Explore the Role of the Sphingosine-1-Phosphate Signalling as a Novel Promising Therapeutic Target for the Management of Parkinson's Disease

Abstract

Sphingosine-1-phosphate (S1P) is a cellular signalling molecule derived from sphingosine, which is a pro-apoptotic sphingolipid. Sphingolipids control various cellular actions like growth, homeostasis, and stress-related responses. The main sources of S1P in our body are erythrocytes. S1P controls both cellular mediators and other second messengers intracellularly. The S1P receptor also helps in inflammatory and neuroprotective effects (required to manage of Parkinsonʼs). A large number of anti-Parkinson drugs are available, but still, there is a need for more effective and safer drugs. S1P and its receptors could be targeted as novel drugs due to their involvement in neuro-inflammation and Parkinsonʼs. The present review effort to explore the biological role of S1P and related receptors, for their possible involvement in PD; furthermore. Overall, S1P and other related metabolizing enzymes have significant therapeutic opportunities for Parkinsonʼs disease along with other neurological disorders.

Keywords

central nervous system - neuroinflammation - neuroprotective - Parkinsonʼs disease - sphingosine 1-phosphate (S1P) signalling

Publication History

Received: 22 May 2024

Accepted: 20 August 2024

Article published online:
01 October 2024

• References

• 1 Motyl J, Strosznajder JB. Sphingosine kinase 1/sphingosine-1-phosphate receptors dependent signalling in neurodegenerative diseases. The promising target for neuroprotection in Parkinsonʼs disease. Pharmacological Reports 2018; 70: 1010-1014
• 2 Winblad B, Amouyel P, Andrieu S. et al. Defeating Alzheimerʼs disease and other dementias: a priority for European science and society. The Lancet Neurology 2016; 15: 455-532
• 3 Perier C, Bove J, Vila M. Mitochondria and programmed cell death in Parkinsonʼs disease: apoptosis and beyond. Antioxidants & Redox Signaling 2012; 16: 883-895
• 4 Al Shahrani M, Heales S, Hargreaves I. et al. Oxidative stress: mechanistic insights into inherited mitochondrial disorders and Parkinsonʼs disease. Journal of Clinical Medicine 2017; 6: 100
• 5 Ganguly G, Chakrabarti S, Chatterjee U. et al. Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimerʼs disease and Parkinsonʼs disease. Drug Design, Development and Therapy 2017; 11: 797
• 6 Assi E, Cazzato D, De Palma C. et al. Sphingolipids and brain resident macrophages in neuroinflammation: an emerging aspect of nervous system pathology. Clinical and Developmental Immunology 2013; 2013: 309302
• 7 Perrotta C, Cervia D, De Palma C. et al. The emerging role of Acid Sphingomyelinase in autophagy. Apoptosis 2015; 20: 635-644
• 8 Lucaciu A, Brunkhorst R, Pfeilschifter JM. et al. The S1P–S1PR axis in neurological disorders-Insights into current and future therapeutic perspectives. Cells. 2020; 9: 1515
• 9 Wang X, Huaqiang Li, Yunjie S. et al. The function of sphingolipids in different pathogenesis of Alzheimerʼs disease: A comprehensive review. Biomedicine & Pharmacotherapy 2024; 171: 116071
• 10 Archbold JK, Martin JL, Sweet MJ. Towards selective lysophospholipid GPCR modulators. Trends in Pharmacological Sciences 2014; 35: 219-226
• 11 Yung YC, Stoddard NC, Mirendil H. et al. Lysophosphatidic acid signaling in the nervous system. Neuron 2015; 85: 669-682
• 12 Ben-Shlomo Y, Darweesh S, Llibre-Guerra J. et al. The epidemiology of Parkinsonʼs disease. The Lancet 2024; 403: 283-292
• 13 Kang SH, Moon SJ, Kang M. et al. Incidence of Parkinsonʼs disease and modifiable risk factors in Korean population: A longitudinal follow-up study of a nationwide cohort. Front. Aging Neurosci. 2023; 15: 1094778
• 14 Zafar S, Yaddanapud SS. Parkinson Disease. Treasure Island (FL): StatPearls Publishing; 2023
• 15 Vasconcellos LFR, Pereira JS, Charchat-Fichman H. et al. Mild cognitive impairment in Parkinsonʼs disease: Characterization and impact on quality of life according to subtype. Geriatrics & Gerontology International 2019; 19: 497-502
• 16 Telarovic S. Epidemiology of Parkinsonʼs Disease. Archives of Psychiatry Research 2023; 59: 147-148
• 17 Prakash K, Nadkarni N, Lye WK. et al. The impact of non-motor symptoms on the quality of life of Parkinsonʼs disease patients: a longitudinal study. European Journal of Neurology 2016; 23: 854-860
• 18 Teive HA, Bertucci Filho DC, Munhoz RP. Unusual motor and non-motor symptoms and signs in the early stage of Parkinsonʼs disease. Arquivos De Neuro-psiquiatria 2016; 74: 781-784
• 19 Al-Khammash N, Al-Jabri N, Albishi A. et al. Quality of Life in Patients With Parkinsonʼs Disease: A Cross-Sectional Study. Cureus 2023; 15: e33989
• 20 Mueller C, Rajkumar AP, Wan YM. et al. Assessment and management of neuropsychiatric symptoms in Parkinsonʼs disease. CNS Drugs 2018; 32: 621-635
• 21 Aarsland D, Bronnick K, Williams-Gray C. et al. Mild cognitive impairment in Parkinson disease: a multicenter pooled analysis. Neurology 2010; 75: 1062-1069
• 22 Tolosa E, Wenning G, Poewe W. The diagnosis of Parkinsonʼs disease. The Lancet Neurology 2006; 5: 75-86
• 23 Zis P, Erro R, Walton CC. et al. The range and nature of non-motor symptoms in drug-naive Parkinsonʼs disease patients: a state-of-the-art systematic review. npj Parkinsonʼs Disease 2015; 1: 1-8
• 24 Martinez-Martinez P, Mencarelli C. Ceramide function in the brain: when a slight tilt is enough. Cellular and Molecular Life Sciences 2013; 70: 181-203
• 25 Martinez-Martin P, Rojo-Abuin JM, Rizos A. et al. Distribution and impact on quality of life of the pain modalities assessed by the Kingʼs Parkinsonʼs disease pain scale. npj Parkinsonʼs Disease 2017; 3: 1-6
• 26 Nakamura SI, Fukai E, Miya S. et al. Sphingolipid signaling and neuronal function. Pharmacological Reports 2011; 63: 1279-1280
• 27 Jesko H, Stepie A, Lukiw WJ. et al. The Cross-Talk Between Sphingolipids and Insulin-Like Growth Factor Signaling: Significance for Aging and Neurodegeneration. Mol. Neurobiol 2019; 56: 3501-3521
• 28 Maceyka M, Spiegel S. Sphingolipid metabolites in inflammatory disease. Nature. 2014; 510: 58-67
• 29 Nagahashi M, Miyoshi Y. Targeting Sphingosine-1-Phosphate Signaling in Breast Cancer. Int J Mol Sci 2024; 25: 3354
• 30 Lee M, Lee SY, Bae YS. Functional roles of sphingolipids in immunity and their implication in disease. Exp Mol Med 2023; 55: 1110-1130
• 31 Seal A, Hughes M, Wei F. et al. Sphingolipid-Induced Bone Regulation and Its Emerging Role in Dysfunction Due to Disease and Infection. International Journal of Molecular Sciences 2024; 25: 3024
• 32 Wang W, Zhao Y, Zhu G. The role of sphingosine-1-phosphate in the development and progression of Parkinsonʼs disease. Front Cell Neurosci 2023; 17: 1288437
• 33 Motyl J, Przykaza Ł, Boguszewski PM. et al. Pramipexole And Fingolimod Exert Neuroprotection In A Mouse Model Of Parkinsonʼs disease by activation of sphingosine kinase 1 and Akt kinase. Neuropharmacology 2018; 135: 139-150
• 34 Breslow DK, Weissman JS. Membranes in balance: mechanisms of sphingolipid homeostasis. Molecular Cell 2010; 40: 267-279
• 35 Breslow DK, Collins SR, Bodenmiller B. et al. Orm family proteins mediate sphingolipid homeostasis. Nature 2010; 463: 1048-1053
• 36 Ali-Berrada S, Guitton J, Tan-Chen S. et al. Circulating Sphingolipids and Glucose Homeostasis: An Update. International Journal of Molecular Sciences 2023; 24: 12720
• 37 Ghasemi R, Dargahi L, Ahmadiani A. Integrated sphingosine-1 phosphate signaling in the central nervous system: from physiological equilibrium to pathological damage. Pharmacological Research 2016; 104: 156-164
• 38 Czubowicz K, Jęśko H, Wencel P. et al. The role of ceramide and sphingosine-1-phosphate in Alzheimerʼs disease and other neurodegenerative disorders. Molecular Neurobiology 2019; 56: 5436-5455
• 39 Sedelis M, Schwarting RK, Huston JP. Behavioral phenotyping of the MPTP mouse model of Parkinsonʼs disease. Behavioural Brain Research 2001; 125: 109-125
• 40 Pyszko J, Strosznajder JB. Sphingosine kinase 1 and sphingosine-1-phosphate in oxidative stress evoked by 1-methyl-4-phenylpyridinium (MPP+) in human dopaminergic neuronal cells. Molecular Neurobiology 2014a 50: 38-48
• 41 Sivasubramanian M, Kanagaraj N, Dheen S. et al. Sphingosine kinase 2 and sphingosine-1-phosphate promotes mitochondrial function in dopaminergic neurons of mouse model of Parkinsonʼs disease and in MPP+-treated MN9D cells in vitro. Neuroscience 2015; 290: 636-648
• 42 Grassi S, Mauri L, Prioni S. et al. Sphingosine 1-phosphate receptors and metabolic enzymes as druggable targets for brain diseases. Frontiers in Pharmacology 2019; 10: 807
• 43 Alkafaas SS, Elsalahaty MI, Ismail DF. The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target. Cancer Cell Int 2024; 24: 89
• 44 Wang D, Tang Y, Tang Y. et al. Role of sphingolipid metabolites in the homeostasis of steroid hormones and the maintenance of testicular functions. Front. Endocrinol. Sec. Cellular Endocrinology 2023; 14: 1170023
• 45 Abul KSB, Dhanushkodi NR, Ardah MT. et al. Silencing of glucocerebrosidase gene in Drosophila enhances the aggregation of Parkinsonʼs disease associated α-synuclein mutant A53T and affects locomotor activity. Frontiers in Neuroscience 2018; 12: 81
• 46 Bras J, Singleton A, Cookson MR. et al. Emerging pathways in genetic Parkinsonʼs disease: potential role of ceramide metabolism in Lewy body disease. The FEBS Journal 2008; 275: 5767-5773
• 47 Sato S, Li Y, Hattori N. Lysosomal defects in ATP13A2 and GBA associated familial Parkinsonʼs disease. Journal of Neural Transmission 2017; 124: 1395-1400
• 48 Taguchi YV, Liu J, Ruan J. et al. Glucosylsphingosine promotes α-synuclein pathology in mutant GBA-associated Parkinsonʼs disease. Journal of Neuroscience 2017; 37: 9617-9631
• 49 Pchelina S, Emelyanov A, Baydakova G. et al. Oligomeric α-synuclein and glucocerebrosidase activity levels in GBA-associated Parkinsonʼs disease. Neuroscience Letters 2017; 636: 70-76
• 50 Mielke MM, Maetzler W, Haughey NJ. et al. Plasma ceramide and glucosylceramide metabolism is altered in sporadic Parkinsonʼs disease and associated with cognitive impairment: a pilot study. PloS One 2013; 8: e73094
• 51 Abbott SK, Li H, Muñoz SS. et al. Altered ceramide acyl chain length and ceramide synthase gene expression in Parkinsonʼs disease. Movement Disorders 2014; 29: 518-526
• 52 Brodowicz J, Przegaliński E, Müller CP. et al. Ceramide and its related neurochemical networks as targets for some brain disorder therapies. Neurotoxicity Research 2018; 33: 474-484
• 53 Xing Y, Tang Y, Zhao L. et al. Associations between plasma ceramides and cognitive and neuropsychiatric manifestations in Parkinsonʼs disease dementia. Journal of the Neurological Sciences 2016; 370: 82-87
• 54 Grinkina NM, Karnabi EE, Damania D. et al. Sphingosine Kinase 1 Deficiency Exacerbates Lps-Induced Neuroinflammation. Plos One 2012; 7: e36475
• 55 Vos M, Christine K, Andrew AH. Role of Ceramides and Sphingolipids in Parkinsonʼs Disease. Journal of Molecular Biology 2023; 435: 168000
• 56 Xiao S, Peng K, Li C. The role of sphingosine-1-phosphate in autophagy and related disorders. Cell Death Discov 2023; 9: 380
• 57 Manchon MJF, Uzor NE, Finkbeiner S. et al. Sphk1/Sphingosine kinase 1-mediated autophagy differs between neurons and SH-SY5Y neuroblastoma cells. Autophagy 2016; 12: 1418-1424
• 58 Moon E, Han JE, Jeon S. et al. Exogenous S1P exposure potentiates ischemic stroke damage that is reduced possibly by inhibiting S1P receptor signaling. Mediators of inflammation 2015; 2015: 492659
• 59 Oʼsullivan S, Dev KK. Sphingosine-1-phosphate receptor therapies: advances in clinical trials for CNS-related diseases. Neuropharmacology 2017; 113: 597-607
• 60 Ishii T, Kinoshita KI, Muroi Y. Serotonin 5-HT4 Receptor Agonists Improve Facilitation of Contextual Fear Extinction in an MPTP-Induced Mouse Model of Parkinsonʼs Disease. International Journal of Molecular Sciences 2019; 20: 5340
• 61 Van Horssen J, Van Schaik P, Witte M. Inflammation And Mitochondrial dysfunction: A vicious circle in neurodegenerative disorders?. Neuroscience Letters 2019; 710: 132931
• 62 Liu Z, Chen HQ, Huang Y. et al. Transforming growth factor-β1 acts via TβR-I on microglia to protect against MPP+-induced dopaminergic neuronal loss. Brain, Behavior, and Immunity 2016; 51: 131-143
• 63 Yao S, Li L, Sun X. et al. FTY720 Inhibits MPP+-Induced Microglial Activation by Affecting NLRP3 Inflammasome Activation. Journal of Neuroimmune Pharmacology 2019; 14: 478-492
• 64 Baeyens A, Fang V, Chen C. et al. Exit strategies: S1P signaling and T cell migration. Trends in Immunology 2015; 36: 778-787
• 65 Chung WS, Allen NJ, Eroglu C. Astrocytes control synapse formation, function, and elimination. Cold Spring Harbor Perspectives in Biology 2015; 7: a020370
• 66 Gualtierotti R, Guarnaccia L, Beretta M. et al. Modulation of neuroinflammation in the central nervous system: role of chemokines and sphingolipids. Advances in Therapy 2017; 34: 396-420
• 67 Marfia G, Navone SE, Hadi LA. et al. The adipose mesenchymal stem cell secretome inhibits inflammatory responses of microglia: evidence for an involvement of sphingosine-1-phosphate signalling. Stem Cells and Development 2016; 25: 1095-1107
• 68 Hisano Y, Kono M, Cartier A. et al. Lysolipid receptor cross-talk regulates lymphatic endothelial junctions in lymph nodes. Journal of Experimental Medicine 2019; 216: 1582-1598
• 69 Park SJ, Im DS. Sphingosine 1-phosphate receptor modulators and drug discovery. Biomolecules & Therapeutics 2017; 25: 80
• 70 Baird JK, Bourdette D, Meshul CK. et al. The key role of T cells in Parkinsonʼs disease pathogenesis and therapy. Parkinsonism & Related Disorders 2019; 60: 25-31
• 71 Zhao P, Yang X, Yang L. et al. Neuroprotective effects of fingolimod in mouse models of Parkinsonʼs disease. The FASEB Journal 2017; 31: 172-179
• 72 Sarkar S, Malovic E, Harishchandra DS. et al. Mitochondrial impairment in microglia amplifies NLRP3 inflammasome proinflammatory signaling in cell culture and animal models of Parkinsonʼs disease. NPJ Parkinsonʼs Disease 2017; 3: 1-15
• 73 Mcmanus RM, Finucane OM, Wilk MM. et al. Fty720 Attenuates Infection-Induced Enhancement Of Aβ Accumulation In App/Ps1 Mice By Modulating Astrocytic Activation. Journal of Neuroimmune Pharmacology 2017; 12: 670-681
• 74 Ren M, Han M, Wei X. et al. FTY720 attenuates 6-OHDA-associated dopaminergic degeneration in cellular and mouse parkinsonian models. Neurochemical Research 2017; 42: 686-696
• 75 Pyszko JA, Strosznajder JB. The key role of sphingosine kinases in the molecular mechanism of neuronal cell survival and death in an experimental model of Parkinsonʼs disease. Folia Neuropathol 2014b 52: 260-269
• 76 Bienias K, Fiedorowicz A, Sadowska A. et al. Regulation of sphingomyelin metabolism. Pharmacological Reports 2016; 68: 570-581
• 77 Badawy SMM, Okada T, Kajimoto T. et al. Extracellular α-synuclein drives sphingosine 1-phosphate receptor subtype 1 out of lipid rafts, leading to impaired inhibitory G-protein signaling. Journal of Biological Chemistry 2018; 293: 8208-8216
• 78 Vidal-Martínez G, Vargas-Medrano J, Gil-Tommee C. et al. FTY720/Fingolimod Reduces Synucleinopathy and Improves Gut Motility in A53T Mice Contributions Of Pro-Brain-Derived Neurotrophic Factor (Pro-Bdnf) And Mature BDNF. Journal of Biological Chemistry 2016; 291: 20811-20821
• 79 Shen T, You Y, Joseph C. et al. BDNF polymorphism: a review of its diagnostic and clinical relevance in neurodegenerative disorders. Aging and Disease 2018; 9: 523
• 80 Pepin E, Jalinier T, Lemieux GL. et al. Sphingosine-1-Phosphate Receptors Modulators Decrease Signs of Neuroinflammation and Prevent Parkinsonʼs Disease Symptoms in the 1-Methyl-4-Phenyl-1, 2, 3, 6-Tetrahydropyridine Mouse Model. Frontiers in Pharmacology 2020; 11: 77
• 81 Pyne S, Adams DR, Pyne NJ. Sphingosine 1-phosphate and sphingosine kinases in health and disease: Recent advances. Progress in Lipid Research 2016; 62: 93-106
• 82 Huwiler A, Zangemeister-Wittke U. The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives. Pharmacology & Therapeutics 2018; 185: 34-49
• 83 Aytan N, Choi JK, Carreras I. et al. Fingolimod modulates multiple neuroinflammatory markers in a mouse model of Alzheimerʼs disease. Scientific Reports 2016; 6: 24939
• 84 Essis SA, Laurier-Laurin ME, Pépin É. et al. Glun2b-containing NMDA Receptors Are Upregulated in Plasma Membranes by the Sphingosine-1-Phosphate analog FTY720P. Brain Research 2015; 1624: 349-358
• 85 Pérez-Jeldres T, Alvarez-Lobos M, Rivera-Nieves J. Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis. Drugs 2021; 81: 985-1002
• 86 Jiang P, Dickson DW. Parkinsonʼs disease: experimental models and reality. Acta Neuropathol 2018; 135: 13-32
• 87 Zeng XS, Geng WS, Jia JJ. Neurotoxin-induced animal models of Parkinson disease: pathogenic mechanism and assessment. ASN Neuro 2018; 10: 17590914-18777438
• 88 Jankovic J. Parkinsonʼs disease: clinical features and diagnosis. Journal of Neurology, Neurosurgery & Psychiatry 2019; 79: 368-376
• 89 Kaegi G. Parkinsonism: heterogeneity of a common neurological syndrome. Swiss Medical Weekly 2011; 141: w13293
• 90 Carranza M, Snyder M, Shaw JD. et al. Parkinsonʼs Disease: A Guide to Medical Treatment. SEEd. 2013
• 91 Bajaj N, Hauser RA, Grachev ID. Clinical utility of dopamine transporter single photon emission CT (DaT-SPECT) with (123I) ioflupane in diagnosis of parkinsonian syndromes. Journal of Neurology, Neurosurgery & Psychiatry 2013; 84: 1288-1295
• 92 Heim B, Krismer F, De Marzi R. et al. Magnetic resonance imaging for the diagnosis of Parkinsonʼs disease. Journal of Neural Transmission 2017; 124: 915-964
• 93 Postuma RB, Berg D, Stern M. et al. MDS clinical diagnostic criteria for Parkinsonʼs disease. Movement Disorders 2015; 30: 1591-1601
• 94 Crosiers D, Santens P, Chaudhuri KR. Prodromal Parkinsonʼs Disease. Frontiers in Neurology 2020; 11: 634490
• 95 Fereshtehnejad SM, Postuma RB. Subtypes of Parkinsonʼs disease: what do they tell us about disease progression?. Current Neurology and Neuroscience Reports 2017; 17: 34
• 96 Stoessl J. Potential therapeutic targets for Parkinsonʼs disease. Expert opinion on therapeutic Targets 2008; 12: 425-436
• 97 Taddei RN, Spinnato F, Jenner P. New symptomatic treatments for the management of motor and nonmotor symptoms of Parkinsonʼs disease. International Review of Neurobiology 2017; 132: 407-452
• 98 Oertel W, Berardelli A, Bloem B. et al. Early (uncomplicated) Parkinsonʼs disease. European handbook of Neurological Management 2011; 1: 217-236
• 99 Sardi SP, Viel C, Clarke J. et al. Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models. Proceedings of the National Academy of Sciences 2017; 114: 2699-2704