Abnormal glycosylation of myelin-associated glycoprotein in quaking mouse brain

Konat, G.; Hogan, Edward L.; Leskawa, Kenneth C.; Gantt, G.; Singh, Inderjit

doi:10.1016/0197-0186(87)90084-2

Cited by 8 publications

(3 citation statements)

References 15 publications

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“…It may be that some of the MAG molecules are inefficiently processed in the endoplasmic reticulum/ Golgi complex of quaking oligodendrocytes and accumulate in the high-mannose form. The greater amount of a lower M,, high-mannose metabolic intermediate of MAG in quaking mice may account for the higher mannose/fucose ratio of sugars incorporated into MAG of this mutant reported by Konat et al (1987). However, our results show that the principal MAG bands of control and quaking mice react with GNA lectin very weakly or not at all, suggesting that they do not contain high mannose oligosaccharides that affect their apparent M,.…”

Section: Discussioncontrasting

confidence: 78%

Abnormal expression and glycosylation of the large and small isoforms of myelin‐associated glycoprotein in dysmyelinating quaking mutants

Bartoszewicz

Noronha

Fujita

et al. 1995

J of Neuroscience Research

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The relative expression of large (L) and small (S) isoforms of the myelin-associated glycoprotein (MAG) and their glycosylation were compared in developing spinal cord of quaking and control mice. Using antisera specific for L- and S-MAG, respectively, it was shown that S-MAG is the principal isoform in quaking mice at all ages between 13 and 72 days, although L-MAG was just detectable by western blotting at the early ages. Both L- and S-MAG have higher apparent molecular weights in quaking mice than in controls. Experiments involving lectin binding and glycosidase treatment demonstrated that the higher molecular weight of MAG in the quaking mutant was due to a higher content of N-acetylneuraminic acid residues linked alpha 2-3 to galactose as well as to more branching of oligosaccharide moieties indicated by a higher content of subterminal galactose residues. The total sialic acid measured by HPAE-chromatography in purified quaking MAG was 40% higher than in control MAG. By contrast, quaking MAG contained less of the adhesion-related, HNK-1 carbohydrate epitope. Another difference was that a lower molecular weight form of MAG with predominantly high mannose oligosaccharides was prominent in young quaking mice, but not in controls. The abnormalities of MAG expression related to splicing of its mRNA and glycosylation may contribute to the myelin pathology in quaking mutants.

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Section: Discussioncontrasting

confidence: 78%

Abnormal expression and glycosylation of the large and small isoforms of myelin‐associated glycoprotein in dysmyelinating quaking mutants

Bartoszewicz

Noronha

Fujita

et al. 1995

J of Neuroscience Research

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“…This glycosylation site might play a regulatory role during myelin development and myelination-related pathologies. MAG glycosylation changes during development44 and abnormal glycosylation of MAG correlates with myelination deficiencies454647. Possibly, modulation of N406 glycosylation, either at the biosynthesis level or by extracellular trimming, affects MAG dimerization and thereby impacts on the myelin–axon interaction (see Supplementary notes for details).…”

Section: Discussionmentioning

confidence: 99%

Structural basis of myelin-associated glycoprotein adhesion and signalling

et al. 2016

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Myelin-associated glycoprotein (MAG) is a myelin-expressed cell-adhesion and bi-directional signalling molecule. MAG maintains the myelin–axon spacing by interacting with specific neuronal glycolipids (gangliosides), inhibits axon regeneration and controls myelin formation. The mechanisms underlying MAG adhesion and signalling are unresolved. We present crystal structures of the MAG full ectodomain, which reveal an extended conformation of five Ig domains and a homodimeric arrangement involving membrane-proximal domains Ig4 and Ig5. MAG-oligosaccharide complex structures and biophysical assays show how MAG engages axonal gangliosides at domain Ig1. Two post-translational modifications were identified—N-linked glycosylation at the dimerization interface and tryptophan C-mannosylation proximal to the ganglioside binding site—that appear to have regulatory functions. Structure-guided mutations and neurite outgrowth assays demonstrate MAG dimerization and carbohydrate recognition are essential for its regeneration-inhibiting properties. The combination of trans ganglioside binding and cis homodimerization explains how MAG maintains the myelin–axon spacing and provides a mechanism for MAG-mediated bi-directional signalling.

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“…Another non-discussed example for lectin-like cell surface binding is the interaction of myelin-associated glycoprotein (MAG) with specific gangliosides, which has been suggested to be critical for myelination of axons (141). Loss of b-series complex gangliosides as well as abnormal N-glycoprotein processing of MAG leads to severe nervous system symptoms such as Wallerian degeneration and demyelination (142-143). The tail (protein or lipid-linked glycan) wags the dog (neuron or glia), so to speak.…”

Section: Conclusion and Epilogue: The Tale Of The Tail That Wags Thementioning

confidence: 99%

Synthesis, Processing, and Function of N-glycans in N-glycoproteins

Bieberich

2014

Advances in Neurobiology

147

120

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Many membrane-resident and secrected proteins, including growth factors and their receptors are N-glycosylated. The initial N-glycan structure consists of 14 sugar residues (Glc3Man9GlcNAc2) that are first synthesized in the endoplasmic reticulum (ER) as a branched structure on a lipid anchor (dolicholpyrophosphate) and then co-translationally, “en bloc” transferred and linked via N-acetylglucosamine (GlcNAc) to asparagine within a specific N-glycosylation acceptor sequence (Asn-X-Ser/Thr) of the nascent recipient protein. In the ER and then the Golgi apparatus, the N-linked glycan structure is modified by hydrolytic removal of sugar residues (“trimming”) followed by re-glycosylation with additional sugar residues (“processing”) such as galactose, fucose or sialic acid in complex N-glycoproteins. While the sequence of the reactions leading to biosynthesis, “en bloc” transfer and processing of N-glycans is well investigated, it is still not completely understood how N-glycans affect the biological fate and function of N-glycoproteins. Initially, N-glycans have been found to be critical for proper protein folding and quality control by chaperones in the ER, a process now known as the “calnexin/calreticulin cycle” in the unfolded protein response and ER-assisted degradation (ERAD). More recently, N-glycans have been shown to modulate the function of many cell surface proteins involved in migration and adhesion, including those regulating myelination. Currently, the Golgi has emerged as an organelle that is intimately linked to editing the function of N-glycans in N-glycoprotein transport and sorting. For one, it has been shown that mutations in Golgi glycosyltransferases and transport proteins lead to defects in N-glycan processing that cause severe congenital disorders of glycosylation (CDG). On the other hand, it has been found that N-glycans affect transport of glycosylated proteins in the Golgi, including sorting of secreted proteins such as prions and amyloid. Our group has shown that N-glycan-dependent enzyme complex formation may entangle processing of N-glycosylated glycosyltransferases with glycosphingolipid metabolism, which appears to be important for ganglioside class switches during embryonic brain development. This review will discuss the biology of N-glycoprotein synthesis, processing and function with specific reference to the physiology and pathophysiology of the nervous system.

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Abnormal glycosylation of myelin-associated glycoprotein in quaking mouse brain

Cited by 8 publications

References 15 publications

Abnormal expression and glycosylation of the large and small isoforms of myelin‐associated glycoprotein in dysmyelinating quaking mutants

Abnormal expression and glycosylation of the large and small isoforms of myelin‐associated glycoprotein in dysmyelinating quaking mutants

Structural basis of myelin-associated glycoprotein adhesion and signalling

Synthesis, Processing, and Function of N-glycans in N-glycoproteins

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