Assembly of recombinant tau into filaments identical to those of Alzheimer's disease and chronic traumatic encephalopathy
- MRC Laboratory of Molecular Biology, United Kingdom
- 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.
Article and author information
Author details
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
- Edward H Egelman, University of Virginia, United States
Version history
- Preprint posted: December 17, 2021 (view preprint)
- Received: December 17, 2021
- Accepted: March 3, 2022
- Accepted Manuscript published: March 4, 2022 (version 1)
- 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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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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