Glial sulfatides and neuronal complex gangliosides are functionally interdependent in maintaining myelinating axon integrity (original) (raw)

McGonigal, R. ORCID: https://orcid.org/0000-0001-9571-2526, Barrie, J.A., Yao, D., McLaughlin, M. ORCID: https://orcid.org/0000-0001-5317-2090, Cunningham, M.E. ORCID: https://orcid.org/0000-0002-7545-6868, Rowan, E.G. and Willison, H.J. ORCID: https://orcid.org/0000-0002-5997-1683(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)

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.

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Funder and Project Information

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The structural and functional diversity of anti-glycolipid antibody repertoires and their nerve binding domains in human autoimmune neuropathy

Hugh Willison

092805/Z/10/Z

III -IMMUNOLOGY

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Pathophysiological factors in the diagnosis and treatment of the Guillain-Barre syndromes

Hugh Willison

202789/Z/16/Z

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