The sheddase ADAM10 is a potent modulator of prion disease
- University Medical Center Hamburg-Eppendorf, Germany
- Christian Albrechts University, Germany
- Medical University Lodz, Poland
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.
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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.
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© 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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The sheddase ADAM10 is a potent modulator of prion disease
eLife 4:e04260.
https://doi.org/10.7554/eLife.04260
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