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- Title
Differential effects of putative N-glycosylation sites in human Tau on Alzheimer's disease-related neurodegeneration.
- Authors
Losev, Yelena; Frenkel-Pinter, Moran; Abu-Hussien, Malak; Viswanathan, Guru Krishnakumar; Elyashiv-Revivo, Donna; Geries, Rana; Khalaila, Isam; Gazit, Ehud; Segal, Daniel
- 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.
- Subjects
HIGH performance liquid chromatography; TAU proteins; POST-translational modification; NEURODEGENERATION; HELICAL structure; ALZHEIMER'S disease
- Publication
Cellular & Molecular Life Sciences, 2021, Vol 78, Issue 5, p2231
- ISSN
1420-682X
- Publication type
Article
- DOI
10.1007/s00018-020-03643-3