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Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules

Nature volume 568, pages 420–423 (2019)Cite this article

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Abstract

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 boxers1,2,3, CTE has since been identified in former participants of other contact sports, ex-military personnel and after physical abuse4,5,6,7. 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 vessels8,9. This, together with the accumulation of tau inclusions in cortical layers II and III, distinguishes CTE from Alzheimer’s disease and other tauopathies10,11. 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 vitro12,13,14,15. Similar to Alzheimer’s disease12,14,16,17,18, 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.

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Fig. 1: Filamentous tau pathology of CTE.
Fig. 2: Cryo-EM structures of CTE type I and type II tau filaments.
Fig. 3: Comparison of the CTE and Alzheimer tau filament folds.

Data availability

Cryo-EM maps for case 1 have been deposited in the Electron Microscopy Data Bank (EMDB) under accession numbers EMD-0527 for CTE type I tau filament and EMD-0528 for CTE type II tau filament. Refined atomic models for case 1 have been deposited in the PDB under accession numbers 6NWP for CTE type I tau filament and 6NWQ for CTE type II tau filament. Whole-exome and whole-genome sequencing, and C9orf72 hexanucleotide repeat expansion results, have been deposited in the National Institute on Ageing Alzheimer’s Disease Data Storage Site (NIAGADS), under accession number NG00077. Any other relevant data are available from the corresponding authors upon reasonable request.

References

  1. Martland, H. S. Punch drunk. J. Am. Med. Assoc. 91, 1103–1107 (1928).

    Article  Google Scholar 

  2. Millspaugh, J. A. Dementia pugilistica. US Nav. Med. Bull. 35, 297–303 (1937).

    Google Scholar 

  3. Corsellis, J. A., Bruton, C. J. & Freeman-Browne, D. The aftermath of boxing. Psychol. Med. 3, 270–303 (1973).

    Article  CAS  Google Scholar 

  4. Omalu, B. I. et al. Chronic traumatic encephalopathy in a National Football League player. Neurosurgery 57, 128–134, discussion 128–134 (2005).

    Article  Google Scholar 

  5. McKee, A. C., Daneshvar, D. H., Alvarez, V. E. & Stein, T. D. The neuropathology of sport. Acta Neuropathol. 127, 29–51 (2014).

    Article  CAS  Google Scholar 

  6. Omalu, B. et al. Chronic traumatic encephalopathy in an Iraqi war veteran with posttraumatic stress disorder who committed suicide. Neurosurg. Focus 31, E3 (2011).

    Article  Google Scholar 

  7. Hof, P. R., Knabe, R., Bovier, P. & Bouras, C. Neuropathological observations in a case of autism presenting with self-injury behavior. Acta Neuropathol. 82, 321–326 (1991).

    Article  CAS  Google Scholar 

  8. Geddes, J. F., Vowles, G. H., Nicoll, J. A. & Révész, T. Neuronal cytoskeletal changes are an early consequence of repetitive head injury. Acta Neuropathol. 98, 171–178 (1999).

    Article  CAS  Google Scholar 

  9. McKee, A. C. et al. The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy. Acta Neuropathol. 131, 75–86 (2016).

    Article  CAS  Google Scholar 

  10. Hof, P. R. et al. Differential distribution of neurofibrillary tangles in the cerebral cortex of dementia pugilistica and Alzheimer’s disease cases. Acta Neuropathol. 85, 23–30 (1992).

    Article  CAS  Google Scholar 

  11. Tokuda, T., Ikeda, S., Yanagisawa, N., Ihara, Y. & Glenner, G. G. Re-examination of ex-boxers’ brains using immunohistochemistry with antibodies to amyloid β-protein and tau protein. Acta Neuropathol. 82, 280–285 (1991).

    Article  CAS  Google Scholar 

  12. Fitzpatrick, A. W. P. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185–190 (2017).

    Article  ADS  CAS  Google Scholar 

  13. Falcon, B. et al. Structures of filaments from Pick’s disease reveal a novel tau protein fold. Nature 561, 137–140 (2018).

    Article  ADS  CAS  Google Scholar 

  14. Falcon, B. et al. Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold. Acta Neuropathol. 136, 699–708 (2018).

    Article  CAS  Google Scholar 

  15. Zhang, W. et al. Heparin-induced tau filaments are polymorphic and differ from those in Alzheimer’s and Pick’s diseases. eLife 8, e43584 (2019).

    Article  Google Scholar 

  16. Schmidt, M. L., Zhukareva, V., Newell, K. L., Lee, V. M. & Trojanowski, J. Q. Tau isoform profile and phosphorylation state in dementia pugilistica recapitulate Alzheimer’s disease. Acta Neuropathol. 101, 518–524 (2001).

    CAS  PubMed  Google Scholar 

  17. Goedert, M., Spillantini, M. G., Cairns, N. J. & Crowther, R. A. Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8, 159–168 (1992).

    Article  CAS  Google Scholar 

  18. Mulot, S. F., Hughes, K., Woodgett, J. R., Anderton, B. H. & Hanger, D. P. PHF-tau from Alzheimer’s brain comprises four species on SDS–PAGE which can be mimicked by in vitro phosphorylation of human brain tau by glycogen synthase kinase-3 β. FEBS Lett. 349, 359–364 (1994).

    Article  CAS  Google Scholar 

  19. Wischik, C. M. et al. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc. Natl Acad. Sci. USA 85, 4884–4888 (1988).

    Article  ADS  CAS  Google Scholar 

  20. He, S. & Scheres, S. H. W. Helical reconstruction in RELION. J. Struct. Biol. 198, 163–176 (2017).

    Article  CAS  Google Scholar 

  21. Carlomagno, Y. et al. An acetylation–phosphorylation switch that regulates tau aggregation propensity and function. J. Biol. Chem. 292, 15277–15286 (2017).

    Article  CAS  Google Scholar 

  22. Goedert, M. et al. Assembly of microtubule-associated protein tau into Alzheimer-like filaments induced by sulphated glycosaminoglycans. Nature 383, 550–553 (1996).

    Article  ADS  CAS  Google Scholar 

  23. Pérez, M., Valpuesta, J. M., Medina, M., Montejo de Garcini, E. & Avila, J. Polymerization of τ into filaments in the presence of heparin: the minimal sequence required for τ–τ interaction. J. Neurochem. 67, 1183–1190 (1996).

    Article  Google Scholar 

  24. Kampers, T., Friedhoff, P., Biernat, J., Mandelkow, E. M. & Mandelkow, E. RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments. FEBS Lett. 399, 344–349 (1996).

    Article  CAS  Google Scholar 

  25. Wilson, D. M. & Binder, L. I. Free fatty acids stimulate the polymerization of tau and amyloid β peptides. In vitro evidence for a common effector of pathogenesis in Alzheimer’s disease. Am. J. Pathol. 150, 2181–2195 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Woerman, A. L. et al. Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells. Proc. Natl Acad. Sci. USA 113, E8187–E8196 (2016).

    Article  CAS  Google Scholar 

  27. Love, S., Bridges, L. R. & Case, C. P. Neurofibrillary tangles in Niemann–Pick disease type C. Brain 118, 119–129 (1995).

    Article  Google Scholar 

  28. Suzuki, K. et al. Neurofibrillary tangles in Niemann–Pick disease type C. Acta Neuropathol. 89, 227–238 (1995).

    Article  CAS  Google Scholar 

  29. Li, B. et al. Cryo-EM of full-length α-synuclein reveals fibril polymorphs with a common structural kernel. Nat. Commun. 9, 3609 (2018).

    Article  ADS  Google Scholar 

  30. Iadanza, M. G. et al. The structure of a β2-microglobulin fibril suggests a molecular basis for its amyloid polymorphism. Nat. Commun. 9, 4517 (2018).

    Article  ADS  Google Scholar 

  31. Li, Y. et al. Amyloid fibril structure of α-synuclein determined by cryo-electron microscopy. Cell Res. 28, 897–903 (2018).

    Article  CAS  Google Scholar 

  32. Guerrero-Ferreira, R. et al. Cryo-EM structure of alpha-synuclein fibrils. eLife 7, e36402 (2018).

    Article  Google Scholar 

  33. Yang, H. & Hu, H. Y. Sequestration of cellular interacting partners by protein aggregates: implication in a loss-of-function pathology. FEBS J. 283, 3705–3717 (2016).

    Article  CAS  Google Scholar 

  34. Donat, C. K., Scott, G., Gentleman, S. M. & Sastre, M. Microglial activation in traumatic brain injury. Front. Aging Neurosci. 9, 208 (2017).

    Article  Google Scholar 

  35. Goldfinger, M. H. et al. The aftermath of boxing revisited: identifying chronic traumatic encephalopathy pathology in the original Corsellis boxer series. Acta Neuropathol. 136, 973–974 (2018).

    Article  Google Scholar 

  36. Pujols, J. et al. Small molecule inhibits α-synuclein aggregation, disrupts amyloid fibrils, and prevents degeneration of dopaminergic neurons. Proc. Natl Acad. Sci. USA 115, 10481–10486 (2018).

    Article  CAS  Google Scholar 

  37. Drachman, D. A. & Newell, K. L. Case 12-1999. A 67-year-old man with three years of dementia. N. Engl. J. Med. 340, 1269–1277 (1999).

    Article  Google Scholar 

  38. McKee, A. C. et al. Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J. Neuropathol. Exp. Neurol. 68, 709–735 (2009).

    Article  Google Scholar 

  39. McKee, A. C. et al. TDP-43 proteinopathy and motor neuron disease in chronic traumatic encephalopathy. J. Neuropathol. Exp. Neurol. 69, 918–929 (2010).

    Article  CAS  Google Scholar 

  40. Kokjohn, T. A. et al. Neurochemical profile of dementia pugilistica. J. Neurotrauma 30, 981–997 (2013).

    Article  Google Scholar 

  41. King, A. et al. Abnormal TDP-43 expression is identified in the neocortex in cases of dementia pugilistica, but is mainly confined to the limbic system when identified in high and moderate stages of Alzheimer’s disease. Neuropathology 30, 408–419 (2010).

    Article  Google Scholar 

  42. Schmidt, S., Kwee, L. C., Allen, K. D. & Oddone, E. Z. Association of ALS with head injury, cigarette smoking and APOE genotypes. J. Neurol. Sci. 291, 22–29 (2010).

    Article  CAS  Google Scholar 

  43. Mackenzie, I. R. et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol. 122, 111–113 (2011).

    Article  Google Scholar 

  44. McKee, A. C. et al. The spectrum of disease in chronic traumatic encephalopathy. Brain 136, 43–64 (2013).

    Article  Google Scholar 

  45. Cherry, J. D. et al. Variation in TMEM106B in chronic traumatic encephalopathy. Acta Neuropathol. Commun. 6, 115 (2018).

    Article  ADS  CAS  Google Scholar 

  46. Hsiung, G. Y., Fok, A., Feldman, H. H., Rademakers, R. & Mackenzie, I. R. rs5848 polymorphism and serum progranulin level. J. Neurol. Sci. 300, 28–32 (2011).

    Article  CAS  Google Scholar 

  47. Zheng, S. Q. et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods 14, 331–332 (2017).

    Article  CAS  Google Scholar 

  48. Zhang, K. Gctf: Real-time CTF determination and correction. J. Struct. Biol. 193, 1–12 (2016).

    Article  ADS  CAS  Google Scholar 

  49. Zivanov, J. et al. New tools for automated high-resolution cryo-EM structure determination in RELION-3. eLife 7, e42166 (2018).

    Article  Google Scholar 

  50. Chen, S. et al. High-resolution noise substitution to measure overfitting and validate resolution in 3D structure determination by single particle electron cryomicroscopy. Ultramicroscopy 135, 24–35 (2013).

    Article  CAS  Google Scholar 

  51. Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D 66, 486–501 (2010).

    Article  CAS  Google Scholar 

  52. Murshudov, G. N., Vagin, A. A. & Dodson, E. J. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr. D 53, 240–255 (1997).

    Article  CAS  Google Scholar 

  53. Chen, V. B. et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D 66, 12–21 (2010).

    Article  CAS  Google Scholar 

  54. Dan, A. et al. Extensive deamidation at asparagine residue 279 accounts for weak immunoreactivity of tau with RD4 antibody in Alzheimer’s disease brain. Acta Neuropathol. Commun. 1, 54 (2013).

    Article  Google Scholar 

  55. Goedert, M., Spillantini, M. G., Jakes, R., Rutherford, D. & Crowther, R. A. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 3, 519–526 (1989).

    Article  CAS  Google Scholar 

  56. Taniguchi-Watanabe, S. et al. Biochemical classification of tauopathies by immunoblot, protein sequence and mass spectrometric analyses of sarkosyl-insoluble and trypsin-resistant tau. Acta Neuropathol. 131, 267–280 (2016).

    Article  CAS  Google Scholar 

  57. Spina, S. et al. The tauopathy associated with mutation +3 in intron 10 of Tau: characterization of the MSTD family. Brain 131, 72–89 (2008).

    Article  Google Scholar 

  58. Yamaguchi, K. et al. Abundant neuritic inclusions and microvacuolar changes in a case of diffuse Lewy body disease with the A53T mutation in the α-synuclein gene. Acta Neuropathol. 110, 298–305 (2005).

    Article  Google Scholar 

  59. Gallyas, F. Silver staining of Alzheimer’s neurofibrillary changes by means of physical development. Acta Morphol. Acad. Sci. Hung. 19, 1–8 (1971).

    CAS  PubMed  Google Scholar 

  60. Braak, H., Braak, E., Ohm, T. & Bohl, J. Silver impregnation of Alzheimer’s neurofibrillary changes counterstained for basophilic material and lipofuscin pigment. Stain Technol. 63, 197–200 (1988).

    Article  CAS  Google Scholar 

  61. Farlow, J. L. et al. Whole-exome sequencing in familial Parkinson disease. JAMA Neurol. 73, 68–75 (2016).

    Article  Google Scholar 

  62. Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).

    Article  Google Scholar 

Download references

Acknowledgements

We thank the patients’ families for donating brain tissue; J. Gonzalez, P. Dooley, F. Epperson, R. M. Richardson, M. Danley and U. Kuederli for brain collection and technical support with neuropathology; M. Hasegawa for antibody TauC4; G. Cannone, C. Savva, Z. Yang and C. Wigger for support with electron microscopy; T. Nakane for help with RELION; G. Murshudov for help with REFMAC; T. Darling and J. Grimmett for help with high-performance computing. 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 (MC_UP_A025_1013 to S.H.W.S. and MC_U105184291 to M.G.), 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 US National Institutes of Health (P30AG010133 and U01NS110437), the Department of Pathology and Laboratory Medicine, Indiana University School of Medicine to B.G. and R.V., and the Department of Pathology and Laboratory Medicine, University of Kansas School of Medicine to K.L.N. Some of the tissue specimens were obtained with support of the Massachusetts Alzheimer’s Disease Research Center (P50 AG005134). This study was supported by the MRC-LMB EM facility. We acknowledge DIAMOND for access to and support of the cryo-EM facilities at the UK electron Bio-Imaging Centre (eBIC), proposal EM17434, funded by the Wellcome Trust, the MRC and the BBSRC, for acquisition of the case 1 cryo-EM dataset; the Midlands Regional Cryo-EM facility at the Leicester Institute of Structural and Chemical Biology (LISCB), major funder MRC, for acquisition of the case 3 cryo-EM dataset; and the Center for Medical Genomics of Indiana University School of Medicine for next-generation sequencing.

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Nature thanks Edward H. Egelman and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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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

    Benjamin Falcon, Jasenko Zivanov, Wenjuan Zhang, Alexey G. Murzin, R. Anthony Crowther, Michel Goedert & Sjors H. W. Scheres

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

    Holly J. Garringer, Ruben Vidal & Bernardino Ghetti

  3. Department of Pathology and Laboratory Medicine, University of Kansas School of Medicine, Kansas City, KS, USA

    Kathy L. Newell

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Contributions

K.L.N. and B.G. identified the patients and performed neuropathology; H.J.G. and R.V. carried out genetic analysis; B.F. extracted tau filaments and conducted immunolabelling; B.F. and W.Z. performed cryo-EM; B.F. and S.H.W.S. analysed the cryo-EM data; J.Z. developed and carried out 3- and 4-fold astigmatism corrections. B.F. and A.G.M. built the atomic models; R.A.C. contributed to the inception of the study; M.G. and S.H.W.S. supervised the project; all authors contributed to writing the manuscript.

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Extended data figures and tables

Extended Data Fig. 1 Further characterization of tau pathologies in CTE cases 1–3.

Coexisting pathologies. a, Staining of tau inclusions in the temporal cortex of CTE cases 1, 2 and 3 using antibodies RD3 (three-repeat tau), anti-4R (four-repeat tau) and AT8 (pS202 and pT205 tau). Scale bar, 50 μm. b, Gallyas–Braak silver staining of tau inclusions in the temporal cortex of CTE cases 2 and 3. Scale bar, 50 μm. c, Staining of tau inclusions in the spinal cord of CTE cases 1 and 2 using antibody AT8. Scale bar, 50 μm. d, Immunoblots of sarkosyl-insoluble tau from the temporal cortices of CTE cases 1, 2 and 3 using antibodies BR133, BR134 and AT8. e, Staining of a TDP-43 inclusion in the spinal cord of CTE case 1. Scale bar, 25 μm. f, Staining of CTE case 2 for poly-GA inclusions in the cerebellum and TDP-43 inclusions in the spinal cord, temporal cortex, hippocampus and amygdala. Top right, double-labelling of tau inclusions (AT8, brown) and TDP-43 inclusions (red) is shown. Scale bars, 25 μm (top), 50 μm (bottom). g, Staining of CTE case 3 for α-synuclein inclusions in the substantia nigra, dorsal motor nucleus (DMN) of the vagus nerve and locus coeruleus. Scale bar, 50 μm. Nuclei were counterstained blue in all images.

Extended Data Fig. 2 Immunolabelling of tau filaments extracted from the brains of CTE cases 1–3.

a, b, Immunoblots and immunolabelling of tau filaments extracted from the temporal cortices of CTE cases 1, 2 and 3. a, Immunoblots of sarkosyl-insoluble tau using antibodies BR136, anti-4R, BR135 and TauC4. b, Representative immuno-EM images of tau filaments labelled with antibodies BR136 and anti-4R. Unlike BR136 and anti-4R, antibodies BR135 and TauC4 did not label the filaments, which indicates that their epitopes lie within the ordered filament cores. Scale bar, 200 nm.

Extended Data Fig. 3 Cryo-EM 2D and 3D classification.

a, Two-dimensional class averages spanning an entire helical crossover of type I and type II tau filaments from CTE cases 1–3. b, Cryo-EM structure of paired helical filaments from the temporal cortex of CTE case 1.

Extended Data Fig. 4 Cryo-EM map and model comparisons.

a, b, Fourier shell correlation curves between two independently refined half-maps (bold black line); between the final cryo-EM reconstruction and refined atomic model (bold red line); between the first half-map and the atomic model refined against the first half-map (brown line); and between the second half-map and the atomic model refined against the first half-map (blue dashed line) for CTE type I (a) and CTE type II (b) filaments. c, d, Local resolution estimates for the CTE type I (c) and CTE type II (d) filament reconstructions. e, f, Views normal to the helical axis of the CTE type I (e) and CTE type II (f) filament reconstructions.

Extended Data Fig. 5 Cryo-EM map of type I tau filaments from CTE case 1.

a–c, Close-up view of the cryo-EM map with the atomic model overlaid, showing densities for oxygens atoms of the peptide groups (a) and ordered solvent molecules (b). c, Side-chain conformations for the alternating positively and negatively charged solvent-exposed side chains of residues 336–343 in successive rungs.

Extended Data Fig. 6 CTE tau filament fold.

a, Schematic of the CTE tau filament fold. b, Rendered view of the secondary structure elements in the CTE fold, depicted as three successive rungs. c, As in b, but in a view perpendicular to the helical axis, revealing the changes in height within a single molecule.

Extended Data Fig. 7 Comparison of CTE type I and CTE type II tau filament folds and protofilament interfaces.

a, The CTE type I protofilament structure is shown in purple and the CTE type II protofilament structure is shown in gold. b, As in a, but showing backbone atoms only. c, d, Packing between residues 322CGSLGNIH329 of the two protofilaments in CTE type I filaments (c) and between residues 331KPGGGQVE338 of the two protofilaments in CTE type II filaments (d).

Extended Data Fig. 8 Measurement and modelling of optical aberrations.

Threefold astigmatism (antisymmetrical; top) and fourfold astigmatism (symmetrical; bottom) measured in per-Fourier-pixel average phase-error plots (left) and represented by our parametric model (right) for CTE type I tau filaments from case 1. The plot shows image frequencies up to 2.9 Å. The outlier ring at 4.7 Å corresponds to the dominant frequency given by a double-repetition of the helix. This ring has been excluded from the parametric fit.

Extended Data Table 1 Cryo-EM data collection, refinement and validation statistics
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Supplementary information

Supplementary Figure 1

This file contains the uncropped western blots from Extended Data Figures 1 and 2.

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Falcon, B., Zivanov, J., Zhang, W. et al. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature 568, 420–423 (2019). https://doi.org/10.1038/s41586-019-1026-5

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