Oxidative Stress Conditions Result in Trapping of PHF-Core Tau (297–391) Intermediates

Mahmoud B. Maina, Youssra K. Al-Hilaly, Gunasekhar Burra, Janet E. Rickard, Charles R. Harrington, Claude M. Wischik, Louise C. Serpell* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The self-assembly of tau into paired helical filaments (PHFs) in neurofibrillary tangles (NFTs) is a significant event in Alzheimer’s disease (AD) pathogenesis. Numerous post-translational modifications enhance or inhibit tau assembly into NFTs. Oxidative stress, which accompanies AD, induces multiple post-translational modifications in proteins, including the formation of dityrosine (DiY) cross-links. Previous studies have revealed that metal-catalysed oxidation (MCO) using Cu2+ and H2O2 leads to the formation of DiY cross-links in two misfolding proteins, Aβ and α-synuclein, associated with AD and Parkinson’s disease respectively. The effect of MCO on tau remains unknown. Here, we examined the effect of MCO and ultra-violet oxidation to study the influence of DiY cross-linking on the self-assembly of the PHF-core tau fragment. We report that DiY cross-linking facilitates tau assembly into tau oligomers that fail to bind thioflavin S, lack β-sheet structure and prevents their elongation into filaments. At a higher concentration, Cu2+ (without H2O2) also facilitates the formation of these tau oligomers. The DiY cross-linked tau oligomers do not cause cell death. Our findings suggest that DiY cross-linking of pre-assembled tau promotes the formation of soluble tau oligomers that show no acute impact on cell viability.
Original languageEnglish
Article number703
Number of pages17
JournalCells
Volume10
Issue number3
DOIs
Publication statusPublished - 22 Mar 2021

Keywords

  • Alzheimer’s disease
  • tau
  • dityrosine
  • paired helical filament
  • Oxidative Stress

Fingerprint Dive into the research topics of 'Oxidative Stress Conditions Result in Trapping of PHF-Core Tau (297–391) Intermediates'. Together they form a unique fingerprint.

Cite this