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ID 114545
Author
Linsenmeier, Luise University Medical Center Hamburg-Eppendorf
Mohammadi, Behnam University Medical Center Hamburg-Eppendorf
Wetzel, Sebastian Christian Albrechts University
Puig, Berta University Medical Center Hamburg-Eppendorf
Jackson, Walker S. German Center for Neurodegenerative Diseases
Hartmann, Alexander University Medical Center Hamburg-Eppendorf
Endres, Kristina Johannes Gutenberg University
Tatzelt, Jörg Ruhr University
Saftig, Paul Christian Albrechts University
Glatzel, Markus University Medical Center Hamburg-Eppendorf
Altmeppen, Hermann C. University Medical Center Hamburg-Eppendorf
Keywords
ADAM10
Antibody
Exosomes
Glycosylation
Membrane anchor
Neurodegeneration
Prion protein
Proteolytic cleavage
Shedding
Content Type
Journal Article
Description
Background: Proteolytic processing of the prion protein (PrPC) by endogenous proteases generates bioactive membrane-bound and soluble fragments which may help to explain the pleiotropic roles of this protein in the nervous system and in brain diseases. Shedding of almost full-length PrPC into the extracellular space by the metalloprotease ADAM10 is of peculiar relevance since soluble PrP stimulates axonal outgrowth and is protective in neurodegenerative conditions such as Alzheimer’s and prion disease. However, molecular determinates and mechanisms regulating the shedding of PrP are entirely unknown.
Methods: We produced an antibody recognizing the neo-epitope of shed PrP generated by ADAM10 in biological samples and used it to study structural and mechanistic aspects affecting the shedding. For this, we investigated genetically modified cellular and murine models by biochemical and morphological approaches.
Results: We show that the novel antibody specifically detects shed PrP in cell culture supernatants and murine brain. We demonstrate that ADAM10 is the exclusive sheddase of PrPC in the nervous system and reveal that the glycosylation state and type of membrane-anchorage of PrPC severely affect its shedding. Furthermore, we provide evidence that PrP shedding can be modulated by pharmacological inhibition and stimulation and present data suggesting that shedding is a relevant part of a compensatory network ensuring PrPC homeostasis of the cell.
Conclusions: With the new antibody, our study introduces a new tool to reliably investigate PrP-shedding. In addition, this study provides novel and important insight into the regulation of this cleavage event, which is likely to be relevant for diagnostic and therapeutic approaches even beyond neurodegeneration.
Journal Title
Molecular Neurodegeneration
ISSN
17501326
Publisher
Springer Nature|BioMed Central
Volume
13
Start Page
18
Published Date
2018-04-06
Rights
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
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language
eng
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departments
Institute of Advanced Medical Sciences