Abstract
For decades, lipids were confined to the field of structural biology and energetics as they were considered only structural constituents of cellular membranes and efficient sources of energy production. However, with advances in our understanding in lipidomics and improvements in the technological approaches, astounding discoveries have been made in exploring the role of lipids as signaling molecules, termed bioactive lipids. Among these bioactive lipids, sphingolipids have emerged as distinctive mediators of various cellular processes, ranging from cell growth and proliferation to cellular apoptosis, executing immune responses to regulating inflammation. Recent studies have made it clear that sphingolipids, their metabolic intermediates (ceramide, sphingosine-1-phosphate, and N-acetyl sphingosine), and enzyme systems (cyclooxygenases, sphingosine kinases, and sphingomyelinase) harbor diverse yet interconnected signaling pathways in the central nervous system (CNS), orchestrate CNS physiological processes, and participate in a plethora of neuroinflammatory and neurodegenerative disorders. Considering the unequivocal importance of sphingolipids in CNS, we review the recent discoveries detailing the major enzymes involved in sphingolipid metabolism (particularly sphingosine kinase 1), novel metabolic intermediates (N-acetyl sphingosine), and their complex interactions in CNS physiology, disruption of their functionality in neurodegenerative disorders, and therapeutic strategies targeting sphingolipids for improved drug approaches.
Highlights
The fundamental principle of nonpolar acyl chains of lipids to self-aggregate in water lays the basis for cell membrane formation
The biology of sphingolipids has been extensively explored in the peripheral system, and the associated pathologies have been thoroughly investigated; despite being major structural components of the brain anatomy, the functional significance of sphingolipid signaling in the central nervous system (CNS) remains underexplored
One study highlights the indirect monitoring of microglia by neuronal sphingosine kinase 1 (Sphk1), which acts as an acetyltransferase for the COX2 enzyme and acetylates it at serine 565, which provides its anti-inflammatory functions
Summary
The fundamental principle of nonpolar acyl chains of lipids to self-aggregate in water lays the basis for cell membrane formation. The heterogeneous functions executed by these lipids are matched by the diversity of the groups that are within the bioactive lipids These species include the following major classes: eicosanoids, phospholipids, sphingolipids, endocannabinoids, and the newly discovered specialized pro-resolving lipid mediators (SPMs) [2]. The crucial contribution of these enzymes and metabolites is highlighted in the etiology of neuroinflammatory and neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and many others [8] This emphasizes the importance of these molecular entities in both health and disease and demonstrates the urgency to investigate the mechanistic pathways that regulate the expression of these lipids along with their functional significance. We assess the role of sphingolipids in CNS physiology and related disorders, with a focus on neuroinflammation and neurodegeneration, and, in the end, discuss the translational and therapeutic implications that target sphingolipids
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