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bioRxiv · 10.1101/2022.06.09.495520

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

Al-Hilaly, Y. K.·Hurt, C.·Rickard, J. E.·Harrington, C. R.·Storey, J. M. D.·Wischik, C. M.·Serpell, L. C.·Siemer, A. B.
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Abstract

Aggregation of the tau protein into fibrillar cross-{beta} aggregates is a hallmark of Alzheimers 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(297-392)+DTT filaments and compare it to existing core structures of tau.

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Al-Hilaly, Y. K., Hurt, C., Rickard, J. E., Harrington, C. R., Storey, J. M. D., Wischik, C. M., Serpell, L. C., Siemer, A. B.. 2022-06-10. Solid-state NMR of paired helical filaments formed by the core tau fragment tau(297-391). https://doi.org/10.1101/2022.06.09.495520

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