Recent Insight into the Role of Sphingosine-1-Phosphate Lyase in Neurodegeneration

Sphingosine-1-phosphate lyase (SPL) is a pyridoxal 5′-phosphate-dependent enzyme involved in the irreversible degradation of sphingosine-1-phosphate (S1P)—a bioactive sphingolipid that modulates a broad range of biological processes (cell proliferation, migration, differentiation and survival; mitochondrial functioning; and gene expression). Although SPL activity leads to a decrease in the available pool of S1P in the cell, at the same time, hexadecenal and phosphoethanolamine, compounds with potential biological activity, are generated. The increased expression and/or activity of SPL, and hence the imbalance between S1P and the end products of its cleavage, were demonstrated in several pathological states. On the other hand, loss-of-function mutations in the SPL encoding gene are a cause of severe developmental impairments. Recently, special attention has been paid to neurodegenerative diseases as the most common pathologies of the nervous system. This review summarizes the current findings concerning the role of SPL in the nervous system with an emphasis on neurodegeneration. Moreover, it briefly discusses pharmacological compounds directed to inhibit its activity.

[1]  Younghun Jung,et al.  Dysregulation of sphingosine-1-phosphate (S1P) and S1P receptor 1 signaling in the 5xFAD mouse model of Alzheimer’s disease , 2022, Brain Research.

[2]  G. Semenkova,et al.  2-Hexadecenal Regulates ROS Production and Induces Apoptosis in Polymorphonuclear Leucocytes , 2022, Cell Biochemistry and Biophysics.

[3]  T. Ziemssen,et al.  Current status and new developments in sphingosine-1-phosphate receptor antagonism: fingolimod and more , 2022, Expert opinion on drug metabolism & toxicology.

[4]  A. Armirotti,et al.  Treatment with THI, an inhibitor of Sphingosine-1-phosphate Lyase (SGPL1), modulates glycosphingolipid metabolism and results therapeutically effective in experimental models of Huntington's disease. , 2022, Molecular Therapy.

[5]  M. Lasaga,et al.  Neuroinflammation in Huntington’s Disease: A Starring Role for Astrocyte and Microglia , 2021, Current neuropharmacology.

[6]  J. Matías‐Guiu,et al.  A Transcriptomic Meta-Analysis Shows Lipid Metabolism Dysregulation as an Early Pathological Mechanism in the Spinal Cord of SOD1 Mice , 2021, International journal of molecular sciences.

[7]  F. Schumacher,et al.  Nuclear Sphingosine-1-phosphate Lyase Generated ∆2-hexadecenal is A Regulator of HDAC Activity and Chromatin Remodeling in Lung Epithelial Cells , 2021, Cell Biochemistry and Biophysics.

[8]  T. Hornemann,et al.  Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis , 2021, Nature Medicine.

[9]  C. Gerloff,et al.  Sphingosine‐1‐Phosphate, Motor Severity, and Progression in Parkinson's Disease (MARK‐PD) , 2021, Movement disorders : official journal of the Movement Disorder Society.

[10]  L. McCullough,et al.  The Functional Role of Sphingosine Kinase 2 , 2021, Frontiers in Molecular Biosciences.

[11]  Guojie Yang,et al.  Bone marrow mesenchymal stem cells‐derived exosomes reduce Aβ deposition and improve cognitive function recovery in mice with Alzheimer's disease by activating sphingosine kinase/sphingosine‐1‐phosphate signaling pathway , 2020, Cell biology international.

[12]  E. Dardiotis,et al.  Neurodegeneration and Inflammation—An Interesting Interplay in Parkinson’s Disease , 2020, International journal of molecular sciences.

[13]  G. van Echten-Deckert,et al.  Neurodegeneration Caused by S1P-Lyase Deficiency Involves Calcium-Dependent Tau Pathology and Abnormal Histone Acetylation , 2020, Cells.

[14]  C. Guatimosim,et al.  Inflammation in Huntington's disease: A few new twists on an old tale , 2020, Journal of Neuroimmunology.

[15]  A. Hołownia,et al.  Pharmacological inhibition of sphingosine-1-phosphate lyase partially reverses spatial memory impairment in streptozotocin-diabetic rats , 2020, Molecular and Cellular Neuroscience.

[16]  P. Bruni,et al.  Sphingosine 1-phosphate lyase blockade elicits myogenic differentiation of murine myoblasts acting via Spns2/S1P2 receptor axis. , 2020, Biochimica et biophysica acta. Molecular and cell biology of lipids.

[17]  R. Schneiter,et al.  Mitochondrial sphingosine-1-phosphate lyase is essential for phosphatidylethanolamine synthesis and survival of Trypanosoma brucei , 2020, Scientific Reports.

[18]  L. Metherell,et al.  A Sphingosine-1-Phosphate Lyase Mutation Associated With Congenital Nephrotic Syndrome and Multiple Endocrinopathy , 2020, Frontiers in Pediatrics.

[19]  L. Walensky,et al.  Site-Dependent Cysteine Lipidation Potentiates the Activation of Proapoptotic BAX , 2020, Cell reports.

[20]  G. Massicotte,et al.  Sphingosine-1-Phosphate Receptors Modulators Decrease Signs of Neuroinflammation and Prevent Parkinson’s Disease Symptoms in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model , 2020, Frontiers in Pharmacology.

[21]  J. Pfeilschifter,et al.  Downregulation of S1P Lyase Improves Barrier Function in Human Cerebral Microvascular Endothelial Cells Following an Inflammatory Challenge , 2020, International journal of molecular sciences.

[22]  L. Metherell,et al.  Sphingosine-1-phosphate lyase (SGPL1) deficiency is associated with mitochondrial dysfunction , 2018, The Journal of Steroid Biochemistry and Molecular Biology.

[23]  E. Clambey,et al.  Sphingosine-1-Phosphate Lyase Inhibition Alters the S1P Gradient and Ameliorates Crohn's-Like Ileitis by Suppressing Thymocyte Maturation. , 2019, Inflammatory bowel diseases.

[24]  T. Fath,et al.  Sphingosine Kinase 2 Potentiates Amyloid Deposition but Protects against Hippocampal Volume Loss and Demyelination in a Mouse Model of Alzheimer's Disease , 2019, The Journal of Neuroscience.

[25]  Sean J. Humphrey,et al.  Sphingosine 1‐phosphate but not Fingolimod protects neurons against excitotoxic cell death by inducing neurotrophic gene expression in astrocytes , 2019, Journal of neurochemistry.

[26]  A. Lebedev,et al.  Changes in the Metabolism of Sphingoid Bases in the Brain and Spinal Cord of Transgenic FUS(1-359) Mice, a Model of Amyotrophic Lateral Sclerosis , 2019, Biochemistry (Moscow).

[27]  I. Glezer,et al.  Alterations in lipid metabolism of spinal cord linked to amyotrophic lateral sclerosis , 2019, Scientific Reports.

[28]  K. Setchell,et al.  Disarranged Sphingolipid Metabolism From Sphingosine-1-Phosphate Lyase Deficiency Leads to Congenital Nephrotic Syndrome , 2019, Kidney international reports.

[29]  B. Levkau,et al.  Agonist-induced activation of the S1P receptor 2 constitutes a novel osteoanabolic therapy for the treatment of osteoporosis in mice. , 2019, Bone.

[30]  G. van Echten-Deckert,et al.  Neural sphingosine 1‐phosphate accumulation activates microglia and links impaired autophagy and inflammation , 2019, Glia.

[31]  E. Amico,et al.  Stimulation of Sphingosine Kinase 1 (SPHK1) Is Beneficial in a Huntington’s Disease Pre-clinical Model , 2019, Front. Mol. Neurosci..

[32]  J. Chun,et al.  Fingolimod: Lessons Learned and New Opportunities for Treating Multiple Sclerosis and Other Disorders. , 2019, Annual review of pharmacology and toxicology.

[33]  Youn-Jeong Choi,et al.  Sphingosine phosphate lyase insufficiency syndrome (SPLIS): A novel inborn error of sphingolipid metabolism. , 2019, Advances in biological regulation.

[34]  A. Baer,et al.  Characterization of the effects of immunomodulatory drug fingolimod (FTY720) on human T cell receptor signaling pathways , 2018, Scientific Reports.

[35]  P. Kosson,et al.  Pramipexole and Fingolimod exert neuroprotection in a mouse model of Parkinson's disease by activation of sphingosine kinase 1 and Akt kinase , 2018, Neuropharmacology.

[36]  L. Weber,et al.  A novel mutation in sphingosine-1-phosphate lyase causing congenital brain malformation , 2018, Brain and Development.

[37]  W. Lukiw,et al.  Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease , 2018, Molecular Neurobiology.

[38]  A. Bereket,et al.  Acquired modification of sphingosine-1-phosphate lyase activity is not related to adrenal insufficiency , 2018, BMC Neurology.

[39]  A. di Pardo,et al.  Sphingolipid Metabolism: A New Therapeutic Opportunity for Brain Degenerative Disorders , 2018, Front. Neurosci..

[40]  C. Duyckaerts,et al.  Neuronal sphingosine kinase 2 subcellular localization is altered in Alzheimer’s disease brain , 2018, Acta neuropathologica communications.

[41]  M. Spedding,et al.  Sphingolipid Metabolism Is Dysregulated at Transcriptomic and Metabolic Levels in the Spinal Cord of an Animal Model of Amyotrophic Lateral Sclerosis , 2018, Front. Mol. Neurosci..

[42]  S. Pena,et al.  Nephrotic syndrome and adrenal insufficiency caused by a variant in SGPL1 , 2017, Clinical kidney journal.

[43]  E. Amico,et al.  De novo Synthesis of Sphingolipids Is Defective in Experimental Models of Huntington's Disease , 2017, Front. Neurosci..

[44]  P. Greengard,et al.  Identifying therapeutic targets by combining transcriptional data with ordinal clinical measurements , 2017, Nature Communications.

[45]  M. D'Esposito,et al.  Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington’s disease , 2017, Scientific Reports.

[46]  F. Schumacher,et al.  The sphingosine 1-phosphate breakdown product, (2E)-hexadecenal, forms protein adducts and glutathione conjugates in vitro[S] , 2017, Journal of Lipid Research.

[47]  N. Putluri,et al.  Inhibiting sphingosine kinase 2 mitigates mutant Huntingtin-induced neurodegeneration in neuron models of Huntington disease , 2017, Human molecular genetics.

[48]  Y. Frishberg,et al.  Deficiency of the sphingosine‐1‐phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications , 2017, Human mutation.

[49]  J. Pfeilschifter,et al.  Characterization of cholesterol homeostasis in sphingosine-1-phosphate lyase-deficient fibroblasts reveals a Niemann-Pick disease type C-like phenotype with enhanced lysosomal Ca2+ storage , 2017, Scientific Reports.

[50]  K. Schwarz,et al.  Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency , 2017, The Journal of clinical investigation.

[51]  G. van Echten-Deckert,et al.  SGPL1 (sphingosine phosphate lyase 1) modulates neuronal autophagy via phosphatidylethanolamine production , 2017, Autophagy.

[52]  T. Hornemann,et al.  Sphingosine 1-phosphate lyase deficiency causes Charcot-Marie-Tooth neuropathy , 2017, Neurology.

[53]  L. Metherell,et al.  Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome , 2017, The Journal of clinical investigation.

[54]  I. Bjelobaba,et al.  Multiple Sclerosis and Neuroinflammation: The Overview of Current and Prospective Therapies. , 2017, Current pharmaceutical design.

[55]  Yuqin Ye,et al.  Activation of Sphingosine 1-Phosphate Receptor 1 Enhances Hippocampus Neurogenesis in a Rat Model of Traumatic Brain Injury: An Involvement of MEK/Erk Signaling Pathway , 2016, Neural plasticity.

[56]  O. Shupliakov,et al.  Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism , 2016, Scientific Reports.

[57]  D. B. Duignan,et al.  Sphingosine-1-Phosphate (S1P) Lyase Inhibition Causes Increased Cardiac S1P Levels and Bradycardia in Rats , 2016, The Journal of Pharmacology and Experimental Therapeutics.

[58]  O. Dzyubachyk,et al.  Correction of lung inflammation in a F508del CFTR murine cystic fibrosis model by the sphingosine-1-phosphate lyase inhibitor LX2931. , 2016, American journal of physiology. Lung cellular and molecular physiology.

[59]  N. Hemdan,et al.  Modulating sphingosine 1‐phosphate signaling with DOP or FTY720 alleviates vascular and immune defects in mouse sepsis , 2016, European journal of immunology.

[60]  Ernest Fraenkel,et al.  Revealing disease-associated pathways by network integration of untargeted metabolomics , 2016, Nature Methods.

[61]  Kendra D Bunner,et al.  Corticostriatal Dysfunction in Huntington’s Disease: The Basics , 2016, Front. Hum. Neurosci..

[62]  T. Kodadek,et al.  The Immune System and Neuroinflammation as Potential Sources of Blood-Based Biomarkers for Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease. , 2016, ACS chemical neuroscience.

[63]  B. Castellotti,et al.  ASAH1 variant causing a mild SMA phenotype with no myoclonic epilepsy: a clinical, biochemical and molecular study , 2016, European Journal of Human Genetics.

[64]  H. Weiner,et al.  Identification of a novel mechanism of action of fingolimod (FTY720) on human effector T cell function through TCF-1 upregulation , 2015, Journal of Neuroinflammation.

[65]  S. Finkbeiner,et al.  Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy , 2015, Scientific Reports.

[66]  M. Spedding,et al.  Amyotrophic lateral sclerosis and denervation alter sphingolipids and up-regulate glucosylceramide synthase , 2015, Human molecular genetics.

[67]  M. Ratajczak,et al.  Pharmacological Elevation of Circulating Bioactive Phosphosphingolipids Enhances Myocardial Recovery After Acute Infarction , 2015, Stem cells translational medicine.

[68]  R. Sidman,et al.  Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis , 2015, Proceedings of the National Academy of Sciences.

[69]  S. Nasoohi,et al.  Sphingosin-1-phosphate Receptor 1: a Potential Target to Inhibit Neuroinflammation and Restore the Sphingosin-1-phosphate Metabolism , 2015, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[70]  G. Semenkova,et al.  Free-radical Destruction of Sphingolipids Resulting in 2-hexadecenal Formation , 2015, Lipid insights.

[71]  S. Côté,et al.  Reduced Activity of Sphingosine-1-Phosphate Lyase Induces Podocyte-related Glomerular Proteinuria, Skin Irritation, and Platelet Activation , 2015, Toxicologic pathology.

[72]  J. Strosznajder,et al.  The key role of sphingosine kinases in the molecular mechanism of neuronal cell survival and death in an experimental model of Parkinson's disease. , 2014, Folia neuropathologica.

[73]  J. Cebon,et al.  Sphingosine‐1‐phosphate lyase is expressed by CD68+ cells on the parenchymal side of marginal reticular cells in human lymph nodes , 2014, European journal of immunology.

[74]  C. Beerli,et al.  Orally active 7-substituted (4-benzylphthalazin-1-yl)-2-methylpiperazin-1-yl]nicotinonitriles as active-site inhibitors of sphingosine 1-phosphate lyase for the treatment of multiple sclerosis. , 2014, Journal of medicinal chemistry.

[75]  P. Calabresi,et al.  FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway , 2014, Journal of Neuroimmunology.

[76]  J. Walter,et al.  Deficiency of Sphingosine-1-phosphate Lyase Impairs Lysosomal Metabolism of the Amyloid Precursor Protein* , 2014, The Journal of Biological Chemistry.

[77]  R. Levenson,et al.  Emotional and behavioral symptoms in neurodegenerative disease: a model for studying the neural bases of psychopathology. , 2014, Annual review of clinical psychology.

[78]  C. Duyckaerts,et al.  Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer’s disease , 2014, Acta neuropathologica communications.

[79]  Russell Pickford,et al.  Loss of the neuroprotective factor Sphingosine 1-phosphate early in Alzheimer’s disease pathogenesis , 2014, Acta neuropathologica communications.

[80]  Ping-ping Liu,et al.  Sphingosine 1-phosphate (S1P) promotes mitochondrial biogenesis in Hep G2 cells by activating Peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) , 2014, Cell Stress and Chaperones.

[81]  Holger Jahn,et al.  Memory loss in Alzheimer's disease , 2013, Dialogues in clinical neuroscience.

[82]  D. Beiser,et al.  Inhibition of sphingosine-1-phosphate lyase rescues sphingosine kinase-1-knockout phenotype following murine cardiac arrest. , 2013, Life sciences.

[83]  J. Sweatt,et al.  Disruption of neocortical histone H3 homeostasis by soluble Aβ: implications for Alzheimer's disease , 2013, Neurobiology of Aging.

[84]  K. Park,et al.  4-deoxypyridoxine improves the viability of isolated pancreatic islets ex vivo , 2013, Islets.

[85]  C. Beerli,et al.  Assay to measure the secretion of sphingosine-1-phosphate from cells induced by S1P lyase inhibitors. , 2013, Biochemical and biophysical research communications.

[86]  Matthias Mueller,et al.  Partial Deficiency of Sphingosine-1-Phosphate Lyase Confers Protection in Experimental Autoimmune Encephalomyelitis , 2013, PloS one.

[87]  M. Nimwegen,et al.  Topical treatment targeting sphingosine‐1‐phosphate and sphingosine lyase abrogates experimental allergic rhinitis in a murine model , 2013, Allergy.

[88]  J. Pfeilschifter,et al.  Evidence for a link between histone deacetylation and Ca²+ homoeostasis in sphingosine-1-phosphate lyase-deficient fibroblasts. , 2012, The Biochemical journal.

[89]  Ashok Kumar,et al.  The sphingolipid degradation product trans-2-hexadecenal forms adducts with DNA. , 2012, Biochemical and biophysical research communications.

[90]  E. Bertini,et al.  Spinal muscular atrophy associated with progressive myoclonic epilepsy is caused by mutations in ASAH1. , 2012, American journal of human genetics.

[91]  O. Cuvillier,et al.  First Evidence of Sphingosine 1-Phosphate Lyase Protein Expression and Activity Downregulation in Human Neoplasm: Implication for Resistance to Therapeutics in Prostate Cancer , 2012, Molecular Cancer Therapeutics.

[92]  M. L. Lachenmayer,et al.  Disrupted Autophagy Leads to Dopaminergic Axon and Dendrite Degeneration and Promotes Presynaptic Accumulation of α-Synuclein and LRRK2 in the Brain , 2012, The Journal of Neuroscience.

[93]  P. Bruni,et al.  Sphingosine 1-phosphate stimulates proliferation and migration of satellite cells: role of S1P receptors. , 2012, Biochimica et biophysica acta.

[94]  S. Haggarty,et al.  An epigenetic blockade of cognitive functions in the neurodegenerating brain , 2012, Nature.

[95]  D. Rubinsztein,et al.  Mechanisms of Autophagosome Biogenesis , 2012, Current Biology.

[96]  H. Hartung,et al.  Fingolimod in multiple sclerosis: mechanisms of action and clinical efficacy. , 2012 .

[97]  Yuan Yuan,et al.  Loss of Sphingosine Kinase 1/S1P Signaling Impairs Cell Growth and Survival of Neurons and Progenitor Cells in the Developing Sensory Ganglia , 2011, PloS one.

[98]  J. Jankovic,et al.  Resveratrol-Activated AMPK/SIRT1/Autophagy in Cellular Models of Parkinson's Disease , 2011, Neurosignals.

[99]  Ashok Kumar,et al.  The sphingolipid degradation product trans-2-hexadecenal induces cytoskeletal reorganization and apoptosis in a JNK-dependent manner. , 2011, Cellular signalling.

[100]  J. Trojanowski,et al.  BACE1 Activity Is Modulated by Cell-Associated Sphingosine-1-Phosphate , 2011, The Journal of Neuroscience.

[101]  J. Morris,et al.  The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer's disease , 2011, Alzheimer's & Dementia.

[102]  Sparsh Gupta,et al.  Fingolimod (FTY720): First approved oral therapy for multiple sclerosis , 2011, Journal of pharmacology & pharmacotherapeutics.

[103]  D. Swandulla,et al.  Sphingosine-1-phosphate links glycosphingolipid metabolism to neurodegeneration via a calpain-mediated mechanism , 2011, Cell Death and Differentiation.

[104]  A. Borowsky,et al.  S1P lyase: a novel therapeutic target for ischemia-reperfusion injury of the heart. , 2011, American journal of physiology. Heart and circulatory physiology.

[105]  D. C. Simpson,et al.  Sphingosine‐1‐phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[106]  S. Milstien,et al.  Sphingosine-1-phosphate phosphohydrolase-1 regulates ER stress-induced autophagy , 2011, Cell Death and Differentiation.

[107]  G. Prestwich,et al.  Characterization of sphingosine-1-phosphate lyase activity by electrospray ionization-liquid chromatography/tandem mass spectrometry quantitation of (2E)-hexadecenal. , 2011, Analytical biochemistry.

[108]  K. Kain,et al.  S1P Is Associated with Protection in Human and Experimental Cerebral Malaria , 2011, Molecular medicine.

[109]  M. Ohno,et al.  Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits. , 2011, Brain : a journal of neurology.

[110]  Alan G. E. Wilson,et al.  Inhibition of sphingosine 1-phosphate lyase for the treatment of rheumatoid arthritis: discovery of (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone oxime (LX2931) and (1R,2S,3R)-1-(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932). , 2010, Journal of medicinal chemistry.

[111]  M. Grütter,et al.  Structure and function of sphingosine-1-phosphate lyase, a key enzyme of sphingolipid metabolism. , 2010, Structure.

[112]  R. Proia,et al.  Sphingosine 1-Phosphate Lyase Deficiency Disrupts Lipid Homeostasis in Liver* , 2010, The Journal of Biological Chemistry.

[113]  M. Maceyka,et al.  Extracellular and intracellular actions of sphingosine-1-phosphate. , 2010, Advances in experimental medicine and biology.

[114]  C. Bauvy,et al.  Experimental Therapeutics , Molecular Targets , and Chemical Biology Disruption of Sphingosine 1-Phosphate Lyase Confers Resistance to Chemotherapy and Promotes Oncogenesis through Bcl-2 / Bcl-xL Upregulation , 2009 .

[115]  Cheng Luo,et al.  Regulation of Histone Acetylation in the Nucleus by Sphingosine-1-Phosphate , 2009, Science.

[116]  Ashok Kumar,et al.  Lyase to live by: Sphingosine phosphate lyase as a therapeutic target , 2009, Expert opinion on therapeutic targets.

[117]  Cihan Çetin,et al.  Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. , 2009, Nature chemical biology.

[118]  Alan G. E. Wilson,et al.  Inhibition of sphingosine-1-phosphate lyase for the treatment of autoimmune disorders. , 2009, Journal of medicinal chemistry.

[119]  R. Proia,et al.  Subcellular Origin of Sphingosine 1-Phosphate Is Essential for Its Toxic Effect in Lyase-deficient Neurons* , 2009, Journal of Biological Chemistry.

[120]  H. Meng,et al.  Differential expression of sphingosine‐1‐phosphate receptors 1‐5 in the developing nervous system , 2009, Developmental dynamics : an official publication of the American Association of Anatomists.

[121]  P. Dolan,et al.  Histone deacetylase 6 interacts with the microtubule‐associated protein tau , 2008, Journal of neurochemistry.

[122]  Yusuf A. Hannun,et al.  Principles of bioactive lipid signalling: lessons from sphingolipids , 2008, Nature Reviews Molecular Cell Biology.

[123]  J. Cyster,et al.  S1P1 receptor signaling overrides retention mediated by G alpha i-coupled receptors to promote T cell egress. , 2008, Immunity.

[124]  T. Ueno,et al.  LC3 and Autophagy. , 2008, Methods in molecular biology.

[125]  E. Persohn,et al.  Brain Penetration of the Oral Immunomodulatory Drug FTY720 and Its Phosphorylation in the Central Nervous System during Experimental Autoimmune Encephalomyelitis: Consequences for Mode of Action in Multiple Sclerosis , 2007, Journal of Pharmacology and Experimental Therapeutics.

[126]  E. Clementi,et al.  Sphingosine 1‐Phosphate Mediates Proliferation and Survival of Mesoangioblasts , 2007, Stem cells.

[127]  F. Hsu,et al.  Redirection of sphingolipid metabolism toward de novo synthesis of ethanolamine in Leishmania , 2007, The EMBO journal.

[128]  T. Ohmori,et al.  Essential Roles of Sphingosine 1‐Phosphate/S1P1 Receptor Axis in the Migration of Neural Stem Cells Toward a Site of Spinal Cord Injury , 2007, Stem cells.

[129]  C. S. Raymond,et al.  PDGF signaling specificity is mediated through multiple immediate early genes , 2007, Nature Genetics.

[130]  M. Salvadori,et al.  FTY720 versus MMF with Cyclosporine in de novo Renal Transplantation: A 1‐Year, Randomized Controlled Trial in Europe and Australasia , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[131]  A. Borowsky,et al.  Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer , 2006, Proceedings of the National Academy of Sciences.

[132]  M. Vasko,et al.  Intracellular sphingosine 1‐phosphate mediates the increased excitability produced by nerve growth factor in rat sensory neurons , 2006, The Journal of physiology.

[133]  G. Russ,et al.  FTY720/Cyclosporine Regimens in De Novo Renal Transplantation: A 1‐Year Dose‐Finding Study , 2006, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[134]  H. Kretzschmar,et al.  Synapse Formation and Function Is Modulated by the Amyloid Precursor Protein , 2006, The Journal of Neuroscience.

[135]  Masaaki Komatsu,et al.  Loss of autophagy in the central nervous system causes neurodegeneration in mice , 2006, Nature.

[136]  Hideyuki Okano,et al.  Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice , 2006, Nature.

[137]  L. Riboni,et al.  Sphingosine‐1‐phosphate is released by cerebellar astrocytes in response to bFGF and induces astrocyte proliferation through Gi‐protein‐coupled receptors , 2006, Glia.

[138]  B. Kinzel,et al.  Sphingosine kinase type 2 is essential for lymphopenia induced by the immunomodulatory drug FTY720. , 2006, Blood.

[139]  H. Matsuyuki,et al.  Role of sphingosine 1-phosphate receptor type 1 in lymphocyte egress from secondary lymphoid tissues and thymus. , 2006, Cellular & molecular immunology.

[140]  R. Proia,et al.  Essential Role for Sphingosine Kinases in Neural and Vascular Development , 2005, Molecular and Cellular Biology.

[141]  K. Chiba FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. , 2005, Pharmacology & therapeutics.

[142]  B. Oskouian,et al.  The Immune Modulator FTY720 Inhibits Sphingosine-1-phosphate Lyase Activity* , 2005, Journal of Biological Chemistry.

[143]  Ying Xu,et al.  Lymphocyte Sequestration Through S1P Lyase Inhibition and Disruption of S1P Gradients , 2005, Science.

[144]  P. Bruni,et al.  Sphingosine 1‐phosphate regulates myogenic differentiation: a major role for S1P2 receptor , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[145]  R. Proia,et al.  Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit , 2005, The Journal of experimental medicine.

[146]  A. Kihara,et al.  Sphingosine-1-phosphate lyase SPL is an endoplasmic reticulum-resident, integral membrane protein with the pyridoxal 5'-phosphate binding domain exposed to the cytosol. , 2004, Biochemical and biophysical research communications.

[147]  Amadeu Llebaria,et al.  Specificity of the Dihydroceramide Desaturase Inhibitor N-[(1R,2S)-2-Hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (GT11) in Primary Cultured Cerebellar Neurons , 2004, Molecular Pharmacology.

[148]  S. Payne,et al.  Differential transactivation of sphingosine-1-phosphate receptors modulates NGF-induced neurite extension , 2004, The Journal of cell biology.

[149]  R. Proia,et al.  Expression of the Sphingosine 1-Phosphate Receptor, S1P1, on T-cells Controls Thymic Emigration* , 2004, Journal of Biological Chemistry.

[150]  M. Moskowitz,et al.  Sphingosine‐1‐phosphate induces proliferation and morphological changes of neural progenitor cells , 2004, Journal of neurochemistry.

[151]  R. Proia,et al.  Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1 , 2004, Nature.

[152]  S. Payne,et al.  The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2 , 2003, FEBS letters.

[153]  K. Budde,et al.  First human trial of FTY720, a novel immunomodulator, in stable renal transplant patients. , 2002, Journal of the American Society of Nephrology : JASN.

[154]  J. Vermeesch,et al.  Human sphingosine-1-phosphate lyase: cDNA cloning, functional expression studies and mapping to chromosome 10q22(1). , 2000, Biochimica et biophysica acta.

[155]  T. Hanano,et al.  Synthesis and immunosuppressive activity of 2-substituted 2-aminopropane-1,3-diols and 2-aminoethanols. , 2000, Journal of medicinal chemistry.

[156]  P. Dash,et al.  Sphingosine-1-phosphate induces apoptosis of cultured hippocampal neurons that requires protein phosphatases and activator protein-1 complexes , 1999, Neuroscience.

[157]  S. Chueh,et al.  Prophylaxis of acute renal allograft rejection using FTY720 in combination with subtherapeutic doses of cyclosporine. , 1999, Transplantation.

[158]  M. Bradbury,et al.  The immunomodulatory compound 2‐acetyl‐4‐tetrahydroxybutyl imidazole causes sequestration of lymphocytes in non‐lymphoid tissues , 1997, Immunology and cell biology.

[159]  S. Spiegel,et al.  Involvement of Sphingosine 1-Phosphate in Nerve Growth Factor-Mediated Neuronal Survival and Differentiation , 1997, The Journal of Neuroscience.

[160]  M. Reale,et al.  Generation of TNF alpha, IFN gamma, IL-6, IL-4 and IL-10 in mouse serum from trichinellosis: effect of the anti-inflammatory compound 4-deoxypyridoxine (4-DPD). , 1996, Immunology letters.

[161]  T. Fujita,et al.  Design, synthesis, and structure-activity relationships of 2-substituted-2-amino-1,3-propanediols: Discovery of a novel immunosuppressant, FTY720 , 1995 .

[162]  T. Okumoto,et al.  Fungal metabolites. Part 11. A potent immunosuppressive activity found in Isaria sinclairii metabolite. , 1994, The Journal of antibiotics.

[163]  Stephen P. Miller,et al.  Synthesis of an inhibitor of sphingosine-1-phosphate lyase , 1994 .

[164]  A. D. de Groot,et al.  The effect of pyridoxine on the number of lymphocytes in the blood of rats fed caramel colour (III). , 1988, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[165]  J. Greef,et al.  2-Acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)imidazole: detection in commercial caramel color III and preparation by a model browning reaction , 1985 .

[166]  W. Stoffel,et al.  Chemistry and biochemistry of 1-desoxysphinganine 1-phosphonate (dihydrosphingosine-1-phosphonate). , 1974, Chemistry and physics of lipids.

[167]  E. P. Kennedy,et al.  The function of cytidine coenzymes in the biosynthesis of phospholipides. , 1956, The Journal of biological chemistry.