Interplay between protein glycosylation pathways in Alzheimer’s disease

Frenkel-Pinter, Moran; Shmueli, Merav D.; Raz, Chen; Yanku, Michaela; Zilberzwige, Shai; Gazit, Ehud; Segal, Daniel

doi:10.1126/sciadv.1601576

Cited by 92 publications

(67 citation statements)

References 57 publications

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“…Many additional potential nucleators of Aβ aggregation have been suggested, not always with well formulated mechanisms. ApoE, [181][182][183] collagens and collagen-related proteins, [184][185][186][187][188] and extracellular matrix glycans, [189][190][191][192][193][194] among other molecules have all been suggested as sites at which Aβ aggregation might begin. Such suggestions in no way diminish the importance of metal ions or membrane lipids but add to the potential complexity of the process.…”

Section: Metal Ionsmentioning

confidence: 99%

β‐Amyloid aggregation and heterogeneous nucleation

et al. 2019

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In this article, we consider the role of heterogeneous nucleation in β‐amyloid aggregation. Heterogeneous nucleation is more common and occurs at lower levels of supersaturation than homogeneous nucleation. The nucleation period is also the stage at which most of the polymorphism of amyloids arises, this being one of the defining features of amyloids. We focus on several well‐known heterogeneous nucleators of β‐amyloid, including lipid surfaces, especially those enriched in gangliosides and cholesterol, and divalent metal ions. These two broad classes of nucleators affect β‐amyloid particularly in light of the amphiphilicity of these peptides: the N‐terminal region, which is largely polar and charged, contains the metal binding site, whereas the C‐terminal region is aliphatic and is important in lipid binding. Notably, these two classes of nucleators can interact cooperatively, aggregation begetting greater aggregation.

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Section: Metal Ionsmentioning

confidence: 99%

β‐Amyloid aggregation and heterogeneous nucleation

et al. 2019

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“…Besides, aberrant levels of O-GlcNAc has been reported also on APP implying that this modification could be involved in the induction of its nonamyloidogenic processing by γ-secretase and to the formation of senile plaques [12]. Noteworthy, recent studies reported that the reduction of protein O-GlcNAcylation in AD and tau-driven pathologies do not occurs indiscriminately in all the brain proteome but it appears to vary between brain regions and a specific subcellular fraction of the neurons [13].…”

Section: Protein O-glcnacylation and Tauopathiesmentioning

confidence: 99%

Therapeutic potential of rescuing protein O-GlcNAcylation in tau-related pathologies

Domenico

Lanzillotta²,

Tramutola³

2018

Expert Review of Neurotherapeutics

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“…Nucleotide sugars serve as building block for glycoproteins, glycolipids and glycosylphosphatidylinositol anchors. These complex glycoconjugates are involved in important biological processes such as cellular communication and signaling and have been associated with numerous human diseases, both acquired [1][2][3][4] and genetic. [5] Disruptions in sugar metabolism have been linked to various diseases such as cancer, [6] neurodegenerative [7] and infectious [8] disease, some of them being treatable via dietary intervention in sugar metabolism like galactose supplementation in PGM1 myopathy.…”

Section: Introductionmentioning

confidence: 99%

Dynamic analysis of sugar metabolism reveals the mechanisms of action of synthetic sugar analogs

Scherpenzeel

Conte

Büll

et al. 2020

Preprint

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Synthetic sugar analogs are widely applied in metabolic oligosaccharide engineering (MOE) and as novel drugs to interfere with glycoconjugate biosynthesis. However, mechanistic insights on their exact metabolism in the cell and over time are mostly lacking. We developed sensitive ion-pair UHPLC-QqQ mass spectrometry methodology for analysis of sugar metabolites in organisms and in model cells and identified novel low abundant nucleotide sugars in human cells, such as ADP-glucose and UDP-arabinose, and CMP-sialic acid (CMP-NeuNAc) in Drosophila. Dynamic tracing of propargyloxycarbonyl (Poc) labeled analogs, commonly used for MOE, revealed that ManNPoc is metabolized to both CMP-NeuNPoc and UDP-GlcNPoc. Finally, combined treatment of B16-F10 melanoma cells with antitumor compound 3Fax-NeuNAc and 13C-labeled GlcNAc revealed that endogenous CMP-NeuNAc levels started to decrease before a subsequent decrease of ManNAc 6-phosphate was observed. This implicates 3Fax-NeuNAc first acts as a substrate for cytosolic CMP-sialic acid synthetase and subsequently its product CMP-3Fax-NeuNAc functions as a feed-back inhibitor for UDP-GlcNAc 2-epimerase/N-acetylmannosamine kinase. Thus, dynamic analysis of sugar metabolites provides key insights into the time-dependent metabolism of synthetic sugars, which is important for the rational design of analogs with optimized effects.

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Interplay between protein glycosylation pathways in Alzheimer’s disease

Abstract: Glycome analysis of Alzheimer’s patients reveals interplay between glycosylation pathways and suggests novel biomarkers.

Cited by 92 publications

References 57 publications

β‐Amyloid aggregation and heterogeneous nucleation

β‐Amyloid aggregation and heterogeneous nucleation

Therapeutic potential of rescuing protein O-GlcNAcylation in tau-related pathologies

Dynamic analysis of sugar metabolism reveals the mechanisms of action of synthetic sugar analogs

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