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Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis

Author

Listed:
  • Zhuohua Zhang

    (The Children's Hospital)

  • Henrike Hartmann

    (The Children's Hospital)

  • Viet Minh Do

    (The Children's Hospital)

  • Dorothee Abramowski

    (Preclinical Research, Novartis Pharma Ltd)

  • Christine Sturchler-Pierrat

    (Preclinical Research, Novartis Pharma Ltd)

  • Matthias Staufenbiel

    (Preclinical Research, Novartis Pharma Ltd)

  • Bernd Sommer

    (Preclinical Research, Novartis Pharma Ltd)

  • Marc van de Wetering

    (University Hospital)

  • Hans Clevers

    (University Hospital)

  • Paul Saftig

    (Zentrum Biochemie und Molekular Zellbiologie, Universität Gottingen)

  • Bart De Strooper

    (Flemish Institute for Biotechnology (VIB4), Center for Human Genetics)

  • Xi He

    (The Children's Hospital)

  • Bruce A. Yankner

    (The Children's Hospital)

Abstract

Mutations of the presenilin-1 gene are a major cause of familial early-onset Alzheimer's disease1,2,3,4. Presenilin-1 can associate with members of the catenin family of signalling proteins, but the significance of this association is unknown5,6. Here we show that presenilin-1 forms a complex with β-catenin in vivo that increases β-catenin stability. Pathogenic mutations in the presenilin-1 gene reduce the ability of presenilin-1 to stabilize β-catenin, and lead to increased degradation of β-catenin in the brains of transgenic mice. Moreover, β-catenin levels are markedly reduced in the brains of Alzheimer's disease patients with presenilin-1 mutations. Loss of β-catenin signalling increases neuronal vulnerability to apoptosis induced by amyloid-β protein. Thus, mutations in presenilin-1 may increase neuronal apoptosis by altering the stability of β-catenin, predisposing individuals to early-onset Alzheimer's disease.

Suggested Citation

  • Zhuohua Zhang & Henrike Hartmann & Viet Minh Do & Dorothee Abramowski & Christine Sturchler-Pierrat & Matthias Staufenbiel & Bernd Sommer & Marc van de Wetering & Hans Clevers & Paul Saftig & Bart De , 1998. "Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis," Nature, Nature, vol. 395(6703), pages 698-702, October.
  • Handle: RePEc:nat:nature:v:395:y:1998:i:6703:d:10.1038_27208
    DOI: 10.1038/27208
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