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Cited by 878Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Structure-based classification of tauopathies

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Shi, Yang, Zhang, Wenjuan, Yang, Yang, Murzin, Alexey G., Falcon, Benjamin, Kotecha, Abhay, van Beers, Mike, Tarutani, Airi +19 more·2021·Nature
DOI 10.1038/s41586-021-03911-7PMC PMC7611841

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Abstract

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.

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  • Tau fibrils assume a plethora of different folds with varying β-sheet interactions and core sizes.

    “Tau fibrils assume a plethora of different folds with varying β-sheet interactions and core sizes (11).”

    From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [11]

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Authors
Shi, Y., Zhang, W., Yang, Y., Murzin, A. G., Falcon, B., Kotecha, A., van Beers, M., Tarutani, A., Kametani, F., Garringer, H. J., Vidal, R., Hallinan, G. I., Lashley, T., Saito, Y., Murayama, S., Yoshida, M., Tanaka, H., Kakita, A., Ikeuchi, T., Robinson, A. C., Mann, D. M. A., Kovacs, G. G., Revesz, T., Ghetti, B., Hasegawa, M., Goedert, M., & Scheres, S. H. W.
Affiliations
  • MRC Laboratory of Molecular Biology (GB)
  • Thermo Fisher Scientific (Netherlands) (NL)
  • Tokyo Metropolitan Institute of Medical Science (JP)
  • Indiana University School of Medicine (US)
  • National Hospital for Neurology and Neurosurgery (GB)
  • Tokyo Metropolitan Institute of Gerontology (JP)
  • Molecular Research Center for Children's Mental Development (JP)
  • Aichi Medical University (JP)
  • Brain Research Institute, Niigata University (JP)
  • Salford Royal NHS Foundation Trust (GB)
Corresponding author
  • Goedert, Michel
  • Scheres, Sjors H. W.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-09-29
Volume
598
Issue
7880
Pages
359-363
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-03911-7
PMC
PMC7611841
OpenAlex
W3202815206
Cited by
878
References
6
Citations by year
2026: 134 · 2025: 150 · 2024: 215 · 2023: 206 · 2022: 141 · 2021: 32
FWCI
94.26
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Research Explorer (The University of Manchester) (submittedVersion, other-oa)
Funders
  • Japan Agency for Medical Research and Development (20ek0109392h0003, JP20dm0207072, 20ek0109391h0003, JP21ek0109545, 21dk0207045h0003)
  • Wellcome Trust
  • Diamond Light Source
  • European Federation of Pharmaceutical Industries and Associations (116060)
  • National Institute for Health and Care Research
  • University of Cambridge
  • National Center of Neurology and Psychiatry
  • Rossy Foundation
  • National Institutes of Health (MC_U105184291, RF1-AG071177)
  • School of Medicine, Indiana University
  • Medical Research Council (MC_UP_A025_1013, MC-U105184291)
  • Biotechnology and Biological Sciences Research Council
  • Japan Society for the Promotion of Science (19K16908, 19H01061, 16H06277)
  • National Institute on Aging (P30AG010133, RF1AG071177, P30AG072976)
  • National Institute of Neurological Disorders and Stroke (U01NS110437)
  • Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology,University College London
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
tauopathy, tau protein, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, Pick's disease, chronic traumatic encephalopathy, Alzheimer's disease, globular glial tauopathy, familial British dementia, familial Danish dementia, primary age-related tauopathy, neurodegenerative disease classification
MeSH terms
Aged, Aged, 80 and over, Amino Acid Sequence, Dementia, Denmark, Female, United Kingdom, Humans, Introns, Male, Middle Aged, Models, Molecular, Mutation, Supranuclear Palsy, Progressive, tau Proteins, Protein Folding, Protein Isoforms, Cryoelectron Microscopy, Tauopathies

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