Oxidative stress conditions result in trapping of PHF-core tau (297-391) intermediates

Maina, Mahmoud B, Al-Hilaly, Youssra K, Burra, Gunasekhar, Rickard, Janet E, Harrington, Charles R, Wischik, Claude M and Serpell, Louise C (2021) Oxidative stress conditions result in trapping of PHF-core tau (297-391) intermediates. Cells, 10 (3). p. 703. ISSN 2073-4409

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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.

Item Type: Article
Keywords: Alzheimer’s disease, dityrosine, oxidative stress, paired helical filaments, tau
Schools and Departments: School of Life Sciences > Biochemistry
School of Life Sciences > Neuroscience
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 16 Sep 2021 13:42
Last Modified: 16 Sep 2021 13:45
URI: http://sro.sussex.ac.uk/id/eprint/101710

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