Myelin is a multilayered membrane that tightly wraps neuronal axons, enabling efficient, high-speed signal propagation. The axon and myelin sheath form tight contacts, mediated by specific plasma membrane
proteins and
lipids, and disruption of these contacts causes devastating
demyelinating diseases. Using two cell-based models of demyelinating
sphingolipidoses, we demonstrate that altered lipid metabolism changes the abundance of specific plasma membrane
proteins. These altered
membrane proteins have known roles in cell adhesion and signaling, with several implicated in neurological diseases. The cell surface abundance of the adhesion molecule neurofascin (NFASC), a
protein critical for the maintenance of myelin-axon contacts, changes following disruption to
sphingolipid metabolism. This provides a direct molecular link between altered
lipid abundance and myelin stability. We show that the NFASC
isoform NF155, but not NF186, interacts directly and specifically with the
sphingolipid sulfatide via multiple binding sites and that this interaction requires the full-length extracellular domain of NF155. We demonstrate that NF155 adopts an S-shaped conformation and preferentially binds
sulfatide-containing membranes in cis, with important implications for
protein arrangement in the tight axon-myelin space. Our work links
glycosphingolipid imbalances to disturbance of
membrane protein abundance and demonstrates how this may be driven by direct
protein-
lipid interactions, providing a mechanistic framework to understand the pathogenesis of galactosphingolipidoses.