Differential effects of putative N-glycosylation sites in human Tau on Alzheimer’s disease-related neurodegeneration

Yelena Losev, Moran Frenkel-Pinter, Malak Abu-Hussien, Guru Krishnakumar Viswanathan, Donna Elyashiv-Revivo, Rana Geries, Isam Khalaila, Ehud Gazit, Daniel Segal*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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.

Original languageAmerican English
Pages (from-to)2231-2245
Number of pages15
JournalCellular and Molecular Life Sciences
Issue number5
StatePublished - Mar 2021
Externally publishedYes

Bibliographical note

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  • Drosophila
  • N-glycosylation
  • N⟶Q mutation
  • SH-SY5Y cells
  • Tau protein


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