The sheddase ADAM10 is a potent modulator of prion disease

Abstract
Article and author information
Metrics

Abstract

The prion protein (PrP^C) is highly expressed in the nervous system and critically involved in prion diseases where it misfolds into pathogenic PrP^Sc. Moreover, it has been suggested as a receptor mediating neurotoxicity in common neurodegenerative proteinopathies such as Alzheimer's disease. PrP^C 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 PrP^C levels. Upon prion infection of these mice, clinical, biochemical, and morphological data reveal that lack of ADAM10 significantly reduces incubation times and increases PrP^Sc 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

Hermann C Altmeppen

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Competing interests
The authors declare that no competing interests exist.
Johannes Prox

Institute of Biochemistry, Christian Albrechts University, Kiel, Germany

Competing interests
The authors declare that no competing interests exist.
Susanne Krasemann

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Competing interests
The authors declare that no competing interests exist.
Berta Puig

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Competing interests
The authors declare that no competing interests exist.
Katharina Kruszewski

Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Competing interests
The authors declare that no competing interests exist.
Frank Dohler

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Competing interests
The authors declare that no competing interests exist.
Christian Bernreuther

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Competing interests
The authors declare that no competing interests exist.
Ana Hoxha

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Competing interests
The authors declare that no competing interests exist.
Luise Linsenmeier

Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Competing interests
The authors declare that no competing interests exist.
Beata Sikorska

Department of Molecular Pathology and Neuropathology, Medical University Lodz, Lodz, Poland

Competing interests
The authors declare that no competing interests exist.
Pawel P Liberski

Department of Molecular Pathology and Neuropathology, Medical University Lodz, Lodz, Poland

Competing interests
The authors declare that no competing interests exist.
Udo Bartsch

Department of Ophthalmology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Competing interests
The authors declare that no competing interests exist.
Paul Saftig

Institute of Biochemistry, Christian Albrechts University, Kiel, Germany

Competing interests
The authors declare that no competing interests exist.
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.

Copyright

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.