Ligands binding to the prion protein induce its proteolytic release with therapeutic potential in neurodegenerative proteinopathies.

Abstract

The prion protein (PrPC) is a central player in neurodegenerative diseases, such as prion diseases or Alzheimer’s disease. In contrast to disease-promoting cell surface PrPC, extracellular fragments act neuroprotective by blocking neurotoxic disease-associated protein conformers. Fittingly, PrPC release by the metalloprotease ADAM10 represents a protective mechanism. We used biochemical, cell biological, morphological, and structural methods to investigate mechanisms stimulating this proteolytic shedding. Shed PrP negatively correlates with prion conversion and is markedly redistributed in murine brain in the presence of prion deposits or amyloid plaques, indicating a sequestrating activity. PrP-directed ligands cause structural changes in PrPC and increased shedding in cells and organotypic brain slice cultures. As an exception, some PrP-directed antibodies targeting repetitive epitopes do not cause shedding but surface clustering, endocytosis, and degradation of PrPC. Both mechanisms may contribute to beneficial actions described for PrP-directed ligands and pave the way for new therapeutic strategies against currently incurable neurodegenerative diseases.

• Authors: Luise Linsenmeier, Behnam Mohammadi, Mohsin Shafiq, Karl Frontzek, Julia Bär, Amulya N Shrivastava, Markus Damme, Feizhi Song, Alexander Schwarz, Stefano Da Vela, Tania Massignan, Sebastian Jung, Angela Correia, Matthias Schmitz, Berta Puig, Simone Hornemann, Inga Zerr, Jörg Tatzelt, Emiliano Biasini, Paul Saftig, Michaela Schweizer, Dmitri Svergun, Ladan Amin, Federica Mazzola, Luca Varani, Simrika Thapa, Sabine Gilch, Hermann Schätzl, David A Harris, Antoine Triller, Marina Mikhaylova, Adriano Aguzzi, Hermann C Altmeppen, Markus Glatzel
• Journal: Science advances (Sci Adv) Vol. 7 Issue 48 Pg. eabj1826 (Nov 26 2021) ISSN: 2375-2548 [Electronic] United States
• PMID: 34818048 (Publication Type: Journal Article)