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
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
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DOI：
10.1016/j.neuroscience.2015.01.032
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发表时间：
2015-04-02
期刊：
影响因子：
3.3
通讯作者：
Tay, S. S. W.
中科院分区：
文献类型：
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作者：
Sivasubramanian, M.;Kanagaraj, N.;Tay, S. S. W.
鞘脂代谢失调已被证明触发许多神经退行性疾病的病理生理学。本研究的重点是两种鞘氨醇激酶之一，Sphk 2及其代谢产物鞘氨醇-1-磷酸（S1 P）信号在帕金森病（PD）中的作用。我们的研究表明，在1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的PD小鼠模型的黑质区域和细胞PD模型中，Sphk 2表达显著下调。定位研究表明Sphk 2主要存在于线粒体中，提出了其在线粒体功能中的潜在作用。由于线粒体功能障碍已被描述为PD的主要病理事件，本研究集中于Sphk 2/S1 P信号在MPTP诱导的PD小鼠模型和1-甲基-4-苯基吡啶（MPP+）处理的MN 9D细胞中促进线粒体功能的作用。我们的研究表明，Sphk 2的抑制降低了过氧化物酶体增殖物激活受体γ共激活因子-1 α（PGC-1 α）及其下游靶点核呼吸因子1（NRF-1）和线粒体转录因子A（TFAM）的表达，这些基因是调节线粒体功能的关键基因。此外，也有一个显着的减少，总细胞三磷酸腺苷（ATP）和超氧化物歧化酶2（SOD 2）与活性氧（ROS）的水平增加，在Sphk 2的情况下。有趣的是，发现用外源性S1 P沿着MPP+处理细胞通过激活MN 9D细胞中的p-CREB、PGC-1 α和NRF-1而发挥神经保护作用。此外，在MPP+处理的细胞中，在S1 P的存在下，ATP的水平不受影响。还观察到，在外源性S1 P存在下，MPP+处理的细胞中的ROS水平显著降低。我们的研究还表明，S1 P通过S1 P1受体发挥其保护作用。综上所述，这些结果表明Sphk 2/S1 P在PD的发病机制中对多巴胺能神经元的存活具有重要作用。(C)2015年IBRO。由Elsevier Ltd.出版。保留所有权利。
Dysregulation of sphingolipid metabolism has been shown to trigger the pathophysiology of many neuro-degenerative 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 gamma coactivator-1 alpha (PGC-1 alpha) 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-1 alpha 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. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.