PERK activation mitigates tau pathology in vitro and in vivo .

Autor: Bruch J; Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Department of Neurology, Technical University of Munich (TUM), Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Xu H; Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Department of Neurology, Technical University of Munich (TUM), Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Rösler TW; Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Department of Neurology, Technical University of Munich (TUM), Munich, Germany., De Andrade A; Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Kuhn PH; Neuroproteomics, Klinikum rechts der Isar and Institute for Advanced Study, Technical University of Munich (TUM), Munich, Germany.; Institute of Pathology, Technical University of Munich (TUM), Munich, Germany., Lichtenthaler SF; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Neuroproteomics, Klinikum rechts der Isar and Institute for Advanced Study, Technical University of Munich (TUM), Munich, Germany.; Neuroproteomics, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany., Arzberger T; Center for Neuropathology and Prion Research (ZNP), University of Munich, Munich, Germany., Winklhofer KF; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.; Department of Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University, Bochum, Germany., Müller U; Institute for Human Genetics, University of Giessen, Giessen, Germany., Höglinger GU; Department of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany guenter.hoeglinger@dzne.de.; Department of Neurology, Technical University of Munich (TUM), Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2017 Mar; Vol. 9 (3), pp. 371-384.
DOI: 10.15252/emmm.201606664
Abstrakt: The RNA-like endoplasmic reticulum kinase (PERK) is genetically associated with the tauopathy progressive supranuclear palsy (PSP). To elucidate the functional mechanisms underlying this association, we explored PERK activity in brains of PSP patients and its function in three tauopathy models (cultured human neurons overexpressing 4-repeat wild-type tau or treated with the environmental neurotoxin annonacin, and P301S tau transgenic mice). In vitro , treatment with a pharmacological PERK activator CCT020312 or PERK overexpression reduced tau phosphorylation, tau conformational change and 4-repeat tau isoforms, and increased cell viability. In vivo , the PERK activator significantly improved memory and locomotor function, reduced tau pathology, and prevented dendritic spine and motoneuron loss in P301S tau mice. Importantly, the PERK substrate EIF2A, mediating some detrimental effects of PERK signaling, was downregulated in PSP brains and tauopathy models, suggesting that the alternative PERK-NRF2 pathway accounts for these beneficial effects in the context of tauopathies. In summary, PERK activation may be a novel strategy to treat PSP and eventually other tauopathies.
(© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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