title: Sphingosine kinase 1 and sphingosine-1-phosphate in oxidative stress evoked by 1-methyl-4-phenylpyridinium (MPP+) in human dopaminergic neuronal cells.
abstract: Sphingosine kinases (Sphk1/2) are crucial enzymes in regulation of the biostat between sphingosine-1-phosphate (S1P) and ceramide and play an important role in the pathogenesis/pathomechanism of Alzheimer's disease (AD). These enzymes synthesise S1P, which regulates neurotransmission, synaptic function and neuron cell proliferation, by activating five G protein-coupled receptors (S1P1-5). However, S1P synthesised by Sphk2 could be involved in amyloid β (Aβ) release by stimulation of Aβ precursor protein degradation. The significance of this bioactive sphingolipid in the pathogenesis of Parkinson's disease (PD) is unknown. The aim of our study was to investigate the expression level of Sphk1 and its role in human dopaminergic neuronal cell (SH-SY5Y) viability under oxidative stress, evoked by 1-methyl-4-phenylpyridinium (MPP+). Moreover, the mechanism of S1P action on the death signalling pathway in these experimental conditions was evaluated. Our study indicated marked downregulation of Sphk1 expression in this cellular PD model. Inhibition of Sphk1 decreased SH-SY5Y cell viability and concomitantly enhanced the reactive oxygen species (ROS) level. It was found that exogenous S1P (1 μM) exerted the neuroprotective effect by activation of Sphk1 and S1P1 receptor gene expression. Moreover, S1P downregulated Bax and harakiri, death protein 5 (Hrk/DP5) expression and enhanced cell viability in MPP+-treated cells. The neuroprotective mechanism of S1P is mainly dependent on S1P1 receptor signalling, which was indicated by using specific agonists and antagonists of S1P1 receptor. The results show that S1P and S1P1 receptor agonists protected a significant population of neuronal cells against death.
authors.affiliation: Department of Cellular Signalling, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Pyszko
authors.forename: Joanna B
authors.initials: JB
authors.lastname: Strosznajder
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D010300:Parkinson Disease / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D015655:1-Methyl-4-phenylpyridinium; D002518:Ceramides; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D017382:Reactive Oxygen Species; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate