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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2018

Open Access 01-12-2018 | Research article

Structural and mechanistic aspects influencing the ADAM10-mediated shedding of the prion protein

Authors: Luise Linsenmeier, Behnam Mohammadi, Sebastian Wetzel, Berta Puig, Walker S. Jackson, Alexander Hartmann, Keiji Uchiyama, Suehiro Sakaguchi, Kristina Endres, Jörg Tatzelt, Paul Saftig, Markus Glatzel, Hermann C. Altmeppen

Published in: Molecular Neurodegeneration | Issue 1/2018

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Abstract

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.
Appendix
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Metadata
Title
Structural and mechanistic aspects influencing the ADAM10-mediated shedding of the prion protein
Authors
Luise Linsenmeier
Behnam Mohammadi
Sebastian Wetzel
Berta Puig
Walker S. Jackson
Alexander Hartmann
Keiji Uchiyama
Suehiro Sakaguchi
Kristina Endres
Jörg Tatzelt
Paul Saftig
Markus Glatzel
Hermann C. Altmeppen
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2018
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-018-0248-6

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