Altered plasma membrane abundance of the sulfatide-binding protein NF155 links glycosphingolipid imbalances to demyelination

ABSTRACT: Myelination of axons enables efficient signal propagation in neurones. Myelin is a multi-layered membrane that wraps around neuronal axons forming extremely tight contacts that insulate the axon. Tight contact between the axon and myelin sheath is mediated by specific plasma membrane proteins and lipids, with disruption to these contacts causing devastating demyelinating diseases. We have generated two cell-based models of demyelinating sphingolipidoses and shown that the altered lipid metabolism changes the plasma membrane protein composition. The proteins that are altered in these cells play roles in cell adhesion and signalling, several of which have previously been implicated in a range of neurological diseases. The adhesion molecule Neurofascin, with a known role in myelin-axon contact sites, is significantly altered in response to sphingolipid imbalances, highlighting a potential new player contributing to the pathogenesis of galactosphingolipid-mediated diseases. We show that the Neurofascin isoform NF155, but not NF186, directly binds the sphingolipid sulfatide, but does not bind other galactosylated-sphingolipids. Furthermore, this interaction requires the full-length extracellular domain of NF155 and that the structure of this domain adopts an S-shape with important implications for the arrangement of proteins in the tight axon-myelin space. Together, this work identifies that glycosphingolipid imbalances drive changes in membrane protein abundance and that this may be driven by direct interactions between extracellular portions of these proteins with specific lipid headgroups.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Oligodendrocyte, Cell Culture

DISEASE(S): Krabbe Disease

SUBMITTER: James Williamson  

LAB HEAD: Paul Lehner

PROVIDER: PXD036727 | Pride | 2023-04-06

REPOSITORIES: Pride