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

R McGonigal, JA Barrie, D Yao, M McLaughlin, ME Cunningham, EG Rowan, HJ Willison

Research output: Contribution to journalArticle

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.SIGNIFICANCE STATEMENTSulfatides and complex gangliosides are membrane glycolipids with important roles in maintaining nervous system integrity. Node of Ranvier maintenance in particular requires stable compartmentalisation of multiple membrane proteins. The axo-glial adhesion molecules neurofascin 155 and myelin-associated glycoprotein require membrane microdomains containing either sulfatides or complex gangliosides to localise and function effectively. The co-operative roles of these microdomains and associated proteins are unknown. Here we show vital interdependent roles for sulfatides and complex gangliosides as double (but not single) deficiency causes a rapidly lethal phenotype in early age. These findings suggests that sulfatides and complex gangliosides on opposing axo-glial membranes are responsible for essential tethering of the axo-glial junction proteins, neurofascin155 and myelin-associated glycoprotein that interact to maintain the nodal complex.

LanguageEnglish
JournalJournal of Neuroscience
Early online date16 Nov 2018
DOIs
Publication statusE-pub ahead of print - 16 Nov 2018

Fingerprint

Sulfoglycosphingolipids
galactosylceramide sulfotransferase
Gangliosides
Neuroglia
Axons
Myelin-Associated Glycoprotein
Ranvier's Nodes
Glycolipids
Phenotype
Membranes
Proteins
Membrane Proteins
Membrane Microdomains
Neurons
Myelin Sheath
Knockout Mice
Nervous System

Keywords

  • complex gangliosides
  • sulfatide gangliosides
  • axon
  • myelination
  • paranodal proteins
  • glia
  • neurones
  • ultrastructural alterations
  • glycolipid raft

Cite this

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title = "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 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.SIGNIFICANCE STATEMENTSulfatides and complex gangliosides are membrane glycolipids with important roles in maintaining nervous system integrity. Node of Ranvier maintenance in particular requires stable compartmentalisation of multiple membrane proteins. The axo-glial adhesion molecules neurofascin 155 and myelin-associated glycoprotein require membrane microdomains containing either sulfatides or complex gangliosides to localise and function effectively. The co-operative roles of these microdomains and associated proteins are unknown. Here we show vital interdependent roles for sulfatides and complex gangliosides as double (but not single) deficiency causes a rapidly lethal phenotype in early age. These findings suggests that sulfatides and complex gangliosides on opposing axo-glial membranes are responsible for essential tethering of the axo-glial junction proteins, neurofascin155 and myelin-associated glycoprotein that interact to maintain the nodal complex.",
keywords = "complex gangliosides, sulfatide gangliosides, axon, myelination, paranodal proteins, glia, neurones, ultrastructural alterations, glycolipid raft",
author = "R McGonigal and JA Barrie and D Yao and M McLaughlin and ME Cunningham and EG Rowan and HJ Willison",
note = "Copyright {\circledC} 2018 McGonigal et al.",
year = "2018",
month = "11",
day = "16",
doi = "10.1523/JNEUROSCI.2095-18.2018",
language = "English",
journal = "Journal of Neuroscience",
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Glial sulfatides and neuronal complex gangliosides are functionally interdependent in maintaining myelinating axon integrity. / McGonigal, R; Barrie, JA; Yao, D; McLaughlin, M; Cunningham, ME; Rowan, EG; Willison, HJ.

In: Journal of Neuroscience, 16.11.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Glial sulfatides and neuronal complex gangliosides are functionally interdependent in maintaining myelinating axon integrity

AU - McGonigal, R

AU - Barrie, JA

AU - Yao, D

AU - McLaughlin, M

AU - Cunningham, ME

AU - Rowan, EG

AU - Willison, HJ

N1 - Copyright © 2018 McGonigal et al.

PY - 2018/11/16

Y1 - 2018/11/16

N2 - 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.SIGNIFICANCE STATEMENTSulfatides and complex gangliosides are membrane glycolipids with important roles in maintaining nervous system integrity. Node of Ranvier maintenance in particular requires stable compartmentalisation of multiple membrane proteins. The axo-glial adhesion molecules neurofascin 155 and myelin-associated glycoprotein require membrane microdomains containing either sulfatides or complex gangliosides to localise and function effectively. The co-operative roles of these microdomains and associated proteins are unknown. Here we show vital interdependent roles for sulfatides and complex gangliosides as double (but not single) deficiency causes a rapidly lethal phenotype in early age. These findings suggests that sulfatides and complex gangliosides on opposing axo-glial membranes are responsible for essential tethering of the axo-glial junction proteins, neurofascin155 and myelin-associated glycoprotein that interact to maintain the nodal complex.

AB - 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.SIGNIFICANCE STATEMENTSulfatides and complex gangliosides are membrane glycolipids with important roles in maintaining nervous system integrity. Node of Ranvier maintenance in particular requires stable compartmentalisation of multiple membrane proteins. The axo-glial adhesion molecules neurofascin 155 and myelin-associated glycoprotein require membrane microdomains containing either sulfatides or complex gangliosides to localise and function effectively. The co-operative roles of these microdomains and associated proteins are unknown. Here we show vital interdependent roles for sulfatides and complex gangliosides as double (but not single) deficiency causes a rapidly lethal phenotype in early age. These findings suggests that sulfatides and complex gangliosides on opposing axo-glial membranes are responsible for essential tethering of the axo-glial junction proteins, neurofascin155 and myelin-associated glycoprotein that interact to maintain the nodal complex.

KW - complex gangliosides

KW - sulfatide gangliosides

KW - axon

KW - myelination

KW - paranodal proteins

KW - glia

KW - neurones

KW - ultrastructural alterations

KW - glycolipid raft

UR - http://www.jneurosci.org/

U2 - 10.1523/JNEUROSCI.2095-18.2018

DO - 10.1523/JNEUROSCI.2095-18.2018

M3 - Article

JO - Journal of Neuroscience

T2 - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

ER -