sphingosine-1-phosphate and Neurodegenerative-Diseases

Neurodegenerative disorders (ND) are progressive diseases of the nervous system, often without resolutive therapy. They are characterized by a progressive impairment and loss of specific brain regions and neuronal populations. Cellular and animal model studies have identified several molecular mechanisms that play an important role in the pathogenesis of ND. Among them are alterations of lipids, in particular sphingolipids, that play a crucial role in neurodegeneration. Overall, during ND, ceramide-dependent pro-apoptotic signalling is promoted, whereas levels of the neuroprotective spingosine-1-phosphate are reduced. Moreover, ND are characterized by alterations of the metabolism of complex sphingolipids. The finding that altered sphingolipid metabolism has a role in ND suggests that its modulation might provide a useful strategy to identify targets for possible therapies. In this review, based on the current literature, we will discuss how bioactive sphingolipids (spingosine-1-phosphate and ceramide) are involved in some ND (Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis) and their possible involvement in therapies.

Topics: Animals; Ceramides; Lysophospholipids; Neurodegenerative Diseases; Phosphates; Sphingolipids; Sphingosine

Alzheimer's disease (AD) is considered the most prevalent neurodegenerative disease and the leading cause of dementia worldwide. Sphingolipids, such as ceramide or sphingosine 1-phosphate, are bioactive molecules implicated in structural and signaling functions. Metabolic dysfunction in the highly conserved pathways to produce sphingolipids may lead to or be a consequence of an underlying disease. Recent studies on transcriptomics and sphingolipidomics have observed alterations in sphingolipid metabolism of both enzymes and metabolites involved in their synthesis in several neurodegenerative diseases, including AD. In this review, we highlight the most relevant findings related to ceramide and neurodegeneration, with a special focus on AD.

Topics: Alzheimer Disease; Ceramides; Humans; Lysophospholipids; Neurodegenerative Diseases; Sphingolipids; Sphingosine

Sphingolipids are a class of lipids highly enriched in the central nervous system (CNS), which shows great diversity and complexity, and has been implicated in CNS development and function. Alterations in sphingolipid metabolism have been described in multiple diseases, including those affecting the central nervous system (CNS). In this review, we discuss the role of sphingolipid metabolism in neurodegeneration, evaluating its direct roles in neuron development and health, and also in the induction of neurotoxic activities in CNS-resident astrocytes and microglia in the context of neurologic diseases such as multiple sclerosis and Alzheimer's disease. Finally, we focus on the metabolism of gangliosides and sphingosine-1-phosphate, its contribution to the pathogenesis of neurologic diseases, and its potential as a candidate target for the therapeutic modulation of neurodegeneration.

Topics: Animals; Central Nervous System Diseases; Gangliosides; Humans; Lipid Metabolism; Lysophospholipids; Neurodegenerative Diseases; Sphingolipids; Sphingosine

Sphingosine 1-phosphates (S1Ps) are bioactive lipids that mediate a diverse range of effects through the activation of cognate receptors, S1P

Topics: Aldehyde-Lyases; Alzheimer Disease; Animals; Cerebrovascular Disorders; Clinical Trials as Topic; Dementia, Vascular; Drug Delivery Systems; Drug Evaluation, Preclinical; Fingolimod Hydrochloride; Humans; Infarction, Middle Cerebral Artery; Inflammation; Ischemic Stroke; Lysophospholipids; Mice; Mice, Knockout; Neurodegenerative Diseases; Phosphotransferases (Alcohol Group Acceptor); Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors

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.

Topics: Alzheimer Disease; Central Nervous System; Ceramides; Eicosanoids; Forecasting; Homeostasis; Humans; Inflammation; Lipoxygenase; Lysophospholipids; Membrane Lipids; Models, Biological; Nerve Degeneration; Neurodegenerative Diseases; Neuroglia; Neurons; Parkinson Disease; Phosphotransferases (Alcohol Group Acceptor); Prostaglandin-Endoperoxide Synthases; Sphingolipids; Sphingosine

Sphingosine 1-phosphate (S1P), a metabolic product of cell membrane sphingolipids, is bound to extracellular chaperones, is enriched in circulatory fluids, and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, postnatal organ function, and disease. S1PRs regulate essential processes such as adaptive immune cell trafficking, vascular development, and homeostasis. Moreover, S1PR signaling is a driver of multiple diseases. The past decade has witnessed an exponential growth in this field, in part because of multidisciplinary research focused on this lipid mediator and the application of S1PR-targeted drugs in clinical medicine. This has revealed fundamental principles of lysophospholipid mediator signaling that not only clarify the complex and wide ranging actions of S1P but also guide the development of therapeutics and translational directions in immunological, cardiovascular, neurological, inflammatory, and fibrotic diseases.

Topics: Animals; Apolipoproteins M; Autoimmune Diseases; Cardiovascular Diseases; Cardiovascular Physiological Phenomena; Cardiovascular System; Central Nervous System; Drug Development; Fibrosis; Homeostasis; Humans; Immune System Phenomena; Lysophospholipids; Mice; Molecular Chaperones; Neurodegenerative Diseases; Signal Transduction; Sphingosine; Sphingosine-1-Phosphate Receptors

For many decades, research on sphingolipids associated with neurodegenerative disease focused on alterations in glycosphingolipids, particularly glycosylceramides (cerebrosides), sulfatides, and gangliosides. This seemed quite natural since many of these glycolipids are constituents of myelin and accumulated in lipid storage diseases (sphingolipidoses) resulting from enzyme deficiencies in glycolipid metabolism. With the advent of recognizing ceramide and its derivative, sphingosine-1-phosphate (S1P), as key players in lipid cell signaling and regulation of cell death and survival, research focus shifted toward these two sphingolipids. Ceramide and S1P are invoked in a plethora of cell biological processes participating in neurodegeneration such as ER stress, autophagy, dysregulation of protein and lipid transport, exosome secretion and neurotoxic protein spreading, neuroinflammation, and mitochondrial dysfunction. Hence, it is timely to discuss various functions of ceramide and S1P in neurodegenerative disease and to define sphingolipid metabolism and cell signaling pathways as potential targets for therapy.

Topics: Animals; Autophagy; Ceramides; Humans; Lysophospholipids; Neurodegenerative Diseases; Sphingolipids; Sphingosine

Sphingoid bases (also known as long-chain bases) form the backbone of sphingolipids. Sphingolipids comprise a large group of lipid molecules, which function as the building blocks of biological membranes and play important signaling and regulatory roles within cells. The roles of sphingoid bases in neurotoxicity and neurodegeneration have yet to be fully elucidated, as they are complex and multi-faceted. This comprises a new frontier of research that may provide us with important clues regarding their involvement in neurological health and disease. This paper explores various neurological diseases and conditions which result when the metabolism of sphingoid bases and some of their derivatives, such as sphingosine-1-phosphate and psychosine, becomes compromised due to the inhibition or mutation of key enzymes. Dysregulation of sphingoid base metabolism very often manifests with neurological symptoms, as sphingolipids are highly enriched in the nervous system, where they play important signaling and regulatory roles.

Topics: Animals; Ceramides; Humans; Lysophospholipids; Neurodegenerative Diseases; Sphingolipids; Sphingosine

Sphingosine kinases (isoforms SK1 and SK2) catalyse the formation of a bioactive lipid, sphingosine 1-phosphate (S1P). S1P is a well-established ligand of a family of five S1P-specific G protein coupled receptors but also has intracellular signalling roles. There is substantial evidence to support a role for sphingosine kinases and S1P in health and disease. This review summarises recent advances in the area in relation to receptor-mediated signalling by S1P and novel intracellular targets of this lipid. New evidence for a role of each sphingosine kinase isoform in cancer, the cardiovascular system, central nervous system, inflammation and diabetes is discussed. There is continued research to develop isoform selective SK inhibitors, summarised here. Analysis of the crystal structure of SK1 with the SK1-selective inhibitor, PF-543, is used to identify residues that could be exploited to improve selectivity in SK inhibitor development for future therapeutic application.

Topics: Animals; Cardiovascular Diseases; Diabetes Mellitus; Humans; Inflammation; Lysophospholipids; Models, Molecular; Neoplasms; Neurodegenerative Diseases; Phosphotransferases (Alcohol Group Acceptor); Protein Kinase Inhibitors; Receptors, G-Protein-Coupled; Signal Transduction; Sphingosine; Structure-Activity Relationship

Gene expression in eukaryotes depends on epigenetic changes that occur on both histones and DNA. Class I histone deacetylases (HDACs) are enzymes that remove acetyl groups from histones and other nuclear proteins, thereby inducing chromatin condensation and transcriptional repression. HDACs belong to a large family of enzymes that undergo posttranslational modifications after the activation of several intracellular pathways. However, the environmental stimuli that change nuclear HDAC functions remain largely unknown. New evidence has demonstrated that the lipid sphingosine-1-phosphate (S1P) inhibits the activity of HDAC1 and HDAC2. Both S1P and sphingosine kinase 2 (SphK2), the enzyme that synthesizes S1P, are assembled in corepressor complexes containing HDAC1 and HDAC2. S1P is among the few endogenous HDAC inhibitors that is synthesized in the nucleus in response to extracellular stimulation, and the first nuclear lipid associated with an epigenetic modification. The discovery of endogenous molecules that regulate HDAC activity in vivo has implications for the development of new therapeutic approaches for a host of human diseases, including cancer and neurodegenerative disorders.

Topics: Animals; Cell Nucleus; Chromatin Assembly and Disassembly; Epigenesis, Genetic; Histone Deacetylase 1; Histone Deacetylase 2; Humans; Lysophospholipids; Neoplasms; Neurodegenerative Diseases; Phosphotransferases (Alcohol Group Acceptor); Sphingosine

There is substantial evidence that the enzymes, sphingosine kinase 1 and 2, which catalyse the formation of the bioactive lipid sphingosine 1-phosphate, are involved in pathophysiological processes. In this chapter, we appraise the evidence that both enzymes are druggable and describe how isoform-specific inhibitors can be developed based on the plasticity of the sphingosine-binding site. This is contextualised with the effect of sphingosine kinase inhibitors in cancer, pulmonary hypertension, neurodegeneration, inflammation and sickling.

Topics: Anemia, Sickle Cell; Binding Sites; Enzyme Inhibitors; Humans; Hypertension, Pulmonary; Inflammation; Lysophospholipids; Neoplasms; Neurodegenerative Diseases; Phosphotransferases (Alcohol Group Acceptor); Sphingosine