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Analysis of the role of Herp in the generation of amyloid β protein and in the ER stress

Research Project

Project/Area Number 16390029
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Biological pharmacy
Research InstitutionNational Institute for Longevity Sciences

Principal Investigator

KOMANO Hiroto  National Institute for Longevity Sciences, Department of Alzheimer's Disease Research, Section Head, (研究所)・アルツハイマー病研究部, 室長 (40170378)

Project Period (FY) 2004 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2006: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2005: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2004: ¥5,400,000 (Direct Cost: ¥5,400,000)
KeywordsER stress / Amyloid β protein / Presenilin / Homocystein / Alzheimer's disease / 細胞死
Research Abstract

Herp is an endoplasmic reticulum (ER)-stress-inducible membrane protein that has a ubiquitin-like domain (ULD). However, its biological function is not yet known. Previously, we reported that a high expression level of Herp in cells enhances the generation of amyloid β-protein (Aβ) and that Herp interacts with presenilin (PS). Aβ is generated from amyloid precursor protein (APP) by sequential proteolytic cleavages catalyzed by β- and γ-secretases. PS is processed to its stable form by endoproteolysis. The cellular level of processed PS is highly regulated, and excess unprocessed PS enters the ubiquitin/proteasome degradation pathway. Processed PS resides in a high-molecular-weight complex that includes three membrane proteins, namely, Nacastrin (NCT), APH-1 and PEN-2. Accumulating evidence shows that the PS complex is responsible for y-secretase activity. In this study, we addressed the role of Herp in the regulation of PS complex formation. We found that the expression of ULD-deleted Herp markedly inhibited the degradation of unprocessed PS or NCT that fails to be incorporated into the PS complex. We also found that the expression of ULD-deleted Herp decreased a degree of ubiqutination of PS and NCT, while the expression of wild-type Herp enhanced it, strongly suggesting that ULD of Herp is involved for the ubiquitination of PS and NCT. Thus, Herp is likely to play a role, through its ubiquitin-like domain, in the elimination of excess PS or PS cofactors which fail to reside in the PS complex, thereby regulating the intracellular level of the PS complex.

Report

(4 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • 2004 Annual Research Report
  • Research Products

    (14 results)

All 2006 2005 2004

All Journal Article (14 results)

  • [Journal Article] Reconstitution of γ -secretase by truncated presenilin (PS) fragments revealed that PS C-terminal transmembrane domain is critical for formation of γ-secretase complex2006

    • Author(s)
      Shiraishi H., et al.
    • Journal Title

      Genes to Cells 11

      Pages: 83-93

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Homocysteine-induced endoplasmic reticulum protein (Herp) is up-regulated in sporadic inclusion-body myositis and in endoplasmic reticulumn stress-induced cultured human muscle fibers2006

    • Author(s)
      Nogalska A., et al.
    • Journal Title

      J. Neurochem. 96

      Pages: 1491-1499

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Characterization of APH-1 mutants with a disrupted transmembrane GxxxG motif2006

    • Author(s)
      Araki W., et al.
    • Journal Title

      J. Mol. Neurosci 29

      Pages: 35-44

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Reconstitution of γ-secretase by truncated presenilin (PS) fragments revealed that PS C-terminal transmembrane domain is critical for formation of γ-secretase complex2006

    • Author(s)
      Shiraishi H., et al.
    • Journal Title

      Genes to Cells 11

      Pages: 83-93

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary 2005 Annual Research Report
  • [Journal Article] Characterization of APH-1 mutants with a disrupted transmembrane GxxxG motif2006

    • Author(s)
      Araki W., et al.
    • Journal Title

      J. Mol. Neurosci. 29

      Pages: 35-44

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Reconstitution of γ-secretase by lruncated presenilin (PS) fragments revealed that PS C-terminal transmembrane domain is criticak formation of γ-secretase complex2006

    • Author(s)
      Shiraishi H., et al.
    • Journal Title

      Genes to Cells 11

      Pages: 83-93

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Homocysteine-induced endoplasmic reticulum protein (Herp) is up-regulated in sporadic inclusion-body myositis and in endoplasmic reticulumn stress-induced cultured human muscle fibers2006

    • Author(s)
      Nogalska A., et al.
    • Journal Title

      J.Neurochem. 96

      Pages: 1491-1499

    • Related Report
      2006 Annual Research Report 2005 Annual Research Report
  • [Journal Article] Characterization of APH-1 mutants with a disrupted transmembrane GxxxG motif2006

    • Author(s)
      Araki W., et al.
    • Journal Title

      J.Mol.Neurosci 29

      Pages: 35-44

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Characterization of APH-1 mutants with a disrupted transmembrane GxxxG motif2006

    • Author(s)
      Araki W., et al.
    • Journal Title

      J.Mol.Neurosci. 印刷中

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Random mutagenesisi of Presenilin 1 identifies novel mutants exclusively generating longer Amyloid β peptides2005

    • Author(s)
      Nakaya Y., et al.
    • Journal Title

      J. Biol. Chem. 280

      Pages: 19070-19077

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Random mutagenesisi of Presenilin 1 identifies novel mutants exclusively generating longer Amyloid β peptides2005

    • Author(s)
      Nakaya Y., et al.
    • Journal Title

      J.Biol.Chem. 280

      Pages: 19070-19077

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Random mutagenesis of Presenilin 1 identifies novel mutants exclusively generating longer amyloid β peptides2005

    • Author(s)
      Nakaya Y. et al.
    • Journal Title

      Journal of Biological Chemistry 印刷中

    • Related Report
      2004 Annual Research Report
  • [Journal Article] PEN-2 enhances γ-cleavage after the formation of Presenilin heterodimer.2004

    • Author(s)
      Shiraishi H., et al.
    • Journal Title

      J. Neurochem. 90

      Pages: 1402-1413

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] PEN-2 enhances γ-cleavage after the formation of Presenilin heterodimer.2004

    • Author(s)
      Shiraishi H., et al.
    • Journal Title

      Journal of Neurochemistry 90

      Pages: 1402-1413

    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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