Glial Sulfatides and Neuronal Complex Gangliosides Are Functionally Interdependent in Maintaining Myelinating Axon Integrity

Abstract

Sulfatides and gangliosides are raft-associated glycolipids essential for maintaining myelinated nerve integrity. Mice deficient in sulfatide (cerebroside sulfotransferase knock-out, CST−/−) or complex gangliosides (β-1,4-N-acetylegalactosaminyltransferase1 knock-out, 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 that these glycolipids stabilize 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−/−× GalNAc-T−/− mice develop normally to postnatal day 10 (P10), but all die between P20 and P25, coinciding with peak myelination. Ultrastructural, immunohistological, and biochemical analysis of either sex revealed widespread axonal degeneration and disruption to the axo–glial junction at the NoR. In addition to sulfatide-dependent loss of NF155, CST−/− × GalNAc-T−/− mice exhibited a major reduction in MAG protein levels in CNS myelin compared with WT and single-lipid-deficient mice. The CST−/− × 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.SIGNIFICANCE STATEMENT Sulfatides and complex gangliosides are membrane glycolipids with important roles in maintaining nervous system integrity. Node of Ranvier maintenance in particular requires stable compartmentalization of multiple membrane proteins. The axo–glial adhesion molecules neurofascin155 (NF155) and myelin-associated glycoprotein (MAG) require membrane microdomains containing either sulfatides or complex gangliosides to localize and function effectively. The cooperative roles of these microdomains and associated proteins are unknown. Here, we show vital interdependent roles for sulfatides and complex gangliosides because double (but not single) deficiency causes a rapidly lethal phenotype at an early age. These findings suggest that sulfatides and complex gangliosides on opposing axo–glial membranes are responsible for essential tethering of the axo–glial junction proteins NF155 and MAG, which interact to maintain the nodal complex.

Myelin uncompaction and axo‐glial detachment in chronic ataxic neuropathy with monospecific IgM antibody to ganglioside GD1b

“…The latter hypothesis would also be consistent with the presence of “breach” in axonal and Schwann cell membranes at sites of extracellular fluid accumulation. While caution is needed, our observation is somehow supported by the striking similarities with ultrastructural changes observed in central myelinated axons of a combined sulfatide and complex ganglioside knock‐out mice . In the present study, the reactivity of IgM paraprotein to ganglioside complexes (GCS) was not tested, since anti‐GSC reactivity has been described only with the IgG isotype and detected in acute ataxic variants of the Guillain‐Barré syndrome.…”

“…Median nerve (III finger) mice. 11 In the present study, the reactivity of IgM paraprotein to ganglioside complexes (GCS) was not tested, since anti-GSC reactivity has been described only with the IgG isotype and detected in acute ataxic variants of the Guillain-Barré syndrome. We also did not test the pres-…”

Importance of Lipids for Nervous System Integrity: Cooperation between Gangliosides and Sulfatides in Myelin Stability

“…Furthermore, paranodal deterioration occurs in MS before demyelination: the paranodal clustering of Caspr and NF155 is reduced (Wolswijk and Balesar, 2003;Howell et al, 2006), and juxtaparanodal proteins invade the paranode (Howell et al, 2006). Together with these results, the study by McGonigal et al (2019) emphasizes the need to better understand lipidprotein interactions and to further elucidate the role of sulfatides and gangliosides in regulating the paranode stability.…”

“…The study by McGonigal et al (2019) demonstrates that gangliosides and sulfatides in neurons and oligodendrocytes cooperate to maintain myelination, highlighting the importance of the lipids for membrane protein localization (Fantini and Yahi, 2015). The results suggest that the subcellular localization and function of proteins responsible for axon integrity, including MAG, Caspr, and NF155, are correlated with, and possibly regulated by, the glycosphingolipid content.…”

“…An alternative explanation of the results of McGonigal et al (2019) relates to glycosphingolipid properties. These lipids participate in plasma membrane organization and influence its physical-chemical properties by regulating fluidity, curvature, and raft organization (Cantù et al, 2011;Patel et al, 2016).…”