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Cambridge Institute for Medical Research


Glycosphingolipids are an important class of lipids enriched in the outer leaflet of the plasma membrane. Disorders that alter glycosphingolipid metabolism cause devastating neurodegenerative and demyelinating diseases. The Deane lab has identified that deletion of the glycosphingolipid metabolising enzymes GALC or UGT8 cause significant changes to the abundance of specific plasma membrane proteins, several of which are implicated in degenerative brain disease. The Deane lab extend this discovery by characterising the specific interaction of the membrane protein Neurofascin with the glycosphingolipid sulfatide and determining the structure of the extracellular domain of NF155. This work reveals that NF155 binds multiple sulfatide molecules allowing it to bind flat along its own membrane explaining its sensitivity to altered lipid composition. This is the first identification of specific changes to proteins at the plasma membrane caused by sphingolipid-mediated disease and provides important insights into new mechanisms driving demyelinating neurodegenerative diseases.