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The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system

Author

Listed:
  • Itika Saha

    (Max Planck Institute of Biochemistry
    Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network)

  • Patricia Yuste-Checa

    (Max Planck Institute of Biochemistry
    Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network)

  • Miguel Silva Padilha

    (Max Planck Institute for Biological Intelligence
    Max Planck Institute for Biological Intelligence
    University of Cologne)

  • Qiang Guo

    (Max Planck Institute of Biochemistry
    Peking University)

  • Roman Körner

    (Max Planck Institute of Biochemistry)

  • Hauke Holthusen

    (Max Planck Institute of Biochemistry)

  • Victoria A. Trinkaus

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

  • Irina Dudanova

    (Max Planck Institute for Biological Intelligence
    Max Planck Institute for Biological Intelligence
    University of Cologne)

  • Rubén Fernández-Busnadiego

    (Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
    Max Planck Institute of Biochemistry
    University Medical Center Göttingen
    University of Göttingen)

  • Wolfgang Baumeister

    (Max Planck Institute of Biochemistry)

  • David W. Sanders

    (University of Texas Southwestern Medical Center
    Princeton University)

  • Saurabh Gautam

    (Max Planck Institute of Biochemistry
    Boehringer Ingelheim International GmbH
    ViraTherapeutics GmbH)

  • Marc I. Diamond

    (University of Texas Southwestern Medical Center)

  • F. Ulrich Hartl

    (Max Planck Institute of Biochemistry
    Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
    Munich Cluster for Systems Neurology (SyNergy))

  • Mark S. Hipp

    (Max Planck Institute of Biochemistry
    Munich Cluster for Systems Neurology (SyNergy)
    Carl von Ossietzky University Oldenburg
    University Medical Center Groningen, University of Groningen)

Abstract

Amyloid-like aggregates of the microtubule-associated protein Tau are associated with several neurodegenerative disorders including Alzheimer’s disease. The existence of cellular machinery for the removal of such aggregates has remained unclear, as specialized disaggregase chaperones are thought to be absent in mammalian cells. Here we show in cell culture and in neurons that the hexameric ATPase valosin-containing protein (VCP) is recruited to ubiquitylated Tau fibrils, resulting in their efficient disaggregation. Aggregate clearance depends on the functional cooperation of VCP with heat shock 70 kDa protein (Hsp70) and the ubiquitin-proteasome machinery. While inhibition of VCP activity stabilizes large Tau aggregates, disaggregation by VCP generates seeding-active Tau species as byproduct. These findings identify VCP as a core component of the machinery for the removal of neurodegenerative disease aggregates and suggest that its activity can be associated with enhanced aggregate spreading in tauopathies.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36058-2
    DOI: 10.1038/s41467-023-36058-2
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    References listed on IDEAS

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    1. 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.
    2. Patricia Yuste-Checa & Victoria A. Trinkaus & Irene Riera-Tur & Rahmi Imamoglu & Theresa F. Schaller & Huping Wang & Irina Dudanova & Mark S. Hipp & Andreas Bracher & F. Ulrich Hartl, 2021. "The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. 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.
    4. Yang Shi & Wenjuan Zhang & Yang Yang & Alexey G. Murzin & Benjamin Falcon & Abhay Kotecha & Mike Beers & Airi Tarutani & Fuyuki Kametani & Holly J. Garringer & Ruben Vidal & Grace I. Hallinan & Tammar, 2021. "Structure-based classification of tauopathies," Nature, Nature, vol. 598(7880), pages 359-363, October.
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