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Structure-based classification of tauopathies
Shi Y, Zhang W, Yang Y, Murzin AG, Falcon B, Kotecha A, van Beers M, Tarutani A et al.. Nature, 2021-09-29
Topic: Brain proteins, microglia and lab models
The ordered assembly of tau protein into filaments characterizes several neurodegenerative diseases, which are called tauopathies. It was previously reported that, by cryo-electron microscopy, the structures of tau filaments from Alzheimer's disease 1,2 , Pick's disease 3 , chronic traumatic encephalopathy 4 and corticobasal degeneration 5 are distinct. Here we show that the structures of tau filaments from progressive supranuclear palsy (PSP) define a new three-layered fold. Moreover, the structures of tau filaments from globular glial tauopathy are similar to those from PSP. The tau filament fold of argyrophilic grain disease (AGD) differs, instead resembling the four-layered fold of corticobasal degeneration. The AGD fold is also observed in ageing-related tau astrogliopathy. Tau protofilament structures from inherited cases of mutations at positions +3 or +16 in intron 10 of MAPT (the microtubule-associated protein tau gene) are also identical to those from AGD, suggesting that relative overproduction of four-repeat tau can give rise to the AGD fold. Finally, the structures of tau filaments from cases of familial British dementia and familial Danish dementia are the same as those from cases of Alzheimer's disease and primary age-related tauopathy. These findings suggest a hierarchical classification of tauopathies on the basis of their filament folds, which complements clinical diagnosis and neuropathology and also allows the identification of new entities-as we show for a case diagnosed as PSP, but with filament structures that are intermediate between those of globular glial tauopathy and PSP.
Key findings
- Tau protofilament structures from inherited cases of mutations at positions +3 or +16 in intron 10 of MAPT (the microtubule-associated protein tau gene) are also identical to those from AGD, suggesting that relative overproduction of four-repeat tau can give rise to the AGD fold.
- These findings suggest a hierarchical classification of tauopathies on the basis of their filament folds, which complements clinical diagnosis and neuropathology and also allows the identification of new entities-as we show for a case diagnosed as PSP, but with filament structures that are intermediate between those of globular glial tauopathy and PSP.
Why it matters
This laboratory study used cryo-electron microscopy to show that tau filaments have distinct structures in different tauopathies, including Alzheimer's disease, and proposes classifying tauopathies by their filament folds. It is structural biology that may complement clinical diagnosis and neuropathology, not a treatment, cure, or prevention.
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Study details
- Evidence strengthLow
How this study scored 63/100
Published in a top-tier journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature) |
| Journal's citation record | 4 / 4 | Nature: journal h-index 1,841 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2021 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 883 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 126.1 citations a year over 7 year(s) since 2021 |
| Impact for its field and year | 6 / 6 | Cited 79.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 4 / 6 | Cited by 30 other studies in this library |
| Still being cited | 4 / 4 | Cited 497 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Sjors H. W. Scheres: h-index 84 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University College London: institution h-index 2,029 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 16 institution(s) in 6 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 34588692) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 63 / 100 | — |
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Read the original
- DOI: 10.1038/s41586-021-03911-7
- PubMed: 34588692
- Original source →
- Free full text: bioRxiv (Cold Spring Harbor Laboratory) →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Shi, Y., Zhang, W., Yang, Y., Murzin, A. G., Falcon, B., Kotecha, A., et al. (2021). Structure-based classification of tauopathies. Nature. https://doi.org/10.1038/s41586-021-03911-7
Vancouver
Shi Y, Zhang W, Yang Y, Murzin AG, Falcon B, Kotecha A, et al. Structure-based classification of tauopathies. Nature. 2021. doi:10.1038/s41586-021-03911-7. PMID: 34588692.
BibTeX
@article{shi2021-34588692,
author = {Shi, Y. and Zhang, W. and Yang, Y. and Murzin, A. G. and Falcon, B. and Kotecha, A. and van Beers, M. and Tarutani, A. and others},
title = {{Structure-based classification of tauopathies}},
journal = {Nature},
year = {2021},
doi = {10.1038/s41586-021-03911-7},
pmid = {34588692},
url = {https://doi.org/10.1038/s41586-021-03911-7}
}
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