Aberrant upregulation of astroglial ceramide potentiates oligodendrocyte injury.
Aberrant upregulation of astroglial ceramide potentiates oligodendrocyte injury.
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DOI：
10.1111/j.1750-3639.2011.00501.x
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发表时间：
2012-01
期刊：
影响因子：
--
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Kim S;Steelman AJ;Zhang Y;Kinney HC;Li J
少突胶质损伤是许多人类白质疾病的病理标志，包括多发性硬化症和脑室周围白质软化症。然而，少突胶质细胞破坏的关键调控机制仍然不完全清楚。神经酰胺是一种生物活性鞘脂，对鞘脂代谢途径至关重要，在多种刺激下调节细胞死亡，并与神经退行性疾病有关。我们在此报道，神经酰胺在多发性硬化症和脑室周围白质软化的活动性病变中的反应性星形胶质细胞中积累，以及在脱髓鞘动物模型中。丝氨酸棕榈酰基转移酶是神经酰胺新生生物合成的限速酶，在铜酮小鼠脱髓鞘模型中的反应性星形细胞中持续上调。质谱分析证实了脱髓鞘过程中特定神经酰胺的上调，并揭示了鞘氨醇的增加以及鞘氨醇-1-磷酸的抑制，鞘氨醇-1-磷酸是一种有效的信号分子，在细胞存活和有丝分裂中起关键作用。重要的是，脱髓鞘过程中鞘脂代谢的改变在活跃的髓鞘再生过程中得以恢复。在培养中，神经酰胺与肿瘤坏死因子协同作用，以星形胶质细胞依赖的方式导致少突胶质细胞凋亡死亡。综上所述，我们的研究结果表明，反应性星形胶质细胞中的鞘脂通路紊乱可能间接导致脑白质疾病中的少突胶质损伤。
Oligodendroglial injury is a pathological hallmark of many human white matter diseases, including multiple sclerosis and periventricular leukomalacia. Critical regulatory mechanisms of oligodendroglia destruction, however, remain incompletely understood. Ceramide, a bioactive sphingolipid pivotal to sphingolipid metabolism pathways, regulates cell death in response to diverse stimuli and has been implicated in neurodegenerative disorders. We report here that ceramide accumulates in reactive astrocytes in active lesions of multiple sclerosis and periventricular leukomalacia, as well as in animal models of demyelination. Serine palmitoyltransferase, the rate-limiting enzyme for ceramide de novo biosynthesis, was consistently upregulated in reactive astrocytes in the cuprizone mouse model of demyelination. Mass spectrometry confirmed the upregulation of specific ceramides during demyelination and revealed a concomitant increase of sphingosine as well as a suppression of sphingosine-1-phosphate, a potent signaling molecule with key roles in cell survival and mitogenesis. Importantly, this altered sphingolipid metabolism during demyelination was restored upon active remyelination. In culture, ceramide acted synergistically with tumor necrosis factor leading to apoptotic death of oligodendroglia in an astrocyte-dependent manner. Taken together, our findings implicate that disturbed sphingolipid pathways in reactive astrocytes may indirectly contribute to oligodendroglial injury in cerebral white matter disorders.