Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer's and Pick's diseases

  1. Wenjuan Zhang
  2. Benjamin Falcon
  3. Alexey G Murzin
  4. Juan Fan
  5. R Anthony Crowther
  6. Michel Goedert  Is a corresponding author
  7. Sjors HW Scheres  Is a corresponding author
  1. MRC Laboratory of Molecular Biology, United Kingdom

Abstract

Assembly of microtubule-associated protein tau into filamentous inclusions underlies a range of neurodegenerative diseases. Tau filaments adopt different conformations in Alzheimer's and Pick's diseases. Here, we used cryo- and immuno- electron microscopy to characterise filaments that were assembled from recombinant full-length human tau with four (2N4R) or three (2N3R) microtubule-binding repeats in the presence of heparin. 2N4R tau assembles into multiple types of filaments, and the structures of three types reveal similar 'kinked hairpin' folds, in which the second and third repeats pack against each other. 2N3R tau filaments are structurally homogeneous, and adopt a dimeric core, where the third repeats of two tau molecules pack in a parallel manner. The heparin-induced tau filaments differ from those of Alzheimer's or Pick's disease, which have larger cores with different repeat compositions. Our results illustrate the structural versatility of amyloid filaments, and raise questions about the relevance of in vitro assembly.

Data availability

EM maps have been submitted to EMDB, under codes 4563, 4564, 4565 and 4566Atomic models have been submitted to PDB under codes 6QJH, 6QJM, 6QJP and 6QJQRaw EM images have been submitted to EMPIAR under codes 10242 and 10243

The following data sets were generated

Article and author information

Author details

  1. Wenjuan Zhang

    Structural Studies, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  2. Benjamin Falcon

    Structural Studies, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  3. Alexey G Murzin

    Structural Studies, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  4. Juan Fan

    Structural Studies, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  5. R Anthony Crowther

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

    Structural Studies, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    For correspondence
    mg@mrc-lmb.cam.ac.uk
    Competing interests
    Michel Goedert, Reviewing editor, eLife.
  7. Sjors HW Scheres

    Structural Studies, 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_U105184291)

  • Michel Goedert

European Union (Joint Programme- Neurodegeneration Research REfrAME)

  • Michel Goedert

Medical Research Council (MC_UP_A025_1013)

  • Sjors HW Scheres

European Union (IMPRIND-116060)

  • 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. Nikolaus Grigorieff, Janelia Research Campus, Howard Hughes Medical Institute, United States

Publication history

  1. Received: November 12, 2018
  2. Accepted: January 31, 2019
  3. Accepted Manuscript published: February 5, 2019 (version 1)
  4. Version of Record published: February 14, 2019 (version 2)

Copyright

© 2019, Zhang 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. Wenjuan Zhang
  2. Benjamin Falcon
  3. Alexey G Murzin
  4. Juan Fan
  5. R Anthony Crowther
  6. Michel Goedert
  7. Sjors HW Scheres
(2019)
Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer's and Pick's diseases
eLife 8:e43584.
https://doi.org/10.7554/eLife.43584

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