Assembly of recombinant tau into filaments identical to those of Alzheimer's disease and chronic traumatic encephalopathy

  1. Sofia Lövestam
  2. Fujiet Adrian Koh
  3. Bart van Knippenberg
  4. Abhay Kotecha
  5. Alexey G Murzin
  6. Michel Goedert  Is a corresponding author
  7. Sjors HW Scheres  Is a corresponding author
  1. MRC Laboratory of Molecular Biology, United Kingdom
  2. Thermo Fisher Scientific, Netherlands

Abstract

Abundant filamentous inclusions of tau are characteristic of more than 20 neurodegenerative diseases that are collectively termed tauopathies. Electron cryo-microscopy (cryo-EM) structures of tau amyloid filaments from human brain revealed that distinct tau folds characterise many different diseases. A lack of laboratory-based model systems to generate these structures has hampered efforts to uncover the molecular mechanisms that underlie tauopathies. Here, we report in vitro assembly conditions with recombinant tau that replicate the structures of filaments from both Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE), as determined by cryo-EM. Our results suggest that post-translational modifications of tau modulate filament assembly, and that previously observed additional densities in AD and CTE filaments may arise from the presence of inorganic salts, like phosphates and sodium chloride. In vitro assembly of tau into disease-relevant filaments will facilitate studies to determine their roles in different diseases, as well as the development of compounds that specifically bind to these structures or prevent their formation.

Data availability

There are no restrictions on data and materials availability. Cryo-EM maps and atomic models have been deposited at the EMDB and the PDB, respectively (see Supplementary Tables 1-25 for their accession codes).In addition, the raw cryo-EM data, together with the relevant intermediate steps of their processing have been deposited at EMPIAR for three data sets: EMPIAR-10940 for data set 11; EMPIAR-10943 for data set 10; EMPIAR-10944 for data set 15.

The following data sets were generated

Article and author information

Author details

  1. Sofia Lövestam

    MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  2. Fujiet Adrian Koh

    Thermo Fisher Scientific, Eindhoven, Netherlands
    Competing interests
    Fujiet Adrian Koh, is affiliated with Thermo Fisher Scientific. The author has no financial interests to declare..
  3. Bart van Knippenberg

    Thermo Fisher Scientific, Eindhoven, Netherlands
    Competing interests
    Bart van Knippenberg, is affiliated with Thermo Fisher Scientific. The author has no financial interests to declare..
  4. Abhay Kotecha

    Thermo Fisher Scientific, Eindhoven, Netherlands
    Competing interests
    Abhay Kotecha, is affiliated with Thermo Fisher Scientific. The author has no financial interests to declare..
  5. Alexey G Murzin

    MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  6. Michel Goedert

    MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    For correspondence
    mg@mrc-lmb.cam.ac.uk
    Competing interests
    No competing interests declared.
  7. Sjors HW Scheres

    MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    For correspondence
    scheres@mrc-lmb.cam.ac.uk
    Competing interests
    Sjors HW Scheres, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0462-6540

Funding

Medical Research Council (MC_UP_A025_1013)

  • Sjors HW Scheres

Medical Research Council (MC-U105184291)

  • Michel Goedert

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Edward H Egelman, University of Virginia, United States

Version history

  1. Preprint posted: December 17, 2021 (view preprint)
  2. Received: December 17, 2021
  3. Accepted: March 3, 2022
  4. Accepted Manuscript published: March 4, 2022 (version 1)
  5. Version of Record published: April 5, 2022 (version 2)

Copyright

© 2022, Lövestam et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Sofia Lövestam
  2. Fujiet Adrian Koh
  3. Bart van Knippenberg
  4. Abhay Kotecha
  5. Alexey G Murzin
  6. Michel Goedert
  7. Sjors HW Scheres
(2022)
Assembly of recombinant tau into filaments identical to those of Alzheimer's disease and chronic traumatic encephalopathy
eLife 11:e76494.
https://doi.org/10.7554/eLife.76494

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https://doi.org/10.7554/eLife.76494

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