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The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends

Author

Listed:
  • Matthias M. Schneider

    (University of Cambridge)

  • Saurabh Gautam

    (Max-Planck Institute of Biochemistry
    ViraTherapeutics GmbH)

  • Therese W. Herling

    (University of Cambridge)

  • Ewa Andrzejewska

    (University of Cambridge)

  • Georg Krainer

    (University of Cambridge)

  • Alyssa M. Miller

    (University of Cambridge)

  • Victoria A. Trinkaus

    (Max-Planck Institute of Biochemistry
    Munich Cluster for Systems Neurology (SyNergy))

  • Quentin A. E. Peter

    (University of Cambridge)

  • Francesco Simone Ruggeri

    (University of Cambridge)

  • Michele Vendruscolo

    (University of Cambridge)

  • Andreas Bracher

    (Max-Planck Institute of Biochemistry)

  • Christopher M. Dobson

    (University of Cambridge)

  • F. Ulrich Hartl

    (Max-Planck Institute of Biochemistry
    Munich Cluster for Systems Neurology (SyNergy))

  • Tuomas P. J. Knowles

    (University of Cambridge
    University of Cambridge)

Abstract

Molecular chaperones contribute to the maintenance of cellular protein homoeostasis through assisting de novo protein folding and preventing amyloid formation. Chaperones of the Hsp70 family can further disaggregate otherwise irreversible aggregate species such as α-synuclein fibrils, which accumulate in Parkinson’s disease. However, the mechanisms and kinetics of this key functionality are only partially understood. Here, we combine microfluidic measurements with chemical kinetics to study α-synuclein disaggregation. We show that Hsc70 together with its co-chaperones DnaJB1 and Apg2 can completely reverse α-synuclein aggregation back to its soluble monomeric state. This reaction proceeds through first-order kinetics where monomer units are removed directly from the fibril ends with little contribution from intermediate fibril fragmentation steps. These findings extend our mechanistic understanding of the role of chaperones in the suppression of amyloid proliferation and in aggregate clearance, and inform on possibilities and limitations of this strategy in the development of therapeutics against synucleinopathies.

Suggested Citation

  • Matthias M. Schneider & Saurabh Gautam & Therese W. Herling & Ewa Andrzejewska & Georg Krainer & Alyssa M. Miller & Victoria A. Trinkaus & Quentin A. E. Peter & Francesco Simone Ruggeri & Michele Vend, 2021. "The Hsc70 disaggregation machinery removes monomer units directly from α-synuclein fibril ends," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25966-w
    DOI: 10.1038/s41467-021-25966-w
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    1. Nadinath B. Nillegoda & Janine Kirstein & Anna Szlachcic & Mykhaylo Berynskyy & Antonia Stank & Florian Stengel & Kristin Arnsburg & Xuechao Gao & Annika Scior & Ruedi Aebersold & D. Lys Guilbride & R, 2015. "Crucial HSP70 co-chaperone complex unlocks metazoan protein disaggregation," Nature, Nature, vol. 524(7564), pages 247-251, August.
    2. Rahmi Imamoglu & David Balchin & Manajit Hayer-Hartl & F. Ulrich Hartl, 2020. "Bacterial Hsp70 resolves misfolded states and accelerates productive folding of a multi-domain protein," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    3. Christopher M. Dobson, 2003. "Protein folding and misfolding," Nature, Nature, vol. 426(6968), pages 884-890, December.
    4. Anne S. Wentink & Nadinath B. Nillegoda & Jennifer Feufel & Gabrielė Ubartaitė & Carolyn P. Schneider & Paolo De Los Rios & Janosch Hennig & Alessandro Barducci & Bernd Bukau, 2020. "Molecular dissection of amyloid disaggregation by human HSP70," Nature, Nature, vol. 587(7834), pages 483-488, November.
    5. Paolo Arosio & Thomas C. T. Michaels & Sara Linse & Cecilia Månsson & Cecilia Emanuelsson & Jenny Presto & Jan Johansson & Michele Vendruscolo & Christopher M. Dobson & Tuomas P. J. Knowles, 2016. "Kinetic analysis reveals the diversity of microscopic mechanisms through which molecular chaperones suppress amyloid formation," Nature Communications, Nature, vol. 7(1), pages 1-9, April.
    6. F. Ulrich Hartl & Andreas Bracher & Manajit Hayer-Hartl, 2011. "Molecular chaperones in protein folding and proteostasis," Nature, Nature, vol. 475(7356), pages 324-332, July.
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    Cited by:

    1. Dhiman Ghosh & Felix Torres & Matthias M. Schneider & Dzmitry Ashkinadze & Harindranath Kadavath & Yanick Fleischmann & Simon Mergenthal & Peter Güntert & Georg Krainer & Ewa A. Andrzejewska & Lily Li, 2024. "The inhibitory action of the chaperone BRICHOS against the α-Synuclein secondary nucleation pathway," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. S. M. Ayala Mariscal & M. L. Pigazzini & Y. Richter & M. Özel & I. L. Grothaus & J. Protze & K. Ziege & M. Kulke & M. ElBediwi & J. V. Vermaas & L. Colombi Ciacchi & S. Köppen & F. Liu & J. Kirstein, 2022. "Identification of a HTT-specific binding motif in DNAJB1 essential for suppression and disaggregation of HTT," Nature Communications, Nature, vol. 13(1), pages 1-25, December.
    3. Vrinda Sant & Dirk Matthes & Hisham Mazal & Leif Antonschmidt & Franz Wieser & Kumar T. Movellan & Kai Xue & Evgeny Nimerovsky & Marianna Stampolaki & Magdeline Nathan & Dietmar Riedel & Stefan Becker, 2025. "Lipidic folding pathway of α-Synuclein via a toxic oligomer," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    4. Itika Saha & Patricia Yuste-Checa & Miguel Silva Padilha & Qiang Guo & Roman Körner & Hauke Holthusen & Victoria A. Trinkaus & Irina Dudanova & Rubén Fernández-Busnadiego & Wolfgang Baumeister & David, 2023. "The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Georg Krainer & Raphael P. B. Jacquat & Matthias M. Schneider & Timothy J. Welsh & Jieyuan Fan & Quentin A. E. Peter & Ewa A. Andrzejewska & Greta Šneiderienė & Magdalena A. Czekalska & Hannes Ausserw, 2024. "Single-molecule digital sizing of proteins in solution," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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