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

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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 languageEnglish
Pages (from-to)2231-2245
Number of pages15
JournalCellular and Molecular Life Sciences
Volume78
Issue number5
DOIs
StatePublished - 1 Mar 2021

Keywords

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

Fingerprint

Dive into the research topics of 'Differential effects of putative N-glycosylation sites in human Tau on Alzheimer’s disease-related neurodegeneration'. Together they form a unique fingerprint.

Cite this