Cross-seeding by prion protein inactivates TDP-43
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Cross-seeding by prion protein inactivates TDP-43. / Polido, Stella A; Stuani, Cristiana; Voigt, Aaron; Banik, Papiya; Kamps, Janine; Bader, Verian; Grover, Prerna; Krause, Laura J; Zerr, Inga; Matschke, Jakob; Glatzel, Markus; Winklhofer, Konstanze F; Buratti, Emanuele; Tatzelt, Jörg.
in: BRAIN, Jahrgang 147, Nr. 1, 04.01.2024, S. 240-254.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Cross-seeding by prion protein inactivates TDP-43
AU - Polido, Stella A
AU - Stuani, Cristiana
AU - Voigt, Aaron
AU - Banik, Papiya
AU - Kamps, Janine
AU - Bader, Verian
AU - Grover, Prerna
AU - Krause, Laura J
AU - Zerr, Inga
AU - Matschke, Jakob
AU - Glatzel, Markus
AU - Winklhofer, Konstanze F
AU - Buratti, Emanuele
AU - Tatzelt, Jörg
N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
PY - 2024/1/4
Y1 - 2024/1/4
N2 - A common pathological denominator of various neurodegenerative diseases is the accumulation of protein aggregates. Neurotoxic effects are caused by a loss of the physiological activity of the aggregating protein and/or a gain of toxic function of the misfolded protein conformers. In transmissible spongiform encephalopathies or prion diseases, neurodegeneration is caused by aberrantly folded isoforms of the prion protein (PrP). However, it is poorly understood how pathogenic PrP conformers interfere with neuronal viability. Employing in vitro approaches, cell culture, animal models and patients' brain samples, we show that misfolded PrP can induce aggregation and inactivation of TAR DNA-binding protein-43 (TDP-43). Purified PrP aggregates interact with TDP-43 in vitro and in cells and induce the conversion of soluble TDP-43 into non-dynamic protein assemblies. Similarly, mislocalized PrP conformers in the cytosol bind to and sequester TDP-43 in cytosolic aggregates. As a consequence, TDP-43-dependent splicing activity in the nucleus is significantly decreased, leading to altered protein expression in cells with cytosolic PrP aggregates. Finally, we present evidence for cytosolic TDP-43 aggregates in neurons of transgenic flies expressing mammalian PrP and Creutzfeldt-Jakob disease patients. Our study identified a novel mechanism of how aberrant PrP conformers impair physiological pathways by cross-seeding.
AB - A common pathological denominator of various neurodegenerative diseases is the accumulation of protein aggregates. Neurotoxic effects are caused by a loss of the physiological activity of the aggregating protein and/or a gain of toxic function of the misfolded protein conformers. In transmissible spongiform encephalopathies or prion diseases, neurodegeneration is caused by aberrantly folded isoforms of the prion protein (PrP). However, it is poorly understood how pathogenic PrP conformers interfere with neuronal viability. Employing in vitro approaches, cell culture, animal models and patients' brain samples, we show that misfolded PrP can induce aggregation and inactivation of TAR DNA-binding protein-43 (TDP-43). Purified PrP aggregates interact with TDP-43 in vitro and in cells and induce the conversion of soluble TDP-43 into non-dynamic protein assemblies. Similarly, mislocalized PrP conformers in the cytosol bind to and sequester TDP-43 in cytosolic aggregates. As a consequence, TDP-43-dependent splicing activity in the nucleus is significantly decreased, leading to altered protein expression in cells with cytosolic PrP aggregates. Finally, we present evidence for cytosolic TDP-43 aggregates in neurons of transgenic flies expressing mammalian PrP and Creutzfeldt-Jakob disease patients. Our study identified a novel mechanism of how aberrant PrP conformers impair physiological pathways by cross-seeding.
U2 - 10.1093/brain/awad289
DO - 10.1093/brain/awad289
M3 - SCORING: Journal article
C2 - 37669322
VL - 147
SP - 240
EP - 254
JO - BRAIN
JF - BRAIN
SN - 0006-8950
IS - 1
ER -