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

TY - JOUR

T1 - 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

AU - Song, Feizhi

AU - Kovac, Valerija

AU - Mohammadi, Behnam

AU - Littau, Jessica L

AU - Scharfenberg, Franka

AU - Matamoros Angles, Andreu

AU - Vanni, Ilaria

AU - Shafiq, Mohsin

AU - Orge, Leonor

AU - Galliciotti, Giovanna

AU - Djakkani, Salma

AU - Linsenmeier, Luise

AU - Černilec, Maja

AU - Hartman, Katrina

AU - Jung, Sebastian

AU - Tatzelt, Jörg

AU - Neumann, Julia E

AU - Damme, Markus

AU - Tschirner, Sarah K

AU - Lichtenthaler, Stefan F

AU - Ricklefs, Franz L

AU - Sauvigny, Thomas

AU - Schmitz, Matthias

AU - Zerr, Inga

AU - Puig, Berta

AU - Tolosa, Eva

AU - Ferrer, Isidro

AU - Magnus, Tim

AU - Rupnik, Marjan S

AU - Sepulveda-Falla, Diego

AU - Matschke, Jakob

AU - Šmid, Lojze M

AU - Bresjanac, Mara

AU - Andreoletti, Olivier

AU - Krasemann, Susanne

AU - Foliaki, Simote T

AU - Nonno, Romolo

AU - Becker-Pauly, Christoph

AU - Monzo, Cecile

AU - Crozet, Carole

AU - Haigh, Cathryn L

AU - Glatzel, Markus

AU - Curin Serbec, Vladka

AU - Altmeppen, Hermann C

N1 - © 2024. The Author(s).

PY - 2024/7/9

Y1 - 2024/7/9

N2 - 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.

AB - 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.

KW - Humans

KW - ADAM10 Protein/metabolism

KW - Neurodegenerative Diseases/metabolism

KW - Amyloid Precursor Protein Secretases/metabolism

KW - Animals

KW - Prion Proteins/metabolism

KW - Membrane Proteins/metabolism

KW - Brain/metabolism

KW - Antibodies

U2 - 10.1007/s00401-024-02763-5

DO - 10.1007/s00401-024-02763-5

M3 - SCORING: Journal article

C2 - 38980441

VL - 148

SP - 2

JO - ACTA NEUROPATHOL

JF - ACTA NEUROPATHOL

SN - 0001-6322

IS - 1

ER -