Sphingolipids as Emerging Mediators in Retina Degeneration

Abstract

The sphingolipids ceramide (Cer), sphingosine-1-phosphate (S1P), sphingosine (Sph), and ceramide-1-phosphate (C1P) are key signaling molecules that regulate major cellular functions. Their roles in the retina have gained increasing attention during the last decade since they emerge as mediators of proliferation, survival, migration, neovascularization, inflammation and death in retina cells. As exacerbation of these processes is central to retina degenerative diseases, they appear as crucial players in their progression. This review analyzes the functions of these sphingolipids in retina cell types and their possible pathological roles. Cer appears as a key arbitrator in diverse retinal pathologies; it promotes inflammation in endothelial and retina pigment epithelium (RPE) cells and its increase is a common feature in photoreceptor death in vitro and in animal models of retina degeneration; noteworthy, inhibiting Cer synthesis preserves photoreceptor viability and functionality. In turn, S1P acts as a double edge sword in the retina. It is essential for retina development, promoting the survival of photoreceptors and ganglion cells and regulating proliferation and differentiation of photoreceptor progenitors. However, S1P has also deleterious effects, stimulating migration of Müller glial cells, angiogenesis and fibrosis, contributing to the inflammatory scenario of proliferative retinopathies and age related macular degeneration (AMD). C1P, as S1P, promotes photoreceptor survival and differentiation. Collectively, the expanding role for these sphingolipids in the regulation of critical processes in retina cell types and in their dysregulation in retina degenerations makes them attractive targets for treating these diseases.

Keywords: ceramide; ceramide-1-phosphate; glia; photoreceptor; pigmented epithelium; sphingosine; sphingosine-1-phosphate.

FIGURE 1

Chemical structures of sphingolipid molecules. The structures of different sphingolipid types are shown. All sphingolipids share a sphingosine backbone (black). This sphingoid backbone is amide-linked to a fatty acid moiety (blue).

FIGURE 2

The sphingolipid network: metabolic interconnection between bioactive sphingolipids. Ceramide, the central hub of sphingolipid metabolism, is synthesized by the de novo pathway (light blue), from serine and palmitoyl CoA, by the sphingomyelinase pathway, i.e., through hydrolysis of sphingomyelin mediated by sphingomyelinases (SMase) (orange) or by the salvage pathway (green). Ceramide can then be phosphorylated to generate Ceramide-1-phosphate and/or deacylated to form sphingosine, which is then phosphorylated to generate sphingosine-1-phosphate (S1P). The catabolism of S1P mediated by S1P lyase provides the only exit route from the sphingolipid network. CDase, ceramidase; CERK, ceramide kinase; GCase, glucosylceramidase; SMase, sphingomyelinase; SM synthase, sphingomyelin synthase; SphK, sphingosine kinase; SPPase, sphingosine phosphate phosphatase. The inhibitors mentioned in this Review are indicated in red.

FIGURE 3

Actions of S1P, Cer, and C1P on retinal neurons and RPE cells. This figure summarizes the effects shown for S1P, Cer, and C1P on different retinal neurons and RPE cells.

FIGURE 4

The relevance of the sphingolipid rheostat in retina photoreceptors. Increases in Cer levels through the activation of its de novo synthesis or the SMase pathway trigger photoreceptor death; this death is also induced after Cer hydrolysis to increase Sph levels, mediated by ceramidase (CDase). In turn, S1P and C1P promote photoreceptor survival and differentiation. Docosahexaenoic acid (DHA) promotes survival by regulating the sphingolipid rheostat, inhibiting SMase or stimulating the synthesis of glucosylceramide (GlucoCer) to decrease Cer levels or enhancing the synthesis of S1P. Exogenous addition of C1P also promotes photoreceptor survival and differentiation.