Mechanistic Basis of Phenothiazine-Driven Inhibition of Tau Aggregation

Authors

  • Elias Akoury,

    1. Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen (Germany)
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    • These authors contributed equally to this work.

  • Dr. Marcus Pickhardt,

    1. DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany)
    2. CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany)
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    • These authors contributed equally to this work.

  • Dr. Michal Gajda,

    1. Max-Planck-Institut für Biophysikalische Chemie, Am Fassberg 11, 37077 Göttingen (Germany)
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  • Dr. Jacek Biernat,

    1. DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany)
    2. CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany)
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  • Prof. Dr. Eckhard Mandelkow,

    1. DZNE, German Center for Neurodegenerative Diseases, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany)
    2. CAESAR Research Center, Ludwig-Erhard-Allee 2, 53175 Bonn (Germany)
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  • Prof. Dr. Markus Zweckstetter

    Corresponding author
    1. 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)
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  • 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.).

Abstract

original image

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.

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