Differential effects of putative N-glycosylation sites in human Tau on Alzheimer’s disease-related neurodegeneration
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Amyloid assemblies of Tau are associated with Alzheimer's disease (AD). In AD Tau undergoes several abnormal post-translational modifications, including hyperphosphorylation and glycosylation, which impact disease progression. N-glycosylated Tau was reported to be found in AD brain tissues but not in healthy counterparts. This is surprising since Tau is a cytosolic protein whereas N-glycosylation occurs in the ER-Golgi. Previous in vitro studies indicated that N-glycosylation of Tau facilitated its phosphorylation and contributed to maintenance of its Paired Helical Filament structure. However, the specific Tau residue(s) that undergo N-glycosylation and their effect on Tau-engendered pathology are unknown. High-performance liquid chromatography and mass spectrometry (LC-MS) analysis indicated that both N359 and N410 were N-glycosylated in wild-type (WT) human Tau (hTau) expressed in human SH-SY5Y cells. Asparagine to glutamine mutants, which cannot undergo N-glycosylation, at each of three putative N-glycosylation sites in hTau (N167Q, N359Q, and N410Q) were generated and expressed in SH-SY5Y cells and in transgenic Drosophila. The mutants modulated the levels of hTau phosphorylation in a site-dependent manner in both cell and fly models. Additionally, N359Q ameliorated, whereas N410Q exacerbated various aspects of hTau-engendered neurodegeneration in transgenic flies.
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Tau undergoes both N-linked glycosylation and O-linked N-acetylglucosaminylation (O-GlcNAcylation), which have been proposed to affect tau phosphorylation and aggregation.
“In addition, tau also undergoes both N-linked glycosylation (N-glycosylation) [171] and O-linked N-acetylglucosaminylation (O-GlcNAcylation) [172], which have been proposed to affect tau phosphorylation and aggregation [173].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [171]
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Glycans to improve efficacy and solubility of protein aggregation inhibitors
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- Authors
- Losev, Y., Frenkel-Pinter, M., Abu-Hussien, M., Viswanathan, G. K., Elyashiv-Revivo, D., Geries, R., Khalaila, I., Gazit, E., & Segal, D.
- Affiliations
- Tel Aviv University (IL)
- Ben-Gurion University of the Negev (IL)
- Corresponding author
- Segal, Daniel
- Venue
- Cellular and Molecular Life Sciences
- Published
- 2020-09-14
- Volume
- 78
- Issue
- 5
- Pages
- 2231-2245
- ISSN
- 1420-682X (ISSN-L)
- 1420-9071
- PMC
- PMC11072875
- OpenAlex
- W3085498329
- Cited by
- 52
- References
- 71
- Citations by year
- 2026: 6 · 2025: 12 · 2024: 8 · 2023: 10 · 2022: 11 · 2021: 5
- FWCI
- 3.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cellular and Molecular Life Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Israel Science Foundation
- Helmholtz Israel Program
- Alliance Family Foundation
- Rosetrees Trust
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau protein, N-glycosylation, Alzheimer's disease, tau hyperphosphorylation, paired helical filaments, neurodegeneration, transgenic Drosophila, SH-SY5Y cells, post-translational modification
- MeSH terms
- Alzheimer Disease, Animals, Binding Sites, Disease Models, Animal, Drosophila, Glycosylation, Humans, Longevity, Phosphorylation, tau Proteins, Neurodegenerative Diseases, Mutation, Missense, Animals, Genetically Modified, Cell Line, Tumor
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