20.500.12556/RUL-182028 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 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. Alzheimer’s disease dementia extracellular vesicles neuroprotection prions proteolytic processing Alzheimerjeva bolezen demenca zunajcelični vezikli nevroprotekcija prioni proteolitska obdelava true false true Angleški jezik Slovenski jezik Članek v reviji 2026-04-23 04:25:55 2026-04-23 06:39:42 2026-07-16 07:05:00 0000-00-00 00:00:00 2024 0 0 33 str. iss. 1, art. 2 Vol. 148 Jul. 2024 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 616.1 1432-0533 10.1007/s00401-024-02763-5 202989827 RAZ_Song_Feizhi_2024.pdf RAZ_Song_Feizhi_2024.pdf 1 203AA61784494CAEB571ED30C57BCD82 8ef8efa8b03e32f72095bd7321515854fb12fabeac1c35824867650fc3f7bd4d 21ad5b81-3ecf-11f1-b0ab-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=232946 https://link.springer.com/article/10.1007/s00401-024-02763-5 1 6d5e55ae-3ece-11f1-b0ab-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=232944 Medicinska fakulteta 0 0 0