1. Microbiology and Infectious Disease
  2. Neuroscience
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The sheddase ADAM10 is a potent modulator of prion disease

  1. Hermann C Altmeppen
  2. Johannes Prox
  3. Susanne Krasemann
  4. Berta Puig
  5. Katharina Kruszewski
  6. Frank Dohler
  7. Christian Bernreuther
  8. Ana Hoxha
  9. Luise Linsenmeier
  10. Beata Sikorska
  11. Pawel P Liberski
  12. Udo Bartsch
  13. Paul Saftig
  14. Markus Glatzel  Is a corresponding author
  1. University Medical Center Hamburg-Eppendorf, Germany
  2. Christian Albrechts University, Germany
  3. Medical University Lodz, Poland
Research Article
  • Cited 39
  • Views 2,706
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Cite this article as: eLife 2015;4:e04260 doi: 10.7554/eLife.04260

Abstract

The prion protein (PrPC) is highly expressed in the nervous system and critically involved in prion diseases where it misfolds into pathogenic PrPSc. Moreover, it has been suggested as a receptor mediating neurotoxicity in common neurodegenerative proteinopathies such as Alzheimer's disease. PrPC is shed at the plasma membrane by the metalloprotease ADAM10 yet the impact of this on prion disease remains enigmatic. Employing conditional knockout mice, we show that depletion of ADAM10 in forebrain neurons leads to posttranslational increase of PrPC levels. Upon prion infection of these mice, clinical, biochemical, and morphological data reveal that lack of ADAM10 significantly reduces incubation times and increases PrPSc formation. In contrast, spatiotemporal analysis indicates that absence of shedding impairs spread of prion pathology. Our data support a dual role for ADAM10-mediated shedding and highlight the role of proteolytic processing in prion disease.

Article and author information

Author details

  1. Hermann C Altmeppen

    Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Johannes Prox

    Institute of Biochemistry, Christian Albrechts University, Kiel, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Susanne Krasemann

    Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Berta Puig

    Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Katharina Kruszewski

    Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Frank Dohler

    Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Christian Bernreuther

    Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Ana Hoxha

    Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Luise Linsenmeier

    Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Beata Sikorska

    Department of Molecular Pathology and Neuropathology, Medical University Lodz, Lodz, Poland
    Competing interests
    The authors declare that no competing interests exist.
  11. Pawel P Liberski

    Department of Molecular Pathology and Neuropathology, Medical University Lodz, Lodz, Poland
    Competing interests
    The authors declare that no competing interests exist.
  12. Udo Bartsch

    Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Paul Saftig

    Institute of Biochemistry, Christian Albrechts University, Kiel, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Markus Glatzel

    Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
    For correspondence
    m.glatzel@uke.de
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: Our study was carried out in accordance with the principles of laboratory animal care (NIH publication No. 86-23, revised 1985) as well as the recommendations in the Guide for the Care and Use of Laboratory Animals of the German Animal Welfare Act on protection of animals. The protocol was approved by the Committee on the Ethics of the Freie und Hansestadt Hamburg - Amt für Gesundheit und Verbraucherschutz (permit number 48/09, 81/07 and 84/13). Every effort was made to minimize suffering.

Reviewing Editor

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

Publication history

  1. Received: August 6, 2014
  2. Accepted: February 4, 2015
  3. Accepted Manuscript published: February 5, 2015 (version 1)
  4. Version of Record published: March 3, 2015 (version 2)

Copyright

© 2015, Altmeppen 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.

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