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Oxidative stress conditions result in trapping of PHF-core tau (297-391) intermediates
journal contribution
posted on 2023-06-10, 00:58 authored by Mahmoud MainaMahmoud Maina, Youssra Al-Hilaly, Gunasekhar Burra, Janet E Rickard, Charles R Harrington, Claude M Wischik, Louise SerpellLouise SerpellThe 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, Aß and a-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 ß-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.
History
Publication status
- Published
File Version
- Published version
Journal
CellsISSN
2073-4409Publisher
MDPIExternal DOI
Issue
3Volume
10Page range
703Event location
SwitzerlandDepartment affiliated with
- Biochemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2021-09-16First Compliant Deposit (FCD) Date
2021-09-15Usage metrics
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