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Structure-based classification of tauopathies


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 disease1,2, Pick’s disease3, chronic traumatic encephalopathy4 and corticobasal degeneration5 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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Fig. 1: Three-layered 4R tau filament structures.
Fig. 2: Four-layered 4R tau filament structures.
Fig. 3: Structure-based classification of tauopathies.

Data availability

Cryo-EM maps have been deposited in the Electron Microscopy Data Bank (EMDB) under accession numbers EMD-13218 for PSP, EMD-13219 for GGT-I, EMD-13220 for GGT-II, EMD-13221 for GGT-III, EMD-13223 for GPT type 1a, EMD-13224 for GPT type 1b, EMD-13225 for GPT type 2, EMD-13226 for AGD type 1 and EMD-13227 for AGD type 2. Corresponding refined atomic models have been deposited in the Protein Data Bank (PDB) under accession numbers 7P65 for PSP, 7P66 for GGT type 1, 7P67 for GGT type 2, 7P68 for GGT type 3, 7P6A for GPT type 1a, 7P6B for GPT type 1b, 7P6C for GPT type 2, 7P6D for AGD type 1 and 7P6E for AGD type 2. Cryo-EM datasets have been deposited in the Electron Microscopy Public Image Archive (EMPIAR) under accession numbers 10765 for PSP-RS case 1, 10766 for the GGT-I case, 10767 for PSP-F case 2, 10768 for AGD case 1, and 10769 for the +16 case. Any other relevant data are available from the corresponding authors upon request.


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We thank the families of the patients for donating brain tissues; U. Kuederli, M. Jacobsen, F. Epperson and R. M. Richardson for human brain collection and technical support; E. Gelpi for preparing brain samples from the ARTAG case; E. de Jong, B. van Knippenberg, L. Yu and E. Ioannou for support with the Krios G4 microscope; T. Darling and J. Grimmett for help with high-performance computing; and S. Lövestam, T. Nakane, R. A. Crowther, F. Clavaguera, K. Del Tredici, H. Braak, Z. Ahmed and M. G. Spillantini for helpful discussions. We acknowledge Diamond Light Source for access to and support with the cryo-EM facilities at the UK’s national Electron Bio-imaging Centre (eBIC) (under proposals BI23268-49 and BI23268-19), funded by the Wellcome Trust, Medical Research Council (MRC) and Biotechnology and Biological Sciences Research Council (BBSRC). This study was supported by the MRC Laboratory of Molecular Biology Electron Microscopy facility. W.Z. was supported by a foundation that prefers to remain anonymous. M.G. is an Honorary Professor in the Department of Clinical Neurosciences of the University of Cambridge. This work was supported by the UK MRC (MC_U105184291 to M.G. and MC_UP_A025_1013 to S.H.W.S.); the EU/EFPIA/Innovative Medicines Initiative (2) Joint Undertaking IMPRiND project 116060 to M.G.; the Japan Agency for Science and Technology (CREST) (JPMJCR18H3 to M.H.); the Japan Agency for Medical Research and Development (AMED) (JP20dm0207072 to M.H. and JP21dk0207045 and JP21ek0109545 to T.I.); JP20ek0109392, JP20ek0109391 and an Intramural Research Grant (number 30–8) for Neurological and Psychiatric Disorders of NCNP to M.Y.; the US National Institutes of Health (P30-AG010133, UO1-NS110437 and RF1-AG071177) to R.V., B.G. R.V. and B.G. were supported by the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine. G.G.K. was supported by the Safra Foundation and the Rossy Foundation. T.R. is supported by the National Institute for Health Research Queen Square Biomedical Research Unit in Dementia. T.L. holds an Alzheimer’s Research UK Senior Fellowship. The Queen Square Brain Bank is supported by the Reta Lila Weston Institute for Neurological Studies.

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T.L., Y. Saito, S.M., M.Y., H.T., A.K., A.C.R., D.M.A.M., G.G.K., T.R. and B.G. identified patients and performed neuropathology. R.V., H.J.G., G.I.H. and T.I. performed genetic analysis. A.T., F.K., M.H., Y. Shi, W.Z., Y.Y. and B.F. prepared tau filament samples and performed biochemical analyses. Y. Shi, W.Z., Y.Y, B.F., A.K. and M.v.B. performed cryo-EM data acquisition. Y. Shi, W.Z., Y.Y., A.G.M. and S.H.W.S. performed cryo-EM structure determination. M.G. and S.H.W.S. supervised the project. All authors contributed to writing the manuscript.

Corresponding authors

Correspondence to Michel Goedert or Sjors H. W. Scheres.

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The authors declare no competing interests.

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Peer review information Nature thanks Gil Rabinovici, Henning Stahlberg and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data figures and tables

Extended Data Fig. 1 Tau immunohistochemistry.

Representative tau staining of the brain regions used for cryo-EM structure determination (see Methods), using antibody AT8 (pS202/pT205 tau). Scale bars are 50 μm, except for GGT Type I, FBD and FDD, for which they are 25 μm. For PSP-RS case 3, both the thalamus (Tha) and the entorhinal cortex (EC) are shown. Similar results were obtained using a minimum of six additional stained sections for each case.

Extended Data Fig. 2 Cryo-EM reconstructions.

a, Cryo-EM maps for tau filaments from six cases of PSP. For each map, a sum of the reconstructed density for several XY-slices is shown, corresponding to approximately 4.7 Å. The disease cases are referenced at the bottom of each image, the filament types at the top left and the percentages of a given filament type among the tau filaments in the dataset at the top right. Scale bar 5 nm. The same scale applies to all panels, except dg. bh, As in a, but a case of GGT-I and a case of GGT-II (b); a case diagnosed as PSP-F, but that contains filaments with the PGT fold (c); two cases of AGD (d); scale bar 5nm, the same scale applies to panels dg; entorhinal cortex of PSP-RS case 3 (e); a case of ARTAG (f); three cases with mutations +16 or +3 in intron 10 of MAPT (g); a case of FBD and a case of FDD (h). Panels df contain blank squares to indicate the absence of AGD type I filaments in some cases. The inset with dashed lines shows 2D class average images of tau filaments from a case of GGT-III without apparent twist.

Extended Data Fig. 3 Cryo-EM resolution estimates.

Fourier Shell Correlation (FSC) curves for cryo-EM maps and atomic structures of PSP filaments (from PSP-RS case 1); GGT filament types 1-3 (from GGT-I); GPT filament types 1a, 1b and 2 (from PSP-F case 2); and AGD filament types 1 and 2 (from AGD case 1 and the +16 case, repectively). FSC curves are shown for two independently refined cryo-EM half-maps (black); for the final refined atomic model against the final cryo-EM map (red); for the atomic model refined in the first half-map against that half-map (blue); and for the refined atomic model in the first half-map against the other half-map (yellow).

Extended Data Fig. 4 Schematics of tau filament folds.

ad, Schematics of the tau folds for PSP (a), GGT (b), GPT (c) and AGD (d). Negatively charged residues are shown in red, positively charged residues in blue, polar residues in green, apolar residues in white, sulfur-containing residues in yellow, prolines in purple and glycines in pink. Thick connecting lines with arrow heads are used to indicate β-strands; additional densities are shown in grey.

Extended Data Fig. 5 Tau pathology in limbic-predominant neuronal inclusion body 4R tauopathy (LNT, PSP-F case 2).

a, Low power view of hippocampus stained with antibody AT8 (pS202/pT205tau). b, Low power view of frontal cortex stained with AT8. c, Higher power view of hippocampus stained with AT8. d, AT8-positive globular astrocyte in hippocampus. e, AT8-positive neurons in hippocampus. f, Hippocampus stained with antibody RD4 (specific for 4R tau). g, Gallyas-Braak silver-positive neurons and glial cells in hippocampus. h, Hippocampus stained with antibody RD3 (specific for 3R tau). i, Higher-power view of frontal cortex stained with AT8. j, AT8-positive globular astrocyte in frontal cortex. k, AT8-positive neurons in frontal cortex. l, Frontal cortex stained with RD4. m, Gallyas-Braak silver-positive neurons and glial cells in frontal cortex. n, Frontal cortex stained with RD3. Representative images are shown. Similar results were obtained using a minimum of six additional stained sections for each panel. Scale bars: 400 μm in (a); 200 μm in (b), 50 μm in (c, f, g, h, i, l, m, n); 10 μm in (d, e, j, k).

Extended Data Fig. 6 Structural comparisons.

a, Comparison of two different main-chain conformations for GPT type 1 filaments (type 1a in purple; type 1b in green) and the main-chain conformation of GPT type 2 filaments (red). b, Comparison of the PSP (orange), GGT (blue) and GPT (purple) folds. c, Comparison of the inter-protofilament interfaces of GGT type 3 and GPT type 2 filaments. d, Comparison of the AGD type 1 (light blue), AGD type 2 (pink) and CBD (grey) folds.

Extended Data Fig. 7 Argyrophilic grains in the entorhinal cortex.

Representative tau staining with antibodies RD4 (4R tau), RD3 (3R tau), AT8 (pS202/pT205 tau), as well as Gallyas-Braak silver, of the entorhinal cortex from cases 1 and 2 with mutation +3 in intron 10 of MAPT and from case 3 of PSP-RS. Similar results were obtained using a minimum of six additional stained sections for each case. Scale bar, 50 μm.

Extended Data Fig. 8 Immunoblot analysis of 4R tauopathies.

Hyperphosphorylated full-length tau (64 and 68 kDa) and C-terminal fragments (33 kDa and 37 kDa) were detected in sarkosyl-insoluble fractions from the brain regions used for cryo-EM by anti-tau antibody T46. A prominent 33-kDa band was characteristic of PSP and GGT; strong 37-kDa bands were in evidence in AGD, ARTAG, cases with intron 10 mutations in MAPT (+3 and +16) and in CBD. PSP-RS case 3 had a strong 33-kDa band in thalamus (Tha) and strong 37-kDa bands in entorhinal cortex (EC), consistent with AGD co-pathology. Similar results were obtained in three independent experiments. The original, uncropped image is available in Supplementary Fig. 1.

Extended Data Table 1 Cryo-EM data collection, refinement and validation statistics
Extended Data Table 2 Cases of tauopathy used for cryo-EM

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Shi, Y., Zhang, W., Yang, Y. et al. Structure-based classification of tauopathies. Nature 598, 359–363 (2021).

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