Ligands binding to the prion protein induce its proteolytic release with therapeutic potential in neurodegenerative proteinopathies
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Ligands binding to the prion protein induce its proteolytic release with therapeutic potential in neurodegenerative proteinopathies. / Linsenmeier, Luise; Mohammadi, Behnam; Shafiq, Mohsin; Frontzek, Karl; Bär, Julia; Shrivastava, Amulya N; Damme, Markus; Song, Feizhi; Schwarz, Alexander; Da Vela, Stefano; Massignan, Tania; Jung, Sebastian; Correia, Angela; Schmitz, Matthias; Puig, Berta; Hornemann, Simone; Zerr, Inga; Tatzelt, Jörg; Biasini, Emiliano; Saftig, Paul; Schweizer, Michaela; Svergun, Dmitri; Amin, Ladan; Mazzola, Federica; Varani, Luca; Thapa, Simrika; Gilch, Sabine; Schätzl, Hermann; Harris, David A; Triller, Antoine; Mikhaylova, Marina; Aguzzi, Adriano; Altmeppen, Hermann C; Glatzel, Markus.
in: SCI ADV, Jahrgang 7, Nr. 48, 26.11.2021, S. eabj1826.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Ligands binding to the prion protein induce its proteolytic release with therapeutic potential in neurodegenerative proteinopathies
AU - Linsenmeier, Luise
AU - Mohammadi, Behnam
AU - Shafiq, Mohsin
AU - Frontzek, Karl
AU - Bär, Julia
AU - Shrivastava, Amulya N
AU - Damme, Markus
AU - Song, Feizhi
AU - Schwarz, Alexander
AU - Da Vela, Stefano
AU - Massignan, Tania
AU - Jung, Sebastian
AU - Correia, Angela
AU - Schmitz, Matthias
AU - Puig, Berta
AU - Hornemann, Simone
AU - Zerr, Inga
AU - Tatzelt, Jörg
AU - Biasini, Emiliano
AU - Saftig, Paul
AU - Schweizer, Michaela
AU - Svergun, Dmitri
AU - Amin, Ladan
AU - Mazzola, Federica
AU - Varani, Luca
AU - Thapa, Simrika
AU - Gilch, Sabine
AU - Schätzl, Hermann
AU - Harris, David A
AU - Triller, Antoine
AU - Mikhaylova, Marina
AU - Aguzzi, Adriano
AU - Altmeppen, Hermann C
AU - Glatzel, Markus
PY - 2021/11/26
Y1 - 2021/11/26
N2 - 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.
AB - 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.
U2 - 10.1126/sciadv.abj1826
DO - 10.1126/sciadv.abj1826
M3 - SCORING: Journal article
C2 - 34818048
VL - 7
SP - eabj1826
JO - SCI ADV
JF - SCI ADV
SN - 2375-2548
IS - 48
ER -