Sphingolipids Lab Report

Sphingolipids and the CNS

Sphingolipids encompass a complex range of membrane lipids in which a fatty acid is linked to a long sphingosine carbon backbone, primarily C18-sphinganine (18:0) and C18-sphingosine (C18:1) in mammals. Figure 1 shows a schematic representation of the sphingolipid metabolic pathway. Ceramide is central in sphingolipid metabolism and is produced by de novo and recycling pathways.37 In de novo synthesis, serine and palmitoyl-CoA are substrates of serine palmitoyl-transferase (SPT), the rate limiting enzyme that generates ketosphinganine (bottom). Ketosphinganine is reduced to form sphinganine, which is then N-acylated with fatty acids of different chain lengths by ceramide synthases (CerS), producing dihydroceramides.

Thus, CerS determine the acyl chain length of sphingolipids, including ceramides, sphingomyelin and glycosphingolipids. The six CerS are differently expressed among tissues and cell types, yielding to distinct sphingolipids-acyl chain length profiles for each cell/tissue. As an example, in the brain, CerS1 (which targets C18 acyl-chains) is distributed primarily in neurons, whereas CerS2, responsible for the synthesis of C22-C24 acyl-chain sphingolipids, is expressed specifically in oligodendrocytes and Schwann cells.38 The next step in de novo synthesis is the desaturation of dihydro-ceramides to generate ceramides, by the dihydroceramide desaturase (DES). Ceramides can be further metabolized to sphingomyelin, by the addition of a phosphocholine head group from phosphatidyl-choline by the sphingomyelin synthases, or to glycosphingolipids, by the addition of a sugar group. Serine-palmitoyl transferase can alternatively utilize alanine instead of serine resulting in the synthesis of deoxyceramides, which

They exert a wide range of functions in neuronal/glial proliferation, differentiation and apoptosis, as well as in maintaining the membrane permeability to ions and in the stabilization of synaptic transporters and receptors, the latest processes relevant to the generation and propagation of the nervous impulse and synaptic transmission.20,39,40 Moreover, cell and animal models underscore the key function of sphingolipids in the neurite growth and myelination of the cerebellum and forebrain, among other brain regions.41,42 Deficiency of ceramide synthase-2 that generates sphingolipids with C22-C24 fatty acyl chains results in 50% loss of compacted myelin and 80% loss of CNS myelin basic protein.42 Similarly, a 60% reduction of myelin-associated glycoprotein in the cerebellum and forebrain characterizes mice deficient in ceramide synthase-1, the enzyme that generates C18:0 sphingolipids.41 Interestingly, mice deficient of ceramide synthase -6, which generates C16:0 sphingolipids, as well as mice deficient of GM3 synthase that is responsible for one of the first steps in the production of gangliosides, both present hyperactive behavior and have been postulated as suitable animal models for