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Structures of filaments from Pick’s disease reveal a novel tau protein fold

Author

Listed:
  • Benjamin Falcon

    (MRC Laboratory of Molecular Biology)

  • Wenjuan Zhang

    (MRC Laboratory of Molecular Biology)

  • Alexey G. Murzin

    (MRC Laboratory of Molecular Biology)

  • Garib Murshudov

    (MRC Laboratory of Molecular Biology)

  • Holly J. Garringer

    (Indiana University School of Medicine)

  • Ruben Vidal

    (Indiana University School of Medicine)

  • R. Anthony Crowther

    (MRC Laboratory of Molecular Biology)

  • Bernardino Ghetti

    (Indiana University School of Medicine)

  • Sjors H. W. Scheres

    (MRC Laboratory of Molecular Biology)

  • Michel Goedert

    (MRC Laboratory of Molecular Biology)

Abstract

The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases1. Tau assemblies seem to spread through specific neural networks in each disease2, with short filaments having the greatest seeding activity3. The abundance of tau inclusions strongly correlates with disease symptoms4. Six tau isoforms are expressed in the normal adult human brain—three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms that lack the second repeat (3R tau)1. In various diseases, tau filaments can be composed of either 3R or 4R tau, or of both. Tau filaments have distinct cellular and neuroanatomical distributions5, with morphological and biochemical differences suggesting that they may be able to adopt disease-specific molecular conformations6,7. Such conformers may give rise to different neuropathological phenotypes8,9, reminiscent of prion strains10. However, the underlying structures are not known. Using electron cryo-microscopy, we recently reported the structures of tau filaments from patients with Alzheimer’s disease, which contain both 3R and 4R tau11. Here we determine the structures of tau filaments from patients with Pick’s disease, a neurodegenerative disorder characterized by frontotemporal dementia. The filaments consist of residues Lys254–Phe378 of 3R tau, which are folded differently from the tau filaments in Alzheimer’s disease, establishing the existence of conformers of assembled tau. The observed tau fold in the filaments of patients with Pick’s disease explains the selective incorporation of 3R tau in Pick bodies, and the differences in phosphorylation relative to the tau filaments of Alzheimer’s disease. Our findings show how tau can adopt distinct folds in the human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers.

Suggested Citation

  • Benjamin Falcon & Wenjuan Zhang & Alexey G. Murzin & Garib Murshudov & Holly J. Garringer & Ruben Vidal & R. Anthony Crowther & Bernardino Ghetti & Sjors H. W. Scheres & Michel Goedert, 2018. "Structures of filaments from Pick’s disease reveal a novel tau protein fold," Nature, Nature, vol. 561(7721), pages 137-140, September.
  • Handle: RePEc:nat:nature:v:561:y:2018:i:7721:d:10.1038_s41586-018-0454-y
    DOI: 10.1038/s41586-018-0454-y
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    Citations

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    Cited by:

    1. Szymon W. Manka & Wenjuan Zhang & Adam Wenborn & Jemma Betts & Susan Joiner & Helen R. Saibil & John Collinge & Jonathan D. F. Wadsworth, 2022. "2.7 Å cryo-EM structure of ex vivo RML prion fibrils," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Binh An Nguyen & Virender Singh & Shumaila Afrin & Anna Yakubovska & Lanie Wang & Yasmin Ahmed & Rose Pedretti & Maria del Carmen Fernandez-Ramirez & Preeti Singh & Maja Pękała & Luis O. Cabrera Herna, 2024. "Structural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    3. Pijush Chakraborty & Gwladys Rivière & Alina Hebestreit & Alain Ibáñez Opakua & Ina M. Vorberg & Loren B. Andreas & Markus Zweckstetter, 2023. "Acetylation discriminates disease-specific tau deposition," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Martin Wilkinson & Rodrigo U. Gallardo & Roberto Maya Martinez & Nicolas Guthertz & Masatomo So & Liam D. Aubrey & Sheena E. Radford & Neil A. Ranson, 2023. "Disease-relevant β2-microglobulin variants share a common amyloid fold," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    5. Gregory E. Merz & Matthew J. Chalkley & Sophia K. Tan & Eric Tse & Joanne Lee & Stanley B. Prusiner & Nick A. Paras & William F. DeGrado & Daniel R. Southworth, 2023. "Stacked binding of a PET ligand to Alzheimer’s tau paired helical filaments," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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