Sphingolipids – roads still to be taken

Despite advances already made towards understanding the biological role(s) of sphingolipids (SLs) there are still a number of questions that need to be addressed. For example, while glycosphingolipids (GSLs) are known to be a component of lipid rafts, where they can provide multivalent ligands for carbohydrate–carbohydrate interactions, their actual function in the rafts is unknown. When gangliosides are added to cells and associate with their plasma membranes are they found in rafts or do they distribute in a relatively even fashion across the entire cell membrane? What happens to raft formation in cells made GSL minus? How do subtle changes in a cell's total SL composition, or in the ceramide or polar portion of a specific SL, affect its behavior? What are the specific functions of the different carbohydrate moieties associated with GSLs? In addition to their known role as ligands for certain pathogens, do they function as specific ligands for endogenous molecules? How does substitution of a deoxy for a hydroxyl group on a sugar molecule in a GSL affect their function? Does replacement of a ganglioside sialic acid with a different, negatively charged, component (e.g. sulfate) alter its behavior? How are GSLs transported from the site of injection to their putative site of action when used in animal or human trials to enhance neuronal recovery? Do they associate with albumin? Are they cleared from the circulation by specific galactose binding proteins? Can their clearance by the liver be reduced by modifying their carbohydrate portion? Each of the above questions describes a road currently in need of more exploration.