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The extracellular chaperone Clusterin enhances Tau aggregate seeding in a cellular model

Author

Listed:
  • Patricia Yuste-Checa

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

  • Victoria A. Trinkaus

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

  • Irene Riera-Tur

    (Max Planck Institute of Neurobiology
    Max Planck Institute of Neurobiology)

  • Rahmi Imamoglu

    (Max Planck Institute of Biochemistry)

  • Theresa F. Schaller

    (Max Planck Institute of Biochemistry
    University Medical Center of the Johannes Gutenberg-University Mainz)

  • Huping Wang

    (Max Planck Institute of Biochemistry)

  • Irina Dudanova

    (Max Planck Institute of Neurobiology
    Max Planck Institute of Neurobiology)

  • Mark S. Hipp

    (Max Planck Institute of Biochemistry
    University of Groningen
    Carl von Ossietzky University Oldenburg)

  • Andreas Bracher

    (Max Planck Institute of Biochemistry)

  • F. Ulrich Hartl

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

Abstract

Spreading of aggregate pathology across brain regions acts as a driver of disease progression in Tau-related neurodegeneration, including Alzheimer’s disease (AD) and frontotemporal dementia. Aggregate seeds released from affected cells are internalized by naïve cells and induce the prion-like templating of soluble Tau into neurotoxic aggregates. Here we show in a cellular model system and in neurons that Clusterin, an abundant extracellular chaperone, strongly enhances Tau aggregate seeding. Upon interaction with Tau aggregates, Clusterin stabilizes highly potent, soluble seed species. Tau/Clusterin complexes enter recipient cells via endocytosis and compromise the endolysosomal compartment, allowing transfer to the cytosol where they propagate aggregation of endogenous Tau. Thus, upregulation of Clusterin, as observed in AD patients, may enhance Tau seeding and possibly accelerate the spreading of Tau pathology.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25060-1
    DOI: 10.1038/s41467-021-25060-1
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    Cited by:

    1. 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.

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