1. Cell Biology
  2. Neuroscience
Download icon

Systematic substrate identification indicates a central role for the metalloprotease ADAM10 in axon targeting and synapse function

  1. Peer-Hendrik Kuhn  Is a corresponding author
  2. Alessio Vittorio Colombo
  3. Benjamin Schusser
  4. Daniela Dreymueller
  5. Sebastian Wetzel
  6. Ute Schepers
  7. Julia Herber
  8. Andreas Ludwig
  9. Elisabeth Kremmer
  10. Dirk Montag
  11. Ulrike Müller
  12. Michaela Schweizer
  13. Paul Saftig
  14. Stefan Bräse
  15. Stefan F Lichtenthaler
  1. Technische Universität München, Germany
  2. Ludwig-Maximilians-Universität München, Germany
  3. Uniklinik RWTH Aachen, Germany
  4. Christian-Albrechts Universität zu Kiel, Germany
  5. Karlsruhe Institute of Technology, Germany
  6. Helmholtz Zentrum München, Germany
  7. Leibniz Institute for Neurobiology, Germany
  8. Heidelberg University, Germany
  9. Zentrum für Molekulare Neurobiologie, Germany
Research Article
  • Cited 78
  • Views 4,136
  • Annotations
Cite this article as: eLife 2016;5:e12748 doi: 10.7554/eLife.12748

Abstract

Metzincin metalloproteases have major roles in intercellular communication by modulating the function of membrane proteins. One of the proteases is the a-disintegrin-and-metalloprotease 10 (ADAM10) which acts as alpha-secretase of the Alzheimer's disease amyloid precursor protein. ADAM10 is also required for neuronal network functions in murine brain, but neuronal ADAM10 substrates are only partly known. With a proteomic analysis of Adam10-deficient neurons we identified 91, mostly novel ADAM10 substrate candidates, making ADAM10 a major protease for membrane proteins in the nervous system. Several novel substrates, including the neuronal cell adhesion protein NrCAM, are involved in brain development. Indeed, we detected mistargeted axons in the olfactory bulb of conditional ADAM10-/- mice, which correlate with reduced cleavage of NrCAM, NCAM and other ADAM10 substrates. In summary, the novel ADAM10 substrates provide a molecular basis for neuronal network dysfunctions in conditional ADAM10-/- mice and demonstrate a fundamental function of ADAM10 in the brain.

Article and author information

Author details

  1. Peer-Hendrik Kuhn

    Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
    For correspondence
    peerhendrik@gmx.net
    Competing interests
    The authors declare that no competing interests exist.
  2. Alessio Vittorio Colombo

    Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Benjamin Schusser

    Department of Animal Science, Institute for Animal Physiology, Ludwig-Maximilians-Universität München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Daniela Dreymueller

    Institute of Pharmacology and Toxicology, Uniklinik RWTH Aachen, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Sebastian Wetzel

    Institute of Biochemistry, Christian-Albrechts Universität zu Kiel, Kiel, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Ute Schepers

    Karlsruhe Institute of Technology, Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Julia Herber

    Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Andreas Ludwig

    Institute for Pharmacology and Toxicology, Uniklinik RWTH Aachen, Aachen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Elisabeth Kremmer

    German Research Center for Environmental Health, Institute of Molecular Tumor immunology, Helmholtz Zentrum München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Dirk Montag

    Neurogenetics, Leibniz Institute for Neurobiology, Magdeburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Ulrike Müller

    Department of Functional Genomics, Institute for Pharmacy and Molecular Biotechnology, Heidelberg University, Heidelberg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Michaela Schweizer

    Service-Gruppe für Elektronenmikroskopie, Zentrum für Molekulare Neurobiologie, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Paul Saftig

    Institute of Biochemistry, Christian-Albrechts Universität zu Kiel, Kiel, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Stefan Bräse

    Karlsruhe Institute of Technology, Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
  15. Stefan F Lichtenthaler

    Neuroproteomics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Bart De Strooper, VIB Center for the Biology of Disease, KU Leuven, Belgium

Publication history

  1. Received: November 2, 2015
  2. Accepted: January 22, 2016
  3. Accepted Manuscript published: January 23, 2016 (version 1)
  4. Version of Record published: February 26, 2016 (version 2)

Copyright

© 2016, Kuhn et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 4,136
    Page views
  • 1,070
    Downloads
  • 78
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)