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Peer-reviewedCC BYActa Neuropathologica

The Pick fold in tau filaments from human MAPT mutants

  • Chao Qi1,2
  • Sofia Lövestam2
  • Jenny Shi2
  • Alexey G. Murzin2
  • Sew‐Yeu Peak‐Chew2
  • Thomas T. Warner3,4
  • Harro Seelaar5
  • Patrick W. Cullinane3,4
  • Zane Jaunmuktane3,4
  • John Cornelis Van Swieten5
  • Sjors H. W. Scheres6
  • Michel Goedert7
7 affiliations
  1. 1Department of Biophysics, School of Basic Medical Sciences and Key Laboratory for Neuroscience, Ministry of Education/National Health Commission of the People's Republic of China, Peking University, Beijing, China
  2. 2Medical Research Council Laboratory of Molecular Biology, Cambridge, UK
  3. 3Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College, London, UK
  4. 4Queen Square Brain Bank for Neurological Disorders, Institute of Neurology, University College, London, UK
  5. 5Department of Neurology, Erasmus University, Rotterdam, The Netherlands
  6. 6Medical Research Council Laboratory of Molecular Biology, Cambridge, UK. [email protected]
  7. 7Medical Research Council Laboratory of Molecular Biology, Cambridge, UK. [email protected]
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Abstract

Mutations in MAPT, the tau gene, give rise to forms of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17 T), with abundant filamentous tau inclusions in brain cells. Some mutations that encode missense and deletion variants can give rise to a clinical picture of Pick's disease and filaments made of three-repeat tau in nerve cells. Here we report the electron cryo-microscopy (cryo-EM) structures of tau filaments from the brains of individuals with MAPT mutations D252V, G272V, S320F and ΔG389-I392. The two-layered Pick fold was present in the brains of individuals with mutations D252V and ΔG389-I392 who had also abundant tau inclusions in glial cells. By contrast, mutations G272V and S320F gave rise to a more open variant of the Pick fold, with residues 272-341 rotated by 20-25° with respect to the rest of the structure. These findings show that missense mutations within the filament core can modify the Pick fold, generating closely related structural variants. In addition, we were able to reconstitute the Pick fold and some of its variants using seeded assembly with recombinant 0N3R tau carrying 12 serine or threonine to aspartate substitutions (PAD12) and missense mutations D252V, G272V and S320F. This work provides a foundation for the development of structure-based diagnostic and therapeutic approaches.

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Cite

BibTeXRIS
BibTeX
@article{qi2026pick,
  title = {{The Pick fold in tau filaments from human MAPT mutants}},
  author = {Chao Qi and Sofia Lövestam and Jenny Shi and Alexey G. Murzin and Sew‐Yeu Peak‐Chew and Thomas T. Warner and Harro Seelaar and Patrick W. Cullinane and Zane Jaunmuktane and John Cornelis Van Swieten and Sjors H. W. Scheres and Michel Goedert},
  journal = {Acta Neuropathologica},
  year = {2026},
  month = jul,
  doi = {10.1007/s00401-026-03049-8},
  url = {https://doi.org/10.1007/s00401-026-03049-8},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - The Pick fold in tau filaments from human MAPT mutants
AU  - Chao Qi
AU  - Sofia Lövestam
AU  - Jenny Shi
AU  - Alexey G. Murzin
AU  - Sew‐Yeu Peak‐Chew
AU  - Thomas T. Warner
AU  - Harro Seelaar
AU  - Patrick W. Cullinane
AU  - Zane Jaunmuktane
AU  - John Cornelis Van Swieten
AU  - Sjors H. W. Scheres
AU  - Michel Goedert
PY  - 2026
DA  - 2026/07/08
JO  - Acta Neuropathologica
DO  - 10.1007/s00401-026-03049-8
UR  - https://doi.org/10.1007/s00401-026-03049-8
AB  - Mutations in MAPT, the tau gene, give rise to forms of frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17 T), with abundant filamentous tau inclusions in brain cells. Some mutations that encode missense and deletion variants can give rise to a clinical picture of Pick's disease and filaments made of three-repeat tau in nerve cells. Here we report the electron cryo-microscopy (cryo-EM) structures of tau filaments from the brains of individuals with MAPT mutations D252V, G272V, S320F and ΔG389-I392. The two-layered Pick fold was present in the brains of individuals with mutations D252V and ΔG389-I392 who had also abundant tau inclusions in glial cells. By contrast, mutations G272V and S320F gave rise to a more open variant of the Pick fold, with residues 272-341 rotated by 20-25° with respect to the rest of the structure. These findings show that missense mutations within the filament core can modify the Pick fold, generating closely related structural variants. In addition, we were able to reconstitute the Pick fold and some of its variants using seeded assembly with recombinant 0N3R tau carrying 12 serine or threonine to aspartate substitutions (PAD12) and missense mutations D252V, G272V and S320F. This work provides a foundation for the development of structure-based diagnostic and therapeutic approaches.
SN  - 0001-6322
SN  - 1432-0533
ER  -