Paper

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

Djakkani, Salma, Smid, Lojze M, Mohammadi, Behnam, Tschirner, Sarah K, Serbec, Vladka Curin, Tolosa, Eva, Schmitz, Matthias, Zerr, Inga, Lichtenthaler, Stefan F, Altmeppen, Hermann C, Kovac, Valerija, Nonno, Romolo, Andreu Matamoros Angles, Crozet, Carole, Orge, Leonor, Neumann, Julia E, Galliciotti, Giovanna, Hartman, Katrina, Linsenmeier, Luise, Foliaki, Simote T, Monzo, Cecile, Haigh, Cathryn L, Vanni, Ilaria, Tatzelt, Joerg, Krasemann, Susanne, Scharfenberg, Franka, Cernilec, Maja, Damme, Markus, Sepulveda-Falla, Diego, Littau, Lisa, Jung, Sebastian, Bresjanac, Mara, Ferrer, Isidro, Becker-Pauly, Christoph, Song, Feizhi, Magnus, Tim, Andreoletti, Olivier, Puig, Berta, Rupnik, Marjan S, Glatzel, Markus, Shafiq, Mohsin, Matschke, Jakob

2023

Overview

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, neither proteolytic PrP shedding and its cleavage site nor involvement of ADAM10 or the biological relevance of this process have been demonstrated for the human body 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 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 aggregates 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.Competing Interest StatementThe authors have declared no competing interest.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Animal models / Antibodies / Body fluids / Cell lines / Cell surface / Evolutionary conservation / Glycosylphosphatidylinositol / Metalloproteinase / Neural stem cells / Neurodegeneration / Neurodegenerative diseases / Neuroscience / Organoids / Physiology / Prion protein / Protein folding / Proteins / Proteolysis