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Novel tau filament fold in corticobasal degeneration

Nature volume 580, pages 283–287 (2020)Cite this article

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Abstract

Corticobasal degeneration (CBD) is a neurodegenerative tauopathy—a class of disorders in which the tau protein forms insoluble inclusions in the brain—that is characterized by motor and cognitive disturbances1,2,3. The H1 haplotype of MAPT (the tau gene) is present in cases of CBD at a higher frequency than in controls4,5, and genome-wide association studies have identified additional risk factors6. By histology, astrocytic plaques are diagnostic of CBD7,8; by SDS–PAGE, so too are detergent-insoluble, 37 kDa fragments of tau9. Like progressive supranuclear palsy, globular glial tauopathy and argyrophilic grain disease10, CBD is characterized by abundant filamentous tau inclusions that are made of isoforms with four microtubule-binding repeats11,12,13,14,15. This distinguishes such ‘4R’ tauopathies from Pick’s disease (the filaments of which are made of three-repeat (3R) tau isoforms) and from Alzheimer’s disease and chronic traumatic encephalopathy (CTE) (in which both 3R and 4R isoforms are found in the filaments)16. Here we use cryo-electron microscopy to analyse the structures of tau filaments extracted from the brains of three individuals with CBD. These filaments were identical between cases, but distinct from those seen in Alzheimer’s disease, Pick’s disease and CTE17,18,19. The core of a CBD filament comprises residues lysine 274 to glutamate 380 of tau, spanning the last residue of the R1 repeat, the whole of the R2, R3 and R4 repeats, and 12 amino acids after R4. The core adopts a previously unseen four-layered fold, which encloses a large nonproteinaceous density. This density is surrounded by the side chains of lysine residues 290 and 294 from R2 and lysine 370 from the sequence after R4.

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Fig. 1: Filamentous tau pathology of CBD.
Fig. 2: Cryo-EM maps of CBD type I and type II tau filaments, and atomic model of type II filaments.
Fig. 3: Structures of tau filament cores from human brain.

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Data availability

Cryo-EM maps for CBD case 1 have been deposited in the Electron Microscopy Data Bank (EMDB; https://www.ebi.ac.uk/pdbe/emdb) under accession numbers EMD-10512 for CBD type I and EMD-10514 for CBD type II filaments. The refined atomic models for CBD type I and type II tau filaments have been deposited in the Protein Data Bank (PDB; https://www.rcsb.org/) under accession numbers 6TJO and 6TJX, respectively. Whole-exome and whole-genome sequencing data and repeat-primed polymerase chain reaction C9orf72 hexanucleotide repeat expansion data have been deposited in the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS; https://www.niagads.org), under accession number NG00098. Any other relevant data are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank the patients’ families for donating brain tissues; F. Epperson, R. M. Richardson and U. Kuederli for brain collection and technical support with neuropathology; T. Nakane for help with RELION; G. Murshudov and R. Warshamanage for help with REFMAC; P. Emsley for help with Coot; T. Darling and J. Grimmett for help with high-performance computing; and R. A. Crowther and S. Lovestam for helpful discussions. 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 Medical Research Council (MRC) (grants MC_U105184291 to M.G. and MC_UP_A025_1013 to S.H.W.S.); the European Union (Joint Programme-Neurodegeneration Research REfrAME, to B.F. and M.G., and the EU/EFPIA/Innovative Medicines Initiative [2] Joint Undertaking IMPRiND, project 116060, to M.G.); the Japan Agency for Science and Technology (Crest, grant JPMJCR18H3, to M.H.); the Japan Agency for Medical Research and Development (grants JP18ek0109391 and JP18dm020719 to M.H., and JP19ek0109392 to T.I.); the US National Institutes of Health (grants P30AGO10133 and UO1NS110437 to R.V. and B.G.); and the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine (to R.V. and B.G.). This study was supported by the MRC Laboratory of Molecular Biology (LMB) electron microscopy facility. We acknowledge the Center for Medical Genomics of Indiana University School of Medicine for next-generation DNA sequencing.

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Author notes

  1. These authors jointly supervised this work: Michel Goedert, Sjors H. W. Scheres

Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Cambridge, UK

    Wenjuan Zhang, Alexey G. Murzin, Benjamin Falcon, Yang Shi, Michel Goedert & Sjors H. W. Scheres

  2. Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Airi Tarutani & Masato Hasegawa

  3. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

    Kathy L. Newell, Ruben Vidal, Holly J. Garringer & Bernardino Ghetti

  4. Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan

    Tomoyasu Matsubara & Shigeo Murayama

  5. Department of Molecular Genetics, Brain Research Institute, Niigata University, Niigata, Japan

    Takeshi Ikeuchi

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Contributions

A.T., K.L.N., T.M., S.M., B.G. and M.H. identified patients, performed neuropathology and extracted tau filaments from CBD cases 1 and 2; R.V., H.J.G. and T.I. carried out genetic analyses; W.Z. extracted tau filaments from CBD case 3 and conducted immunolabelling of tau filaments from CBD cases 1–3; W.Z. and B.F. performed cryo-EM; W.Z., Y.S. and S.H.W.S. analysed the cryo-EM data; W.Z. and A.G.M. built the atomic models; A.T. and M.H. carried out seeded aggregation; 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 Jawdat Al-Bassam, Edward Egelman and Markus Zweckstetter for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Immunolabelling of tau filaments extracted from the frontal cortex of CBD cases 1–3.

Representative immunogold negative-stain electron microscopy images of type I and type II tau filaments extracted from the frontal cortex of CBD cases 1–3. Filaments were labelled with antibodies BR133, BR136 and BR134. Antibodies anti-4R, BR135 and TauC4 did not label filaments, indicating that their epitopes lie within the ordered filament cores. Scale bars, 50 nm.

Extended Data Fig. 2 Immunolabelling of tau filaments extracted from additional brain regions of CBD cases 1–3.

Representative immunogold negative-stain electron microscopy images of type I and type II tau filaments extracted from the putamen of CBD cases 1–3, and from the globus pallidus and thalamus of CBD case 3. Similar to filaments extracted from frontal cortex (Extended Data Fig. 1), tau filaments were labelled with antibodies BR133, BR136 and BR134, but not with antibodies anti-4R, BR135 and TauC4. Scale bars, 50 nm.

Extended Data Fig. 3 Assembled TDP-43 in the frontal cortex of CBD cases 1–3.

Immunoblots were obtained using anti-phosphorylated-TDP-43 antibody. Sarkosyl-insoluble material was prepared as described and all the samples were applied to the same gel. The 43 kDa band (*) corresponds to full-length TDP-43 and the 18–26 kDa bands (**) to C-terminal fragments. The experiment was repeated twice with similar results.

Extended Data Fig. 4 Cryo-EM images and characteristics of tau filaments from the frontal cortex of CBD cases 1–3.

a, Representative cryo-EM images. Total numbers of acquired micrographs are shown in Extended Data Table 1. Scale bars, 20 nm. b, Characteristics of tau filaments. Minimum width, maximum width and crossover distance were measured by hand from the cryo-EM images. Graphs show the mean, standard deviation and individual values from n = 25 independent measurements for each filament type and each CBD case. Statistical analyses of these measurements were performed using a one-way ANOVA, followed by Tukey’s multiple comparisons test; n.s., not significant.

Extended Data Fig. 5 Cryo-EM map and model comparisons.

a, b, Fourier shell correlation curves between two independently refined half-maps (black solid curves), of the final model versus the full map (red solid curves), of a model refined in the first half-map versus the first half-map (green solid curves), and of the same model versus the second half-map (blue dashed curves) for CBD type I (a) and type II (b) filaments. c, d, Local resolution estimates for the CBD type I (c) and type II (d) filament reconstructions. e, f, Side views of the 3D reconstructions of CBD type I (e) and type II (f) filaments. g, h, Sharpened, high-resolution cryo-EM maps of CBD type I (g) and type II (h) tau filaments with their corresponding atomic models overlaid.

Extended Data Fig. 6 CBD tau filament fold.

a, Diagram showing the CBD fold. b, Rendered view of the secondary structure elements in the CBD fold, depicted as three successive rungs. c, As for b, but in a view perpendicular to the helical axis, revealing the changes in height within a single molecule. d, Comparison of the protofilament structures of CBD type I (blue) and type II (pink).

Extended Data Fig. 7 Protofilament interface in CBD type II tau filaments.

Packing between residues 343KLDFKDR349 of the two protofilaments. Interprotofilament hydrogen bonds are in yellow; intraprotofilament hydrogen bonds are in green.

Extended Data Fig. 8 Seeded tau aggregation induced by CBD filaments in SH-SY5Y cells.

a, Immunoblotting of sarkosyl-insoluble (Ppt) and sarkosyl-soluble (Sup) fractions extracted from mock-transfected SH-SY5Y cells and from cells transfected with tau seeds from the frontal cortex of CBD cases 1–3. SH-SY5Y cells transiently expressed either haemagglutinin (HA)-tagged 1N4R or HA-tagged 1N3R human tau. Insoluble tau was detected with anti-HA and anti-pS396 antibodies. Total tau was detected with anti-TauC. Blotting with an anti-α-tubulin antibody served as a loading control. b, Quantification of anti-HA-positive bands. The results are expressed as the mean ± s.e.m. (n = 3).

Extended Data Table 1 Cryo-EM data collection, refinement and validation statistics
Full size table

Supplementary information

Supplementary Figure 1

This file contains source images for Western blots. (a), Source images for Western blots shown in Fig. 1g. (b), Source images for Western blots shown in Extended_Data_Fig. 3. (c) Source images for Western blots shown in Extended_Data_Figure 8a.

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Zhang, W., Tarutani, A., Newell, K.L. et al. Novel tau filament fold in corticobasal degeneration. Nature 580, 283–287 (2020). https://doi.org/10.1038/s41586-020-2043-0

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