title: Sphingosine kinase 2 and sphingosine-1-phosphate promotes mitochondrial function in dopaminergic neurons of mouse model of Parkinson's disease and in MPP+ -treated MN9D cells in vitro.
abstract: Dysregulation of sphingolipid metabolism has been shown to trigger the pathophysiology of many neurodegenerative disorders. The present study focuses on the role of one of the two sphingosine kinases, Sphk2 and its metabolite sphingosine-1-phosphate (S1P) signaling in Parkinson's disease (PD). Our study indicated a marked down regulation of Sphk2 expression in the substantia nigra region of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model and in the cellular PD model. Localization studies indicated that Sphk2 was predominantly present in mitochondria, proposing for its potential role in mitochondrial functions. Since mitochondrial dysfunction has been described to be the major pathological event in PD, the present study focused on the role of Sphk2/S1P signaling in promoting mitochondrial functions in the MPTP-induced mouse model of PD and in 1-methyl-4 phenylpyridinium (MPP(+))-treated MN9D cells. Our study demonstrated that inhibition of Sphk2 decreased the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and its downstream targets nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM) which are the key genes regulating mitochondrial function. In addition, there was also a significant reduction in the total cellular adenosine triphosphate (ATP) and superoxide dismutase 2 (SOD 2) with an associated increase in levels of reactive oxygen species (ROS) in the absence of Sphk2. Interestingly, it was found that treating the cells with exogenous S1P along with MPP(+) exerted a neuroprotective effect by activation of p-CREB, PGC-1α and NRF-1 in the MN9D cells. Moreover, the level of ATP was unaffected in the MPP(+)-treated cells in the presence of S1P. It was also observed that levels of ROS were significantly decreased in the MPP(+)-treated cells in the presence of exogenous S1P. Our study also demonstrated that S1P exerted its protective effect through the S1P1 receptor. Taken together, these results show that Sphk2/S1P has an important role to play in the survival of the dopaminergic neurons, in the pathogenesis of PD.
authors: Department of Anatomy, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore 117594, Singapore.
authors: M
authors: M
authors: Sivasubramanian
authors: Department of Anatomy, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore 117594, Singapore.
authors: N
authors: N
authors: Kanagaraj
authors: Department of Anatomy, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore 117594, Singapore.
authors: S T
authors: ST
authors: Dheen
authors: Department of Anatomy, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, Singapore 117594, Singapore. Electronic address: anttaysw@nus.edu.sg.
authors: S S W
authors: SS
authors: Tay
mesh_terms: D000199:Actins / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000473:pathology / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006609:High Mobility Group Proteins / Q000378:metabolism; D008246:Lysophospholipids / Q000008:administration & dosage / Q000378:metabolism*; D020267:MPTP Poisoning / Q000473:pathology / Q000503:physiopathology*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000502:physiology*; D051266:Nuclear Respiratory Factor 1 / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D013378:Substantia Nigra / Q000473:pathology / Q000503:physiopathology; D014157:Transcription Factors / Q000378:metabolism; D000099157:Sphingosine Kinase
chemical_list: D000199:Actins; D000255:Adenosine Triphosphate; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D008246:Lysophospholipids; D051266:Nuclear Respiratory Factor 1; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017853:Phosphotransferases (Alcohol Group Acceptor); D012333:RNA, Messenger; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D014157:Transcription Factors; C492004:Creb1 protein, mouse; C495634:Nrf1 protein, mouse; C485290:Ppargc1a protein, mouse; C081930:Tfam protein, mouse; C060506:sphingosine 1-phosphate; C000603447:sphingosine kinase 2, mouse; D000099157:Sphingosine Kinase
keywords: Parkinson’s disease; nuclear respiratory factor 1 (NRF-1); peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α); sphingosine kinase 2 (Sphk2); sphingosine-1-phosphate (S1P)