2+ eleva … More tion and proteolytic activity induced by glutamate. Further, overexpressicn of ORP150 in CA1 neurons by the adenovirus carrying ORP150-sense struciture suppressed delayed neuronal cell death after ischemia. These data suggest a possible function of ORP150 as an intracellular apparatus, which participates in a protective response in ischemic tolerance.
A series of events initiated by glutamate-receptor interaction perturbs cellular homeostasis resulting in elevation of intracellular free calcium and cell death. Cells subject to such environmental change express stress proteins, which contribute importantly to maintenance of metabolic homeostasis and viability. We show that an inducible chaperone present in endoplasmic reticulum (ER), the 150 kDa oxygen-regulated protein (ORP150) is expressed both in human brain after seizure attack and in mice hippocampus after kainite administration. Using mice heterozygous for ORP150 deficiency, exposure to excitatory stimuli caused hippocampal neurons to display exaggerated elevation of cytosolic calcium accompanied by activation of μ-calpain and cathepsin B, as well as increased vulnerability to glutamate-induced cell death in vitro and decreased survival to kainate in vivo. In contrast, targeted neuronal overexpression of ORP150 suppressed each of these events, and enhanced neuronal and animal survival in parallel with diminished seizure intensity. Studies using cultured hippocampal neurons showed that ORP150 regulates cytosolic free calcium and activation of proteolytic pathways causing cell death in neurons subject to excitatory stress. Our data underscore a pivotal role for ER stress in glutamate toxicity, and pinpoint a key ER chaperone, ORP150, which orchestrates the protective stress response critical for neuronal survival. Less

Report

(4 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • 2002 Annual Research Report
  • Research Products

    (23 results)

All 2005 2004 2003 2002 Other

All Journal Article (19 results) Publications (4 results)

  • [Journal Article] The ER chaperone 150 kDa Oxygen Regulated Protein (ORP150) improves insulin resistance in Type 2 Diabetes Mellitus. Diabetes.2005

    • Author(s)
      小澤, 北尾ほか
    • Journal Title

      Diabetes. 54

      Pages: 657-663

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The ER chaperone 150 kDa Oxygen Regulated Protein (ORP150) improves insulin resistance in Type 2 Diabetes Mellitus.2005

    • Author(s)
      Ozawa K, Miyazaki T, Hori O, Kitao Y, Tamatani T, Ogawa S.
    • Journal Title

      Diabetes. 54(3)

      Pages: 657-663

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The ER chaperone 150 kDa Oxygen Regulated Protein(ORP150) improves insulin resistance in Type 2 Diabetes Mellitus.2005

    • Author(s)
      小澤, 北尾ほか
    • Journal Title

      Diabetes. 54

      Pages: 657-663

    • Related Report
      2004 Annual Research Report
  • [Journal Article] PR150/HSP12A regulates Purkinje cell survival : a role for endoplasmic reticulum stress in cerebellar development.2004

    • Author(s)
      北尾ほか
    • Journal Title

      J Neurosci. 24

      Pages: 1486-1496

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ORP150/HSP12A protects renal tubular epithelium from ischemia-induced cell death.2004

    • Author(s)
      板東, 北尾ほか
    • Journal Title

      FASEB J. 18

      Pages: 1401-1403

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] ORP150/HSP12A regulates Purkinje cell survival : a role for endoplasmic reticulum stress in cerebellar development.2004

    • Author(s)
      Kitao Y, Hashimoto K, Matsuyama T, Iso H, Tamatani T, Hori O, Stern DM, Kano M, Ozawa K, Ogawa S.
    • Journal Title

      J Neurosci. 24

      Pages: 1486-1496

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Role of Herp in the endoplasmic reticulum (ER) stress response.2004

    • Author(s)
      Hori O, Ichinoda F, Yamaguchi A, Taniguchi M, Koyama Y, Tohyama M, Stem D, Ozawa K, Kitao Y, Ogawa S.
    • Journal Title

      Genes Cells.

      Pages: 457-469

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Prolonged ER Stress in Hypertrophic and Failing Heart Following Aortic Constriction : Possible Contribution of ER Stress to Cardiac Myocyte Apoptosis.2004

    • Author(s)
      Okada K, Minamino T, Tsukamoto Y, Liao Y, Hirota A, Yurtani A, Ozawa K, Ogawa S, Tomoike H, Hori M, Kitakaze M.
    • Journal Title

      Circulation. 110

      Pages: 705-712

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ORP150/HSP12A protects renal tubular epithelium from ischemia-induced cell death.2004

    • Author(s)
      Bando Y, Tsukamoto Y, Katayama T, Ozawa K, Kitao Y, Hori O, Stern DM, Yamauchi A, Ogawa S.
    • Journal Title

      FASEB J. 18

      Pages: 1401-1403

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ORP150/HSP12A regulates Purkinje cell survival : a role for endoplasmic reticulum stress in cerebellar development.2004

    • Author(s)
      北尾ほか
    • Journal Title

      J Neurosci. 24

      Pages: 1486-1496

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The expression of a novel stress protein 150-kDa oxygen regulated protein in sudden infant death.2003

    • Author(s)
      Ikematsu K, Tsuda R, Kondo T, Kondo H, Ozawa K, Ogawa S, Nakasono I.
    • Journal Title

      Leg Med (Tokyo) 5

      Pages: 15-19

    • NAID

      10018966334

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Accumulation of microglial cells expressing ELR motif-positive CXC chemokines and their receptors CXCR2 in monkey hippocanpus after ischemia-reperfusion.2003

    • Author(s)
      Popivanova BK, Koike K, Tonchev AB, Ishida Y, Kondo T, Ogawa S, Mukaida N, Inoue M, Yamashima T.
    • Journal Title

      Brain Res 970

      Pages: 195-204

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transmission of cell stress from endoplasmic reticulum to mitochondria : enhanced expression of Lon protease2002

    • Author(s)
      Hori, O他
    • Journal Title

      J Cell Biol. 157(7)

      Pages: 1151-1160

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression of 150-kd oxygen-regulated protein in the hippocampus suppresses delayed neuronal cell death.2002

    • Author(s)
      Miyazaki, M他
    • Journal Title

      J Cereb Blood Flow Metab. 22

      Pages: 979-987

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Peg3/Pw1 Is Involved in p53-mediated Cell Death Pathway in Brain Ischemia/Hypoxia.2002

    • Author(s)
      Yamaguchi A, Taniguchi M, Hori O, Ogawa S, Tojo N, Matsuoka N, Miyake Si S, Kasai K, Sugimoto H, Tamatani M, Yamashita T, Tohyama M.
    • Journal Title

      J.Biol.Chem. 277

      Pages: 623-629

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Transmission of cell stress from endoplasmic reticulum to mitochondria : expression of Lon protease.2002

    • Author(s)
      Hori O, Ichinoda F, Tamatani T, Yamaguchi A, Sato N, Ozawa K, Kitao Y, Miyazaki M, Harding HP, Ron D, Tohyama M, Stern DM, Ogawa S.
    • Journal Title

      J.Cell Biol. 157

      Pages: 1151-1160

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression of ORP150 (150 kDa oxygen regulated protein) in the hippocampus suppresses delayed neuronal cell death.2002

    • Author(s)
      Miyazaki M, Ozawa K, Hori O, Kitao Y, Matsushita K, Ogawa S, Matsuyama T.
    • Journal Title

      J.Cereb.Blood Flow Metab. 22

      Pages: 979-987

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Antitumor effect of reduction of 150-kDa oxygen-regulated protein expression on human prostate cancer cells.2002

    • Author(s)
      Miyagi T, Hori O, Koshida K, Egawa M, Kato H, Kitagawa Y, Ozawa K, Ogawa S, Namiki M.
    • Journal Title

      Int J Urol. 9

      Pages: 577-585

    • NAID

      50000709953

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Immunohistochemical detection of the 150-kDa oxygen-regulated protein in bladder cancer.2002

    • Author(s)
      Asahi H, Koshida K, Hori O, Ogawa S, Namiki M.
    • Journal Title

      BJU Int. 90

      Pages: 462-466

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] 北尾 ほか: "ORP15O/HSP12A regulates purkinje cell survival : a role for ER stress in cerebellar development"J.Neurosci.. 24. 1486-1496 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 堀 ほか: "Role of Herp in the endoplasmic reticulum stress response"Genes to Cells. (in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Hori, O他: "Transmission of cell stress from endoplasmic reticulum to mitochondria : enhanced expression of Lon protease"J Cell Biol.. 157(7). 1151-1160 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Miyazaki, M他: "Expression of 150-kd oxygen-regulated protein in the hippocampus suppresses delayed neuronal cell death"J Cereb Blood Flow Metab.. 22. 979-987 (2002)

    • Related Report
      2002 Annual Research Report

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Published: 2002-04-01   Modified: 2016-04-21  

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