Journal
FRONTIERS IN MOLECULAR NEUROSCIENCE
Volume 14, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fnmol.2021.661368
Keywords
Alzheimer's disease; microtubule-associated protein tau; phosphorylation; O-GlcNAc glycosylation; protein aggregation; NMR spectroscopy
Categories
Funding
- Mizutani Foundation for Glycoscience [180122]
- program PHC Procope/DAAD 2015 [33334TK]
- LabEx (Laboratory of Excellence) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer's disease)
- Council of Region Nord
- CNRS
- Pasteur Institute of Lille
- European Community (FEDER)
- French Research Ministry
- University of Lille
- CTRL CPER
- European Regional Development Fund (ERDF)
- Hauts-de-France Regional Council
- Metropole Europeenne de Lille
- TGE RMN THC (FR-3050, France)
- Lille NMR
- RPE Health and Biology core facility
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Phosphorylation of Tau protein plays a critical role in the aggregation process observed in Alzheimer's disease brains. Recent research has highlighted the regulatory role of O-GlcNAcylation in modulating Tau phosphorylation and aggregation. Results showed that O-GlcNAcylation reduces phosphorylation of PHF-1 epitope, which is hyperphosphorylated in AD brains, and impacts the rate of fibrillar assembly in in-vitro assays.
Phosphorylation of the neuronal microtubule-associated Tau protein plays a critical role in the aggregation process leading to the formation of insoluble intraneuronal fibrils within Alzheimer's disease (AD) brains. In recent years, other posttranslational modifications (PTMs) have been highlighted in the regulation of Tau (dys)functions. Among these PTMs, the O-beta-linked N-acetylglucosaminylation (O-GlcNAcylation) modulates Tau phosphorylation and aggregation. We here focus on the role of the PHF-1 phospho-epitope of Tau C-terminal domain that is hyperphosphorylated in AD (at pS396/pS404) and encompasses S400 as the major O-GlcNAc site of Tau while two additional O-GlcNAc sites were found in the extreme C-terminus at S412 and S413. Using high resolution NMR spectroscopy, we showed that the O-GlcNAc glycosylation reduces phosphorylation of PHF-1 epitope by GSK3 beta alone or after priming by CDK2/cyclin A. Furthermore, investigations of the impact of PTMs on local conformation performed in small peptides highlight the role of S404 phosphorylation in inducing helical propensity in the region downstream pS404 that is exacerbated by other phosphorylations of PHF-1 epitope at S396 and S400, or O-GlcNAcylation of S400. Finally, the role of phosphorylation and O-GlcNAcylation of PHF-1 epitope was probed in in-vitro fibrillization assays in which O-GlcNAcylation slows down the rate of fibrillar assembly while GSK3 beta phosphorylation stimulates aggregation counteracting the effect of glycosylation.
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