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

Publication 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.

Metrics

  • 7,742
    Page views
  • 1,492
    Downloads
  • 35
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Biochemistry and Chemical Biology
    2. Neuroscience
    Hilary Scott, Boris Novikov ... Vladislav Panin
    Research Article

    Modification by sialylated glycans can affect protein functions, underlying mechanisms that control animal development and physiology. Sialylation relies on a dedicated pathway involving evolutionarily conserved enzymes, including CMP-sialic acid synthetase (CSAS) and sialyltransferase (SiaT) that mediate the activation of sialic acid and its transfer onto glycan termini, respectively. In Drosophila, CSAS and DSiaT genes function in the nervous system, affecting neural transmission and excitability. We found that these genes function in different cells: the function of CSAS is restricted to glia, while DSiaT functions in neurons. This partition of the sialylation pathway allows for regulation of neural functions via a glia-mediated control of neural sialylation. The sialylation genes were shown to be required for tolerance to heat and oxidative stress and for maintenance of the normal level of voltage-gated sodium channels. Our results uncovered a unique bipartite sialylation pathway that mediates glia-neuron coupling and regulates neural excitability and stress tolerance.

    1. Neuroscience
    Alana Jaskir, Michael J Frank
    Research Article

    The basal ganglia (BG) contribute to reinforcement learning (RL) and decision making, but unlike artificial RL agents, it relies on complex circuitry and dynamic dopamine modulaton of opponent striatal pathways to do so. We develop the OpAL* model to assess the normative advantages of this circuitry. In OpAL*, learning induces opponent pathways to differentially emphasize the history of positive or negative outcomes for each action. Dynamic DA modulation then amplifies the pathway most tuned for the task environment. This efficient coding mechanism avoids a vexing explore-exploit tradeoff that plagues traditional RL models in sparse reward environments. OpAL* exhibits robust advantages over alternative models, particularly in environments with sparse reward and large action spaces. These advantages depend on opponent and nonlinear Hebbian plasticity mechanisms previously thought to be pathological. Finally, OpAL* captures risky choice patterns arising from DA and environmental manipulations across species, suggesting that they result from a normative biological mechanism.