Cleavage site-directed antibodies reveal the prion protein in humans is shed by ADAM10 at Y226 and associates with misfolded protein deposits in neurodegenerative diseases
Year: 2024
Type: article
Abstract: Proteolytic cell surface release ('shedding') of the prion protein (PrP), a broadly expressed GPI-anchored glycoprotein, by the metalloprotease ADAM10 impacts on neurodegenerative and other diseases in animal and in vitro models. Recent studies employing the latter also suggest shed PrP (sPrP) to be a ligand in intercellular communication and critically involved in PrP-associated physiological tasks. Although expectedly an evolutionary conserved event, and while soluble forms of PrP are present in human tissues and body fluids, for the human body neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated thus far. In this study, cleavage site prediction and generation (plus detailed characterization) of sPrP-specific antibodies enabled us to identify PrP cleaved at tyrosin 226 as the physiological and apparently strictly ADAM10-dependent shed form in humans. Using cell lines, neural stem cells and brain organoids, we show that shedding of human PrP can be stimulated by PrP-binding ligands without targeting the protease, which may open novel therapeutic perspectives. Site-specific antibodies directed against human sPrP also detect the shed form in brains of cattle, sheep and deer, hence in all most relevant species naturally affected by fatal and transmissible prion diseases. In human and animal prion diseases, but also in patients with Alzheimer`s disease, sPrP relocalizes from a physiological diffuse tissue pattern to intimately associate with extracellular aggregated deposits of misfolded proteins characteristic for the respective pathological condition. Findings and research tools presented here will accelerate novel insight into the roles of PrP shedding (as a process) and sPrP (as a released factor) in neurodegeneration and beyond.
Source: Acta Neuropathologica
Authors: Feizhi Song, Valerija Kovac, Behnam Mohammadi, Jessica L. Littau, Franka Scharfenberg, Andreu Matamoros Angles, Ilaria Vanni, Mohsin Shafiq, Leonor Orge, Giovanna Galliciotti, Salma Djakkani, Luise Linsenmeier, Maja Černilec, Katrina Hartman, Sebastian Jung, Jörg Tatzelt, Julia E. Neumann, Markus Damme, Sarah K. Tschirner, Stefan F. Lichtenthaler, Franz L. Ricklefs, Thomas Sauvigny, Matthias Schmitz, Inga Zerr, Berta Puig, Eva Tolosa, Isidro Ferrer, Tim Magnus, Marjan S. Rupnik, Diego Sepulveda-Falla, Jakob Matschke, Lojze M. Šmid, Mara Bresjanac, Olivier Andreoletti, Susanne Krasemann, Simote T. Foliaki, Romolo Nonno, Christoph Becker-Pauly, Cecile Monzo, Carole Crozet, Cathryn L. Haigh, Markus Glatzel, Vladka Curin Serbec, Hermann C. Altmeppen
Institutions: University Medical Center Hamburg-Eppendorf, Blood Transfusion Centre of Slovenia, Christian-Albrechts-Universität zu Kiel, Istituto Superiore di Sanità, University of Trás-os-Montes and Alto Douro, Instituto Nacional de Investigação Agrária e Veterinária, Centro de Ciência Animal e Veterinária, Ruhr University Bochum, German Center for Neurodegenerative Diseases, TUM Klinikum, Technical University of Munich, Munich Cluster for Systems Neurology, Universitätsmedizin Göttingen, Institut d'Investigació Biomédica de Bellvitge, Universitat de Barcelona, Medical University of Vienna, University of Ljubljana, École Nationale Vétérinaire de Toulouse, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement, Interactions hôtes-agents pathogènes, National Institutes of Health, Rocky Mountain Laboratories, Inserm, Institute for Regenerative Medicine & Biotherapy
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,790
Funders: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Alzheimer Forschung Initiative, European Commission, Deutsche Forschungsgemeinschaft, China Scholarship Council, Université de Lausanne, Centre Hospitalier Universitaire Vaudois, Univerza v Ljubljani, Werner Otto Stiftung, National Institutes of Health, Horizon 2020 Framework Programme, Universitätsklinikum Hamburg-Eppendorf, National Institute of Allergy and Infectious Diseases, Creutzfeldt-Jakob Disease Foundation
Awards: EXC 2033: RESOLV (Ruhr Explores Solvation), G1789099517, G199205490, G2085232509, G2283679336, G2302657751, G2329248152, G2588154941, G274347230, G3128737150, EXC 2145: Munich Cluster for Systems Neurology (SyNergy), G3973982371, G434337789, G4454383122, G649001848, The role of extracellular vesicles in Alzheimer’s Disease: towards obtaining mechanistic insights to intrinsic protection mechanisms
OpenAlex ID: W4400465432