Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains

Tamta Arakhamia, Christina E. Lee, Yari Carlomagno, Duc M. Duong, Sean R. Kundinger, Kevin Wang, Dewight Williams, Michael DeTure, Dennis W. Dickson, Casey N. Cook, Nicholas T. Seyfried, Leonard Petrucelli, Anthony W.P. Fitzpatrick

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Tau aggregation into insoluble filaments is the defining pathological hallmark of tauopathies. However, it is not known what controls the formation and templated seeding of strain-specific structures associated with individual tauopathies. Here, we use cryo-electron microscopy (cryo-EM) to determine the structures of tau filaments from corticobasal degeneration (CBD) human brain tissue. Cryo-EM and mass spectrometry of tau filaments from CBD reveal that this conformer is heavily decorated with posttranslational modifications (PTMs), enabling us to map PTMs directly onto the structures. By comparing the structures and PTMs of tau filaments from CBD and Alzheimer's disease, it is found that ubiquitination of tau can mediate inter-protofilament interfaces. We propose a structure-based model in which cross-talk between PTMs influences tau filament structure, contributing to the structural diversity of tauopathy strains. Our approach establishes a framework for further elucidating the relationship between the structures of polymorphic fibrils, including their PTMs, and neurodegenerative disease. Structural and mass spectrometry-based proteomics of tau filaments, including their posttranslational modifications, from corticobasal degeneration and Alzheimer's disease point to how cross-talk between posttranslational modifications influences fibril structure, contributing to the structural diversity of tauopathy strains.

Original languageEnglish (US)
Pages (from-to)633-644.e12
JournalCell
Volume180
Issue number4
DOIs
StatePublished - Feb 20 2020

Keywords

  • Alzheimer's disease
  • acetylation
  • corticobasal degeneration
  • cryo-EM
  • integrated structural biology
  • posttranslational modifications
  • tau strains
  • tauopathy
  • templated seeding
  • ubiquitination

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Arakhamia, T., Lee, C. E., Carlomagno, Y., Duong, D. M., Kundinger, S. R., Wang, K., Williams, D., DeTure, M., Dickson, D. W., Cook, C. N., Seyfried, N. T., Petrucelli, L., & Fitzpatrick, A. W. P. (2020). Posttranslational Modifications Mediate the Structural Diversity of Tauopathy Strains. Cell, 180(4), 633-644.e12. https://doi.org/10.1016/j.cell.2020.01.027