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

Cellular and Molecular Life Sciences volume 78, pages 2231–2245 (2021)Cite this article

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.

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Abbreviations

AD:

Alzheimer’s disease

CLN5:

Ceroid-lipofuscinosis neuronal protein 5

dgPhy:

Deglycosylated phytase

DTT:

Dl-Dithiothreitol

GlcNAc:

β-N-Acetylglucosamine

GSK3β:

Glycogen synthase kinase 3β

hTau:

Human Tau

NFTs:

Neurofibrillary tangles

OST:

Oligosaccharyltransferase

PHFs:

Paired helical filaments

PKA:

Protein kinase A (cyclic AMP-dependent protein kinase)

PP2:

Protein phosphatase 2

PP5:

Protein phosphatase 5

SP:

Signal peptide

SP-hTau:

Signal peptide human Tau

TRP-1:

Tyrosine-related protein 1

WT:

Wild type

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Acknowledgements

The authors acknowledge Prof. Eckhard Mandelkow (DZNE, Bonn, Germany) for help with plasmid vectors and Dr. Alex Barbul for assistance with confocal microscopy. Authors are grateful to the members of the E.G. and D.S. research groups for discussion. G.K.V thanks TATA trusts for the post-doctoral scholarship.

Funding

This work was supported in part by the Israel Science Foundation, the Helmholtz Israel Program, the Alliance Family Foundation, and the RoseTrees Trust (to D.S.).

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Author notes

  1. Authors Yelena Losev and Moran Frenkel-Pinter contributed equally to this work

Affiliations

  1. Department of Molecular Microbiology and Biotechnology, School of Molecular Cell Biology and Biotechnology, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel

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

  2. Department of Biotechnology Engineering, Ben-Gurion University of Negev, 84105, Beer Sheva, Israel

    Isam Khalaila

  3. Department of Materials Science and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel

    Ehud Gazit

  4. Sagol Interdisciplinary School of Neuroscience, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel

    Daniel Segal

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Contributions

YL, MF and DS planned and designed the experiments with inputs from EG. YL, MF, MAH, GKV, DER and RG carried out the experiments. IK performed LC–MS analysis. YL and GKV prepared the figures, analyzed the results and wrote the manuscript with DS. All authors read and approved the manuscript.

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Correspondence to Daniel Segal.

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Losev, Y., Frenkel-Pinter, M., Abu-Hussien, M. et al. Differential effects of putative N-glycosylation sites in human Tau on Alzheimer’s disease-related neurodegeneration. Cell. Mol. Life Sci. 78, 2231–2245 (2021). https://doi.org/10.1007/s00018-020-03643-3

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Keywords

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