Frontiers in Neuroscience (Dec 2022)

Solid-state NMR of paired helical filaments formed by the core tau fragment tau(297-391)

  • Youssra K. Al-Hilaly,
  • Youssra K. Al-Hilaly,
  • Connor Hurt,
  • Janet E. Rickard,
  • Charles R. Harrington,
  • Charles R. Harrington,
  • John M. D. Storey,
  • John M. D. Storey,
  • Claude M. Wischik,
  • Claude M. Wischik,
  • Louise C. Serpell,
  • Ansgar B. Siemer

DOI
https://doi.org/10.3389/fnins.2022.988074
Journal volume & issue
Vol. 16

Abstract

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Aggregation of the tau protein into fibrillar cross-β aggregates is a hallmark of Alzheimer’s diseases (AD) and many other neurodegenerative tauopathies. Recently, several core structures of patient-derived tau paired helical filaments (PHFs) have been solved revealing a structural variability that often correlates with a specific tauopathy. To further characterize the dynamics of these fibril cores, to screen for strain-specific small molecules as potential biomarkers and therapeutics, and to develop strain-specific antibodies, recombinant in-vitro models of tau filaments are needed. We recently showed that a 95-residue fragment of tau (from residue 297 to 391), termed dGAE, forms filaments in vitro in the absence of polyanionic co-factors often used for in vitro aggregation of full-length tau. Tau(297-391) was identified as the proteolytic resistant core of tau PHFs and overlaps with the structures characterized by cryo-electron microscopy in ex vivo PHFs, making it a promising model for the study of AD tau filaments in vitro. In the present study, we used solid-state NMR to characterize tau(297-391) filaments and show that such filaments assembled under non-reducing conditions are more dynamic and less ordered than those made in the presence of the reducing agent DTT. We further report the resonance assignment of tau(297-391)+DTT filaments and compare it to existing core structures of tau.

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