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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, Vol. 7, No. 48, 26.11.2021, p. eabj1826.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Linsenmeier, L, Mohammadi, B, Shafiq, M, Frontzek, K, Bär, J, Shrivastava, AN, Damme, M, Song, F, Schwarz, A, Da Vela, S, Massignan, T, Jung, S, Correia, A, Schmitz, M, Puig, B, Hornemann, S, Zerr, I, Tatzelt, J, Biasini, E, Saftig, P, Schweizer, M, Svergun, D, Amin, L, Mazzola, F, Varani, L, Thapa, S, Gilch, S, Schätzl, H, Harris, DA, Triller, A, Mikhaylova, M, Aguzzi, A, Altmeppen, HC & Glatzel, M 2021, 'Ligands binding to the prion protein induce its proteolytic release with therapeutic potential in neurodegenerative proteinopathies', SCI ADV, vol. 7, no. 48, pp. eabj1826. https://doi.org/10.1126/sciadv.abj1826

APA

Linsenmeier, L., Mohammadi, B., Shafiq, M., Frontzek, K., Bär, J., Shrivastava, A. N., Damme, M., Song, F., Schwarz, A., Da Vela, S., Massignan, T., Jung, S., Correia, A., Schmitz, M., Puig, B., Hornemann, S., Zerr, I., Tatzelt, J., Biasini, E., ... Glatzel, M. (2021). Ligands binding to the prion protein induce its proteolytic release with therapeutic potential in neurodegenerative proteinopathies. SCI ADV, 7(48), eabj1826. https://doi.org/10.1126/sciadv.abj1826

Vancouver

Linsenmeier L, Mohammadi B, Shafiq M, Frontzek K, Bär J, Shrivastava AN et al. Ligands binding to the prion protein induce its proteolytic release with therapeutic potential in neurodegenerative proteinopathies. SCI ADV. 2021 Nov 26;7(48):eabj1826. https://doi.org/10.1126/sciadv.abj1826

Bibtex

@article{47771acdadec434abb308feb8e07fb15,
title = "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{\textquoteright}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.",
author = "Luise Linsenmeier and Behnam Mohammadi and Mohsin Shafiq and Karl Frontzek and Julia B{\"a}r and Shrivastava, {Amulya N} and Markus Damme and Feizhi Song and Alexander Schwarz and {Da Vela}, Stefano and Tania Massignan and Sebastian Jung and Angela Correia and Matthias Schmitz and Berta Puig and Simone Hornemann and Inga Zerr and J{\"o}rg Tatzelt and Emiliano Biasini and Paul Saftig and Michaela Schweizer and Dmitri Svergun and Ladan Amin and Federica Mazzola and Luca Varani and Simrika Thapa and Sabine Gilch and Hermann Sch{\"a}tzl and Harris, {David A} and Antoine Triller and Marina Mikhaylova and Adriano Aguzzi and Altmeppen, {Hermann C} and Markus Glatzel",
year = "2021",
month = nov,
day = "26",
doi = "10.1126/sciadv.abj1826",
language = "English",
volume = "7",
pages = "eabj1826",
journal = "SCI ADV",
issn = "2375-2548",
publisher = "American Association for the Advancement of Science",
number = "48",

}

RIS

TY - JOUR

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 -