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

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

doi:10.1007/s00018-020-03643-3

Cited by 36 publications

(27 citation statements)

References 70 publications

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“…Glycosylation mainly occurs in the endoplasmic reticulum and Golgi apparatus and is involved in the regulation of various diseases, such as Alzheimer's disease, cancer, and inflammatory diseases. [50][51][52][53] However, there are only a few reports of N-glycosylation in PH, suggesting that our understanding of its function is limited. The use of tunicamycin as a glycosylation inhibitor confirmed the role of glycosylation in PH.…”

Section: Discussionmentioning

confidence: 99%

RPS4XL encoded by lnc-Rps4l inhibits hypoxia-induced pyroptosis by binding HSC70 glycosylation site

Zhang

Sun

et al. 2022

Molecular Therapy - Nucleic Acids

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Section: Discussionmentioning

confidence: 99%

RPS4XL encoded by lnc-Rps4l inhibits hypoxia-induced pyroptosis by binding HSC70 glycosylation site

Zhang

Sun

et al. 2022

Molecular Therapy - Nucleic Acids

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“…However, such N-glycosylation has been identified in AD patients, but not in healthy control brains, indicating an altered glycosylation process in such patients. These N-glycans have been identified at three sites; Asn359-Ile-Thr, Asn167-Ala-Thr and Asn410-Val-Ser (Sato et al, 2001;Liu et al, 2002;Losev et al, 2020), and have been proposed to affect the aggregation of Tau (Losev et al, 2019). Tau also undergoes O-GlcNAcylation, and four sites have been mapped to human Tau; Thr-123, Ser-208, Ser-400, Ser-409/Ser-412/Ser-413 (Zhu et al, 2014).…”

Section: Taumentioning

confidence: 99%

Implications of Glycosylation in Alzheimer’s Disease

Haukedal

Freude

2021

Front. Neurosci.

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Alzheimer’s disease (AD) is the most common cause of dementia, affecting millions of people worldwide, and no cure is currently available. The major pathological hallmarks of AD are considered to be amyloid beta plaques and neurofibrillary tangles, generated by respectively APP processing and Tau phosphorylation. Recent evidence imply that glycosylation of these proteins, and a number of other AD-related molecules is altered in AD, suggesting a potential implication of this process in disease pathology. In this review we summarize the understanding of glycans in AD pathogenesis, and discuss how glycobiology can contribute to early diagnosis and treatment of AD, serving as potential biomarkers and therapeutic targets. Furthermore, we look into the potential link between the emerging topic neuroinflammation and glycosylation, combining two interesting, and until recent years, understudied topics in the scope of AD. Lastly, we discuss how new model platforms such as induced pluripotent stem cells can be exploited and contribute to a better understanding of a rather unexplored area in AD.

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“…SH-SY5Y cells and transgenic Drosophila expressing tau protein with asparagine to glutamine mutants at the putative N-glycosylation sites were generated, and it was found that N-glycosylation at Asn167 & Asn359 enhances the tau aggregation, while Asn410 reduces tau aggregation. They also found that expression of the N359Q hTau mutant leads to amelioration of AD-like symptoms, reduced neurodegeneration and importantly, N359Q is the only mutant that improved the lifespan of the flies 31 .…”

Section: Introductionmentioning

confidence: 96%

N-glycosylation induced changes in tau protein dynamics reveal its role in tau misfolding and aggregation: A microsecond long molecular dynamics study

Mathew

Baidya

Das

et al. 2022

Preprint

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Various post translational modifications like hyper phosphorylation, O-GlycNAcylation, and acetylation have been attributed to induce the abnormal folding in tau protein. Recent in vitro studies revealed the possible involvement of N–glycosylation of tau protein in the abnormal folding and tau aggregation. Hence in this study, we performed microsecond long all atom molecular dynamics simulation to gain insights into the effects of N-glycosylation on Asn-359residue which forms part of the microtubule binding region. Trajectory analysis of the stimulations coupled with essential dynamics and free energy landscape analysis suggested that tau, in its N-glycosylated form tend to exist in a largely folded conformation having high beta sheet propensity as compared to unmodified tau which exists in a large extended form with very less beta sheet propensity. Residue interaction network analysis of the lowest energy conformations further revealed that Phe378 and Lys353 are the functionally important residues in the peptide which helped in initiating the folding process and Phe378, Lys347&Lys370 helped maintaining the stability of the protein in the folded state.

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

Cited by 36 publications

References 70 publications

RPS4XL encoded by lnc-Rps4l inhibits hypoxia-induced pyroptosis by binding HSC70 glycosylation site

RPS4XL encoded by lnc-Rps4l inhibits hypoxia-induced pyroptosis by binding HSC70 glycosylation site

Implications of Glycosylation in Alzheimer’s Disease

N-glycosylation induced changes in tau protein dynamics reveal its role in tau misfolding and aggregation: A microsecond long molecular dynamics study

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