Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 78, Issue 5, Pages 2231-2245Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-020-03643-3
Keywords
Tau protein; N-glycosylation; N -> Q mutation; Drosophila; SH-SY5Y cells
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Funding
- Israel Science Foundation
- Helmholtz Israel Program
- Alliance Family Foundation
- RoseTrees Trust
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Tau protein undergoes abnormal post-translational modifications in Alzheimer's disease, such as hyperphosphorylation and glycosylation, impacting disease progression. N-glycosylated Tau has been found in AD brain tissues and specific residues N359 and N410 were identified as undergoing N-glycosylation in wild-type human Tau. Mutants at these glycosylation sites modulate Tau phosphorylation levels and affect neurodegeneration in cell and fly models.
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 whereasN-glycosylation occurs in the ER-Golgi. Previous in vitro studies indicated thatN-glycosylation of Tau facilitated its phosphorylation and contributed to maintenance of its Paired Helical Filament structure. However, the specific Tau residue(s) that undergoN-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 wereN-glycosylated in wild-type (WT) human Tau (hTau) expressed in human SH-SY5Y cells. Asparagine to glutamine mutants, which cannot undergoN-glycosylation, at each of three putativeN-glycosylation sites inhTau (N167Q, N359Q, and N410Q) were generated and expressed in SH-SY5Y cells and in transgenicDrosophila. The mutants modulated the levels ofhTau phosphorylation in a site-dependent manner in both cell and fly models. Additionally, N359Q ameliorated, whereas N410Q exacerbated various aspects ofhTau-engendered neurodegeneration in transgenic flies.
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