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A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain

Nature volume 398, pages 518–522 (1999)Cite this article

Abstract

Signalling through the receptor protein Notch, which is involved in crucial cell-fate decisions during development, requires ligand-induced cleavage of Notch. This cleavage occurs within the predicted transmembrane domain, releasing the Notch intracellular domain (NICD), and is reminiscent of γ-secretase-mediated cleavage of β-amyloid precursor protein (APP), a critical event in the pathogenesis of Alzheimer's disease. A deficiency in presenilin-1 (PS1) inhibits processing of APP by γ-secretase in mammalian cells, and genetic interactions between Notch and PS1 homologues in Caenorhabditis elegans indicate that the presenilins may modulate the Notch signalling pathway1,2,3,4. Here we report that, in mammalian cells, PS1 deficiency also reduces the proteolytic release of NICD from a truncated Notch construct, thus identifying the specific biochemical step of the Notch signalling pathway that is affected by PS1. Moreover, several γ-secretase inhibitors block this same step in Notch processing, indicating that related protease activities are responsible for cleavage within the predicted transmembrane domains of Notch and APP. Thus the targeting of γ-secretase for the treatment of Alzheimer's disease may risk toxicity caused by reduced Notch signalling.

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Figure 1: Proteolytic cleavage of Notch, APP and SREBP (not to scale).
Figure 2: Processing of APP and Notch-1 in PS1−/− mouse brain and MEFs.
Figure 3: Nuclear transport of the intracellular domain (NICD) of Notch-1.
Figure 4: Generation of NICD in PS1+/+ and PS1−/− neurons.
Figure 5: Effect of γ-secretase inhibitors on mNotchΔE processing.
Figure 6: Effect of γ-secretase inhibitor MW167 on processing of mNotchΔE (upper panel) and APP (lower panels).

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Acknowledgements

This work was supported by the FWO-Vlaanderen, the Human Frontier of Science Program, the Flemish Institute for Biotechnology (VIB) and the K. U. Leuven. B.D.S., W.A., P.C. and K.C. are researchers of the FWO. R.K., M.S.W. and A.G. are supported by the NIH; W.J.R. is supported by a fellowship from the KECK foundation; J.S.M. is supported in part by the Markey Special Emphasis Pathway in Human Pathobiology; P.S. is supported by the Deutsche Forschungsgemeinschaft. We thank A. Roebroek and J. Gordon for helpful comments.

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Authors and Affiliations

  1. Neuronal Cell Biology and Gene Transfer Laboratory, Flanders Institute for Biotechnology (VIB4), Center for Human Genetics, KU Leuven, B-3000, Leuven, Belgium

    Bart De Strooper, Wim Annaert, Philippe Cupers, Katleen Craessaerts & Vincent Schrijvers

  2. Abteilung Biochemie II, Zentrum Biochemie und Molekulare Zellbiologie, Universität Göttingen, B-37073, Germany

    Paul Saftig

  3. Division of Dermatology and the Department of Molecular Biology and Pharmacology, Washington University, St Louis, 63110, Missouri, USA

    Jeffrey S. Mumm, Eric H. Schroeter & Raphael Kopan

  4. Department of Pharmaceutical Sciences, University of Tennessee, Memphis, 38138, Tennesse, USA

    Michael S. Wolfe

  5. Departments of Psychiatry and Genetics, Washington University School of Medicine, St Louis, 63110, Missouri, USA

    William J. Ray & Alison Goate

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  1. Bart De Strooper
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Correspondence to Bart De Strooper or Raphael Kopan.

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De Strooper, B., Annaert, W., Cupers, P. et al. A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522 (1999). https://doi.org/10.1038/19083

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