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Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing

Author

Listed:
  • Gang Yu

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Masaki Nishimura

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Shigeki Arawaka

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Diane Levitan

    (Schering Plough Research Institute)

  • Lili Zhang

    (Schering Plough Research Institute)

  • Anurag Tandon

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • You-Qiang Song

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Ekaterina Rogaeva

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Fusheng Chen

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Toshitaka Kawarai

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Agnes Supala

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Lyne Levesque

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Haung Yu

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Dun-Sheng Yang

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Erin Holmes

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Paul Milman

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Yan Liang

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Dong Mei Zhang

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Dong Hong Xu

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Christine Sato

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Evgeny Rogaev

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Marsha Smith

    (Schering Plough Research Institute)

  • Christopher Janus

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Yanni Zhang

    (Molecular Biotechnology, University of Washington)

  • Ruedi Aebersold

    (Molecular Biotechnology, University of Washington)

  • Lindsay Farrer

    (Genetics Program, Boston University School of Medicine)

  • Sandro Sorbi

    (University of Florence)

  • Amalia Bruni

    (Centro Regionale di Neurogenetica, USL 6)

  • Paul Fraser

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

  • Peter St George-Hyslop

    (Centre for Research in Neurodegenerative Diseases
    University of Toronto, Tanz Neuroscience Building
    The University Health Network (Toronto Western Hospital)
    Centro Regionale di Neurogenetica, USL 6)

Abstract

Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal derivatives of β-amyloid precursor protein (βAPP), and modulates the production of the amyloid β-peptide (Aβ) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase Aβ42 and Aβ40 peptide secretion. Deletions in this domain inhibit Aβ production. Nicastrin and presenilins are therefore likely to be functional components of a multimeric complex necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and βAPP.

Suggested Citation

  • Gang Yu & Masaki Nishimura & Shigeki Arawaka & Diane Levitan & Lili Zhang & Anurag Tandon & You-Qiang Song & Ekaterina Rogaeva & Fusheng Chen & Toshitaka Kawarai & Agnes Supala & Lyne Levesque & Haung, 2000. "Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and βAPP processing," Nature, Nature, vol. 407(6800), pages 48-54, September.
    • Handle: RePEc:nat:nature:v:407:y:2000:i:6800:d:10.1038_35024009
    DOI: 10.1038/35024009
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