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Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules
Falcon B, Zivanov J, Zhang W, Murzin AG, Garringer HJ, Vidal R, Crowther RA, Newell KL et al.. Nature, 2019-03-20
Topic: Brain proteins, microglia and lab models
Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves. First described as punch-drunk syndrome and dementia pugilistica in retired boxers 1-3 , CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse 4-7 . No disease-modifying therapies currently exist, and diagnosis requires an autopsy. CTE is defined by an abundance of hyperphosphorylated tau protein in neurons, astrocytes and cell processes around blood vessels 8,9 . This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer's disease and other tauopathies 10,11 . However, the morphologies of tau filaments in CTE and the mechanisms by which brain trauma can lead to their formation are unknown. Here we determine the structures of tau filaments from the brains of three individuals with CTE at resolutions down to 2.3 Å, using cryo-electron microscopy. We show that filament structures are identical in the three cases but are distinct from those of Alzheimer's and Pick's diseases, and from those formed in vitro 12-15 . Similar to Alzheimer's disease 12,14,16-18 , all six brain tau isoforms assemble into filaments in CTE, and residues K274-R379 of three-repeat tau and S305-R379 of four-repeat tau form the ordered core of two identical C-shaped protofilaments. However, a different conformation of the β-helix region creates a hydrophobic cavity that is absent in tau filaments from the brains of patients with Alzheimer's disease. This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE. Moreover, filaments in CTE have distinct protofilament interfaces to those of Alzheimer's disease. Our structures provide a unifying neuropathological criterion for CTE, and support the hypothesis that the formation and propagation of distinct conformers of assembled tau underlie different neurodegenerative diseases.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Falcon, B., Zivanov, J., Zhang, W., Murzin, A. G., Garringer, H. J., Vidal, R., et al. (2019). Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature. https://doi.org/10.1038/s41586-019-1026-5
Vancouver
Falcon B, Zivanov J, Zhang W, Murzin AG, Garringer HJ, Vidal R, et al. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature. 2019. doi:10.1038/s41586-019-1026-5. PMID: 30894745.
BibTeX
@article{falcon2019-30894745,
author = {Falcon, B. and Zivanov, J. and Zhang, W. and Murzin, A. G. and Garringer, H. J. and Vidal, R. and Crowther, R. A. and Newell, K. L. and others},
title = {{Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules}},
journal = {Nature},
year = {2019},
doi = {10.1038/s41586-019-1026-5},
pmid = {30894745},
url = {https://doi.org/10.1038/s41586-019-1026-5}
}
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Key findings
- Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that is associated with repetitive head impacts or exposure to blast waves.
- This cavity encloses an additional density that is not connected to tau, which suggests that the incorporation of cofactors may have a role in tau aggregation in CTE.
Why it matters
This laboratory study used cryo-electron microscopy to determine the structure of tau filaments from the brains of three people with chronic traumatic encephalopathy, finding they differ from those in Alzheimer's disease. It describes filament structure and notes that no disease-modifying therapies currently exist, so it reports no treatment, cure or prevention.
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Study details
- Evidence strengthLow
How this study scored 59/100
Published in a top-tier journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / 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 | 2 / 5 | 2019 — within 10 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) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 6 / 7 | Cited 722 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 80.2 citations a year over 9 year(s) since 2019 |
| Impact for its field and year | 6 / 6 | Cited 57.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 17 other studies in this library |
| Still being cited | 4 / 4 | Cited 213 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 | 1 / 3 | MRC Laboratory of Molecular Biology: institution h-index 816 (OpenAlex) |
| Multicenter collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 30894745) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 59 / 100 | — |
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