Glial sulfatides and neuronal complex gangliosides are functionally interdependent in maintaining myelinating axon integrity

McGonigal, R., Barrie, J.A., Yao, D., McLaughlin, M. , Cunningham, M.E. , Rowan, E.G. and Willison, H.J. (2019) Glial sulfatides and neuronal complex gangliosides are functionally interdependent in maintaining myelinating axon integrity. Journal of Neuroscience, 39(1), pp. 63-77. (doi:10.1523/JNEUROSCI.2095-18.2018) (PMID:30446529) (PMCID:PMC6325269)

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Abstract

Sulfatides and gangliosides are raft-associated glycolipids essential for maintaining myelinated nerve integrity. Mice deficient in sulfatide (cerebroside sulfotransferase knockout, CST-/-) or complex gangliosides (β-1,4-N-acetylegalactosaminyltransferase1 knockout, GalNAc-T-/-) display prominent disorganization of proteins at the node of Ranvier (NoR) in early life, and age-dependent neurodegeneration. Loss of neuronal rather than glial complex gangliosides underpins the GalNAc-T-/- phenotype, as shown by neuron or glial-specific rescue, whereas sulfatide is principally expressed and functional in glial membranes. The similarities in NoR phenotype of CST-/-, GalNAc-T-/- and axo-glial protein deficient mice suggests these glycolipids stabilise membrane proteins including neurofascin155 (NF155) and myelin-associated glycoprotein (MAG) at axo-glial junctions. To assess the functional interactions between sulfatide and gangliosides, CST-/- and GalNAc-T-/- genotypes were interbred. CST-/-x GalNAc-T-/- mice develop normally to P10, but all die between P20-P25, coinciding with peak myelination. Ultrastructural, immunohistological and biochemical analysis of either sex reveals widespread axonal degeneration and disruption to the axo-glial junction at the NoR. In addition to sulfatide-dependent loss of NF155, CST-/-x GalNAc-T-/- mice exhibited a major reduction in MAG protein levels in CNS myelin, compared to wild type and single lipid deficient mice. The CST-/-x GalNAc-T-/- phenotype was fully restored to that of CST-/- mice by neuron-specific expression of complex gangliosides, but not by their glial-specific expression nor by the global expression of a-series gangliosides. These data indicate that sulfatide and complex b-series gangliosides on the glial and neuronal membranes respectively act in concert to promote NF155 and MAG in maintaining the stable axo-glial interactions essential for normal nerve function.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Barrie, Mrs Jennifer and Yao, Dr Denggao and Willison, Professor Hugh and McLaughlin, Dr Mark and Cunningham, Dr Madeleine and McGonigal, Dr Rhona
Authors: McGonigal, R., Barrie, J.A., Yao, D., McLaughlin, M., Cunningham, M.E., Rowan, E.G., and Willison, H.J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Neuroscience
Publisher:Society for Neuroscience
ISSN:0270-6474
ISSN (Online):1529-2401
Published Online:16 November 2018
Copyright Holders:Copyright © 2018 McGonigal et al.
First Published:First published in Journal of Neuroscience 39(1): 63-77
Publisher Policy:Reproduced under a Creative Commons License

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