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Mechanistic Basis of Phenothiazine‐Driven Inhibition of Tau Aggregation

2013; Wiley; Volume: 52; Issue: 12 Linguagem: Inglês

10.1002/anie.201208290

1521-3773

Elias Akoury, Marcus Pickhardt, Michał J. Gajda, Jacek Biernat, Eckhard Mandelkow�, Markus Zweckstetter,

Neuroscience and Neuropharmacology Research

Angewandte Chemie International EditionVolume 52, Issue 12 p. 3511-3515 Communication Mechanistic Basis of Phenothiazine-Driven Inhibition of Tau Aggregation† Elias Akoury, Elias Akoury Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen (Germany) These authors contributed equally to this work.Search for more papers by this authorDr. Marcus Pickhardt, Dr. Marcus Pickhardt DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany) CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany) These authors contributed equally to this work.Search for more papers by this authorDr. Michal Gajda, Dr. Michal Gajda Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen (Germany)Search for more papers by this authorDr. Jacek Biernat, Dr. Jacek Biernat DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany) CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany)Search for more papers by this authorProf. Dr. Eckhard Mandelkow, Prof. Dr. Eckhard Mandelkow DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany) CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany)Search for more papers by this authorProf. Dr. Markus Zweckstetter, Corresponding Author Prof. Dr. Markus Zweckstetter markus.zweckstetter@dzne.de Max-Planck-Institut für Biophysikalische Chemie und Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Am Fassberg 11, 37077 Göttingen (Germany)Max-Planck-Institut für Biophysikalische Chemie und Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Am Fassberg 11, 37077 Göttingen (Germany)Search for more papers by this author Elias Akoury, Elias Akoury Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen (Germany) These authors contributed equally to this work.Search for more papers by this authorDr. Marcus Pickhardt, Dr. Marcus Pickhardt DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany) CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany) These authors contributed equally to this work.Search for more papers by this authorDr. Michal Gajda, Dr. Michal Gajda Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen (Germany)Search for more papers by this authorDr. Jacek Biernat, Dr. Jacek Biernat DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany) CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany)Search for more papers by this authorProf. Dr. Eckhard Mandelkow, Prof. Dr. Eckhard Mandelkow DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany) CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany)Search for more papers by this authorProf. Dr. Markus Zweckstetter, Corresponding Author Prof. Dr. Markus Zweckstetter markus.zweckstetter@dzne.de Max-Planck-Institut für Biophysikalische Chemie und Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Am Fassberg 11, 37077 Göttingen (Germany)Max-Planck-Institut für Biophysikalische Chemie und Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Am Fassberg 11, 37077 Göttingen (Germany)Search for more papers by this author First published: 11 February 2013 https://doi.org/10.1002/anie.201208290Citations: 102 † We thank Dr. Andrei Leonov, Prof. Dr. Christian Griesinger, Dr. Eva-Maria Mandelkow, Prof. Dr. R. Heiner Schirmer, Dr. Bruno Bulic, and Dr. Dmitri Svergun for stimulating discussions and Ilka Lindner for sample preparation. This work was supported by the Cluster of Excellence and DFG Research Center “Nanoscale Microscopy and Molecular Physiology of the Brain”, the MPG consortium Toxic Protein Conformation, the Tau Consortium, and the DFG (ZW 71/2-2, 3-2 to M.Z.). Read the full textAboutRelatedInformationPDFPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessClose modalShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Graphical Abstract Blues brothers: Aggregation of the Tau protein is a key event in Alzheimer's disease and Tau aggregation inhibitors are important as potential drugs. Phenothiazines, such as methylene blue and its azure derivatives, have a unique mechanism, specifically modifying the Tau cysteine residues. The modification keeps Tau in a monomeric disordered conformation preventing the formation of filaments and their toxic precursors. Citing Literature Supporting Information As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Filename Description anie_201208290_sm_miscellaneous_information.pdf2.8 MB miscellaneous_information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume52, Issue12March 18, 2013Pages 3511-3515 RelatedInformation RecommendedTau‐tubulin kinase 1 (TTBK1), a neuron‐specific tau kinase candidate, is involved in tau phosphorylation and aggregationShinji Sato, Ronald L. Cerny, James L. Buescher, Tsuneya Ikezu, Journal of NeurochemistryTau Protein Associated Inhibitors in Alzheimer DiseaseQian-Qian Li, Ting-Ting Chu, Yong-Xiang Chen, Yan-Mei Li, Chinese Journal of ChemistryRelationship Between Tau Pathology and Neuroinflammation in Alzheimer's DiseaseMaria Jose Metcalfe MS, Maria E. Figueiredo-Pereira PhD, Mount Sinai Journal of Medicine: A Journal of Translational and Personalized MedicineDevelopment of Tau Aggregation Inhibitors for Alzheimer's DiseaseBruno Bulic Dr., Marcus Pickhardt Dr., Boris Schmidt Prof., Eva-Maria Mandelkow Dr., Herbert Waldmann Prof., Eckhard Mandelkow Prof., Angewandte Chemie International EditionSite-Specific Hyperphosphorylation Inhibits, Rather than Promotes, Tau Fibrillization, Seeding Capacity, and Its Microtubule Binding Mahmood Haj-Yahya, Pushparathinam Gopinath, Kolla Rajasekhar, Hilda Mirbaha, Marc I. Diamond, Hilal A. Lashuel, Angewandte Chemie International Edition