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Review
, 70 (2), 181-203

Ceramide Function in the Brain: When a Slight Tilt Is Enough

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Review

Ceramide Function in the Brain: When a Slight Tilt Is Enough

Chiara Mencarelli et al. Cell Mol Life Sci.

Abstract

Ceramide, the precursor of all complex sphingolipids, is a potent signaling molecule that mediates key events of cellular pathophysiology. In the nervous system, the sphingolipid metabolism has an important impact. Neurons are polarized cells and their normal functions, such as neuronal connectivity and synaptic transmission, rely on selective trafficking of molecules across plasma membrane. Sphingolipids are abundant on neural cellular membranes and represent potent regulators of brain homeostasis. Ceramide intracellular levels are fine-tuned and alteration of the sphingolipid-ceramide profile contributes to the development of age-related, neurological and neuroinflammatory diseases. The purpose of this review is to guide the reader towards a better understanding of the sphingolipid-ceramide pathway system. First, ceramide biology is presented including structure, physical properties and metabolism. Second, we describe the function of ceramide as a lipid second messenger in cell physiology. Finally, we highlight the relevance of sphingolipids and ceramide in the progression of different neurodegenerative diseases.

Figures

Fig. 1
Fig. 1
Chemical structure of sphingoid bases (sphinganine, sphingosine, phytosphingosine), ceramide species (dihydroceramide, ceramide and phytoceramide) and complex sphingolipids. Sphingomyelin, synthesized by the transfer of the phosphorylcholine moiety to the C-1 hydroxyl group of ceramides, is the only cell membrane phospholipid not derived from glycerol. Alternatively, modification of a ceramide by addition of one or more sugars directly connected at the primary alcohol group yields complex glycosphingolipids. Galactosylceramide and glucosylceramide (cerebrosides) have a single monosaccharide (galactose or glucose) as polar head group; sulfatides are the sulfuric acid esters of galactocerebrosides. Addition of a galactose to glucosylceramide gives rise to lactosylceramide, precursor of globo-, ganglio- and lactosides. Globosides contain multiple sugar moieties. Ganglio- and lactosides have a complex oligosaccharide core structures with one or more sialic acids in the polar head
Fig. 2
Fig. 2
Overview of the metabolic pathways involved in the synthesis of endogenous ceramide. Ceramide can be formed by de novo synthesis, by degradation of complex SLs or by re-acylation of sphingoid long-chain bases (salvage pathway). The de novo pathway involves several enzymatic steps. Through catabolic pathways ceramide is generated by either hydrolysis of the membrane lipid SM by the SMase enzymes or by lysosomal breakdown of complex GSLs. Ceramide itself is degraded by ceramidase to regenerate sphingoid bases. The sphingosine formed is then phosphorylated and finally degraded to phosphoethanolamine and C16-fatty aldehyde by the action of S1P lyase. A salvage pathway uses the enzyme ceramide synthase to produce ceramide from sphingosine. Once generated, ceramide can serve as a substrate for the synthesis of SM and GSLs or be converted into various metabolites such as sphingosine or Cer1P
Fig. 3
Fig. 3
Schematic representation of lipid raft structures in a plasma membrane. The phospholipid bilayer of cellular plasma membranes contains many different lipid components such as glycerophospholipids, sphingolipids and cholesterol. The compositions of the inner and outer membrane leaflets are different. The cytoplasmic monolayer is largely composed of aminophospholipids as phosphatidylserine (4) and phosphatidylethanolamine (3). By contrast, the choline-containing lipids SM (6) and phosphatidylcholine (5) and a variety of glycolipids (7, 8) are significant components of the exofacial leaflet of plasma membranes [45]. SM (6) together with cholesterol and different GSLs (7, 8), form highly organized microdomains called lipid rafts on the plasma membrane. Since these microstructures are formed by lipid species with long saturated acyl chains, rafts are rigid platforms which float in the more fluid surrounding membrane that consists of phospholipids with saturated (1) and unsaturated (2) fatty acyl chains and less cholesterol. Lipids rafts are enriched in glycosylphosphatidylinositol (GPI)-anchored proteins (8) at their external surface and studded with transmembrane integral proteins
Fig. 4
Fig. 4
Scheme of lipid raft reorganization up in ceramide formation by SMase activity. Hydrolysis of SM through the enzyme Smase generates ceramide in the outer leaflet of the cell membrane. For its biochemical features, ceramide mixes poorly with the other rafts components and shows self-assembling capability in the membranous environment forming large distinct ceramide-enriched membrane platforms which serve to reorganize the cell membrane, resulting in clustering of activated receptor molecules
Fig. 5
Fig. 5
Ceramide production occurs in response to diverse apoptotic stimuli and with different mechanisms. Many inducers of cell death activate one or more ceramide generation pathways. For example both SM hydrolysis (by either a nSMase or an aSMase) and the de novo pathway have been implicated in the action TNFα, radiation, doxorubicin and UV. Ultimately, ceramide production results in cell death regardless of the pathway

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