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

  1. Song, Feizhi
  2. Kovac, Valerija
  3. Mohammadi, Behnam
  4. Littau, Jessica L.
  5. Scharfenberg, Franka
  6. Matamoros Angles, Andreu
  7. Vanni, Ilaria
  8. Shafiq, Mohsin
  9. Orge, Leonor
  10. Galliciotti, Giovanna
  11. Djakkani, Salma
  12. Linsenmeier, Luise
  13. Černilec, Maja
  14. Hartman, Katrina
  15. Jung, Sebastian
  16. Tatzelt, Jörg
  17. Neumann, Julia E.
  18. Damme, Markus
  19. Tschirner, Sarah K.
  20. Lichtenthaler, Stefan F.
  21. Ricklefs, Franz L.
  22. Sauvigny, Thomas
  23. Schmitz, Matthias
  24. Zerr, Inga
  25. Puig, Berta
  26. Tolosa, Eva
  27. Ferrer, Isidro
  28. Magnus, Tim
  29. Rupnik, Marjan S.
  30. Sepulveda-Falla, Diego
  31. Matschke, Jakob
  32. Šmid, Lojze M.
  33. Bresjanac, Mara
  34. Andreoletti, Olivier
  35. Krasemann, Susanne
  36. Foliaki, Simote T.
  37. Nonno, Romolo
  38. Becker-Pauly, Christoph
  39. Monzo, Cecile
  40. Crozet, Carole
  41. Haigh, Cathryn L.
  42. Glatzel, Markus
  43. Curin Serbec, Vladka
  44. Altmeppen, Hermann ORCID logo

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1000 Titel
  • 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
1000 Autor/in
  1. Song, Feizhi |
  2. Kovac, Valerija |
  3. Mohammadi, Behnam |
  4. Littau, Jessica L. |
  5. Scharfenberg, Franka |
  6. Matamoros Angles, Andreu |
  7. Vanni, Ilaria |
  8. Shafiq, Mohsin |
  9. Orge, Leonor |
  10. Galliciotti, Giovanna |
  11. Djakkani, Salma |
  12. Linsenmeier, Luise |
  13. Černilec, Maja |
  14. Hartman, Katrina |
  15. Jung, Sebastian |
  16. Tatzelt, Jörg |
  17. Neumann, Julia E. |
  18. Damme, Markus |
  19. Tschirner, Sarah K. |
  20. Lichtenthaler, Stefan F. |
  21. Ricklefs, Franz L. |
  22. Sauvigny, Thomas |
  23. Schmitz, Matthias |
  24. Zerr, Inga |
  25. Puig, Berta |
  26. Tolosa, Eva |
  27. Ferrer, Isidro |
  28. Magnus, Tim |
  29. Rupnik, Marjan S. |
  30. Sepulveda-Falla, Diego |
  31. Matschke, Jakob |
  32. Šmid, Lojze M. |
  33. Bresjanac, Mara |
  34. Andreoletti, Olivier |
  35. Krasemann, Susanne |
  36. Foliaki, Simote T. |
  37. Nonno, Romolo |
  38. Becker-Pauly, Christoph |
  39. Monzo, Cecile |
  40. Crozet, Carole |
  41. Haigh, Cathryn L. |
  42. Glatzel, Markus |
  43. Curin Serbec, Vladka |
  44. Altmeppen, Hermann |
1000 Verlag Springer Berlin Heidelberg
1000 Erscheinungsjahr 2024
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2024-07-09
1000 Erschienen in
1000 Quellenangabe
  • 148(1):2
1000 Copyrightjahr
  • 2024
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1007/s00401-024-02763-5 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11233397/ |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • <jats:title>Abstract</jats:title><jats:p>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.</jats:p>
1000 Sacherschließung
lokal Dementia
lokal Brain/pathology [MeSH]
lokal Prions
lokal Proteolytic processing
lokal ADAM10 Protein/metabolism [MeSH]
lokal Humans [MeSH]
lokal Neurodegenerative Diseases/metabolism [MeSH]
lokal Neurodegenerative Diseases/pathology [MeSH]
lokal Animals [MeSH]
lokal Alzheimer’s disease
lokal Extracellular vesicles
lokal Prion Proteins/metabolism [MeSH]
lokal Brain/metabolism [MeSH]
lokal Membrane Proteins/metabolism [MeSH]
lokal Amyloid Precursor Protein Secretases/metabolism [MeSH]
lokal Original Paper
lokal Neuroprotection
lokal Antibodies [MeSH]
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
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  1. Creutzfeldt-Jakob Disease Foundation |
  2. Alzheimer Forschung Initiative |
  3. Werner Otto Stiftung |
  4. Deutsche Forschungsgemeinschaft |
  5. China Scholarship Council |
  6. Slovene Research Agency |
  7. Division of Intramural Research |
  8. Horizon 2020 Framework Programme |
  9. Universitätsklinikum Hamburg-Eppendorf (UKE) |
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