High N-glycan multiplicity is critical for neuronal adhesion and sensitizes the developing cerebellum to N-glycosylation defect

Medina-Cano, Daniel; Ucuncu, Ekin; Nguyen, Lam Son; Nicouleau, Michaël; Lipecka, Joanna; Bizot, Jean-Charles; Thiel, Christian; Foulquier, François; Lefort, Nathalie; Faivre‐Sarrailh, Catherine; Colleaux, Laurence; Guerrera, Ida Chiara; Cantagrel, Vincent

doi:10.7554/elife.38309

Cited by 51 publications

(50 citation statements)

References 87 publications

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“…CDG phenotypes can result from altered activation or transport of sugar precursors; and altered expression and/or activity of enzymes (glycosidases or glycosyltransferases) or proteins implicated in the Golgi apparatus functioning. A clear illustration of congenital glycosylation disorder is the family of α-dystroglycanopathies whom frequently include alterations in the central nervous system [62] and ocular disease manifestations, in addition to muscular dystrophy, intellectual disability, developmental delay, hypotonia, macrocephaly, growth retardation, adducted thumbs, failure to thrive, cardiac anomalies, wrinkled skin, and early death. [39,63] Genetic alterations support the development of various pathologies, including neoplastic ones, but epigenetic changes in response to stimuli can significantly influence the genesis and neoplastic transformation.…”

Section: Genetic Defects and Cancermentioning

confidence: 99%

Protein Glycosylation Investigated by Mass Spectrometry: An Overview

Illiano

Pinto

Melchiorre

et al. 2020

Cells

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The protein glycosylation is a post-translational modification of crucial importance for its involvement in molecular recognition, protein trafficking, regulation, and inflammation. Indeed, abnormalities in protein glycosylation are correlated with several disease states such as cancer, inflammatory diseases, and congenial disorders. The understanding of cellular mechanisms through the elucidation of glycan composition encourages researchers to find analytical solutions for their detection. Actually, the multiplicity and diversity of glycan structures bond to the proteins, the variations in polarity of the individual saccharide residues, and the poor ionization efficiencies make their detection much trickier than other kinds of biopolymers. An overview of the most prominent techniques based on mass spectrometry (MS) for protein glycosylation (glycoproteomics) studies is here presented. The tricks and pre-treatments of samples are discussed as a crucial step prodromal to the MS analysis to improve the glycan ionization efficiency. Therefore, the different instrumental MS mode is also explored for the qualitative and quantitative analysis of glycopeptides and the glycans structural composition, thus contributing to the elucidation of biological mechanisms.

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Section: Genetic Defects and Cancermentioning

confidence: 99%

Protein Glycosylation Investigated by Mass Spectrometry: An Overview

Illiano

Pinto

Melchiorre

et al. 2020

Cells

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“…In particular, N-glycosylation begins in the endoplasmic reticulum by the synthesis of a lipid-linked oligosaccharide (LLO) precursor, comprising a 14 monosaccharide (Glc 3 Man 9 GlcNAc 2 ) sequential assembly on a phosphorylated lipid carrier dolichol. An oligosaccharyltransferase (OST) complex transfers en bloc the oligosaccharide part of LLO to the specific site of Asn residue [ 12 ]. Differently, O-glycosylation often initiates by the addition of GalNAc to the hydroxyl group of Ser or Thr residues in a polypeptide chain.…”

Section: Introductionmentioning

confidence: 99%

The Glucose Metabolic Pathway as A Potential Target for Therapeutics: Crucial Role of Glycosylation in Alzheimer’s Disease

Bukke

Villani

Moola

et al. 2020

IJMS

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Glucose uptake in the brain decreases because of normal aging but this decline is accelerated in Alzheimer’s disease (AD) patients. In fact, positron emission tomography (PET) studies have shown that metabolic reductions in AD patients occur decades before the onset of symptoms, suggesting that metabolic deficits may be an upstream event in at least some late-onset cases. A decrease in availability of glucose content induces a considerable impairment/downregulation of glycosylation, which is an important post-translational modification. Glycosylation is an important and highly regulated mechanism of secondary protein processing within cells and it plays a crucial role in modulating stability of proteins, as carbohydrates are important in achieving the proper three-dimensional conformation of glycoproteins. Moreover, glycosylation acts as a metabolic sensor that links glucose metabolism to normal neuronal functioning. All the proteins involved in β-amyloid (Aβ) precursor protein metabolism have been identified as candidates of glycosylation highlighting the possibility that Aβ metabolism could be regulated by their glycosylation. Within this framework, the present review aims to summarize the current understanding on the role of glycosylation in the etiopathology of AD, emphasizing the idea that glucose metabolic pathway may represent an alternative therapeutic option for targeting AD. From this perspective, the pharmacological modulation of glycosylation levels may represent a ‘sweet approach’ to treat AD targeting new mechanisms independent of the amyloid cascade and with comparable impacts in familial and sporadic AD.

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“…neurexins 2 , neuroligins 3 , synaptic adhesion like molecules (SALMs) 4 , leucine-rich repeat (LRR) transmembrane neuronal proteins (LRRTMs) 5 , leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) 6 and netrin-G ligands (NGLs) 7 . The dysfunction of synaptic adhesion molecules have been proposed to be involved in onset and progression of various neurological disorders, which includes autism spectrum disorders, schizophrenia and Alzheimer's disease [8][9][10][11] .…”

Section: Introductionmentioning

confidence: 99%

Structural basis of SALM3 dimerization and synaptic adhesion complex formation with PTPσ

Karki

Shkumatov

Bae

et al. 2020

Preprint

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Synaptic adhesion molecules play an important role in the formation, maintenance and refinement of neuronal connectivity. Recently, several leucine rich repeat (LRR) domain containing neuronal adhesion molecules have been characterized including netrin G-ligands, SLITRKs and the synaptic adhesion-like molecules (SALMs). Dysregulation of these adhesion molecules have been genetically and functionally linked to various neurological disorders. Here we investigated the molecular structure and mechanism of ligand interactions for the postsynaptic SALM3 adhesion protein with its presynaptic ligand, receptor protein tyrosine phosphatase σ (PTPσ). We solved the crystal structure of the dimerized leucine rich repeat (LRR) domain of SALM3, revealing the conserved structural features and mechanism of dimerization. Furthermore, we determined the complex structure of SALM3 with PTPσ using small angle X-ray scattering, revealing a 2:2 complex similar to that observed for SALM5. Solution studies unraveled additional flexibility for the complex structure, but validated the uniform mode of action for SALM3 and SALM5 to promote synapse formation. The relevance of the key interface residues was further confirmed by mutational analysis with cellular binding assays and artificial synapse formation assays.Collectively, our results suggest that SALM3 dimerization is a pre-requisite for the SALM3-PTPσ complex to exert synaptogenic activity.

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High N-glycan multiplicity is critical for neuronal adhesion and sensitizes the developing cerebellum to N-glycosylation defect

Cited by 51 publications

References 87 publications

Protein Glycosylation Investigated by Mass Spectrometry: An Overview

Protein Glycosylation Investigated by Mass Spectrometry: An Overview

The Glucose Metabolic Pathway as A Potential Target for Therapeutics: Crucial Role of Glycosylation in Alzheimer’s Disease

Structural basis of SALM3 dimerization and synaptic adhesion complex formation with PTPσ

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