Sphingolipids in spinal cord injury

Abstract

Spinal cord injury (SCI) is a debilitating condition that affects millions of individuals worldwide. Despite progress over the last few decades, the molecular mechanisms of secondary SCI that continue to occur days and weeks after the original trauma remain poorly understood. As a result, current therapies for SCI are only marginally effective. Sphingolipids, a diverse class of bioactive lipids, have been shown to regulate SCI repair and key secondary injury processes such as apoptosis, ischemia and inflammation. This review will discuss the numerous roles of sphingolipids and highlight the potential of sphingolipid-targeted therapies for SCI.

Keywords: S1P; Spinal cord injury; apoptosis; ceramide; inflammation; sphingolipid metabolism.

Figure 1

Structure of sphingoid bases and simple sphingolipids. A. The sphingoid bases sphingosine, sphinganine and phytosphingosine are long-chain acyclic aliphatic compounds. B. Sphingosine, shown in red, is the base for the other three simple sphingolipids: S1P, ceramide and C1P. Note the variable chain length of ceramide which adds to the complexity of sphingolipid metabolism.

Figure 2

Sphingolipid Metabolism. Once ceramide is synthesized de novo from serine and palmitoyl-CoA, it can undergo one of several reversible reactions. Ceramide can be phosphorylated by CERK to form C1P. Ceramide is a precursor to the complex sphingolipids including sphingomyelin, cerebrosides, sulfatides, globosides and gangliosides. Breakdown of sphingolipids proceeds via hydrolysis of ceramide to sphingosine, phosphorylation by SPHK to form S1P, and lysis to PE and hexadecenal. Per the “sphingolipid rheostat” model, C1P and S1P (green) have pro-survival effects, whereas ceramide and sphingosine (red) have pro-apoptotic effects. Abbreviations: SPT = Serine Palmitoyltransferase, S1P = Sphingosine-1-phosphate, C1P = Ceramide-1-phosphate, ACER = Acid/Alkaline Ceramidase, CERS = Ceramide Synthase, SPHK = Sphingosine Kinase, S1PP = S1P Phosphatase, LPP = Lipid Phosphate Phosphatase, SGPL = S1P Lyase, PE = Phosphoethanolamine, C1PP = C1P Phosphatase, CERK = Ceramide Kinase, SMPD = Sphingomyelin Phosphodiesterase, SGMS = Sphingomyelin Synthase, GALC = Galactosylceramidase, GBA = Glucosidase Beta Acid, UGT = UDP Glycosyltransferase, UGCG = UDP-Glucose Ceramide Glucosyltransferase, ARS = Arylsulfatase, GAL3ST = Galactose-3-O-Sulfotransferase, GLA = Galactosidase, GALT = Galactosyltransferase, NEU = Sialidase, SAT = Sialyltransferase.

Figure 3

Structure of complex sphingolipids. Phosphosphingolipids and glycosphingolipids are synthesized via modifications to ceramide, shown in blue. Addition of phosphocholine to ceramide yields sphingomyelin. Addition of glucose or galactose to ceramide yields the cerebrosides glucosylceramide and galactosylceramide, respectively. These cerebrosides can be further glycosylated (globoside), sulfated (sulfatide) or sialyated (ganglioside).