Sphingolipids in neurodegeneration (with focus on ceramide and S1P)

For many decades, research on sphingolipids associated with neurodegenerative disease focused on alterations in glycosphingolipids, particularly glycosylceramides (cerebrosides), sulfatides, and gangliosides. This seemed quite natural since many of these glycolipids are constituents of myelin and accumulated in lipid storage diseases (sphingolipidoses) resulting from enzyme deficiencies in glycolipid metabolism. With the advent of recognizing ceramide and its derivative, sphingosine-1-phosphate (S1P), as key players in lipid cell signaling and regulation of cell death and survival, research focus shifted toward these two sphingolipids. Ceramide and S1P are invoked in a plethora of cell biological processes participating in neurodegeneration such as ER stress, autophagy, dysregulation of protein and lipid transport, exosome secretion and neurotoxic protein spreading, neuroinflammation, and mitochondrial dysfunction. Hence, it is timely to discuss various functions of ceramide and S1P in neurodegenerative disease and to define sphingolipid metabolism and cell signaling pathways as potential targets for therapy.