Department of Neurology and Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA.
Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, 6439 Garners Ferry Road, Columbia, SC, 29209, USA.
Neurochem Res. 2017 Oct;42(10):2755-2768. doi: 10.1007/s11064-017-2280-2. Epub 2017 May 5.
Multiple sclerosis (MS) is a demyelinating disorder characterized by massive neurodegeneration and profound axonal loss. Since myelin is enriched with sphingolipids and some of them display toxicity, biological function of sphingolipids in demyelination has been investigated in MS brain tissues. An elevation of sphingosine with a decrease in monoglycosylceramide and psychosine (myelin markers) was observed in MS white matter and plaque compared to normal brain tissue. This indicated that sphingosine toxicity might mediate oligodendrocyte degeneration. To explain the source of sphingosine accumulation, total sphingolipid profile was investigated in Lewis rats after inducing experimental autoimmune encephalomyelitis (EAE) and also in human oligodendrocytes in culture. An intermittent increase in ceramide followed by sphingosine accumulation in EAE spinal cord along with a stimulation of serine-palmitoyltransferase (SPT) activity was observed. Apoptosis was identified in the lumbar spinal cord, the most prominent demyelinating area, in the EAE rats. TNFα and IFNγ stimulation of oligodendrocytes in culture also led to an accumulation of ceramide with an elevation of sphingosine. Ceramide elevation was drastically blocked by myriocin, an inhibitor of SPT, and also by FTY720. Myriocin treatment also protected oligodendrocytes from cytokine mediated apoptosis or programmed cell death. Hence, we propose that sphingosine toxicity may contribute to demyelination in both EAE and MS, and the intermittent ceramide accumulation in EAE may, at least partly, be mediated via SPT activation, which is a novel observation that has not been previously reported.
多发性硬化症 (MS) 是一种脱髓鞘疾病，其特征是大量神经退行性变和轴突严重丢失。由于髓鞘富含神经酰胺，其中一些具有毒性，因此研究了鞘脂在 MS 脑组织脱髓鞘中的生物学功能。与正常脑组织相比，MS 白质和斑块中观察到神经酰胺的升高伴随着单糖神经酰胺和神经肌醇（髓鞘标志物）的降低。这表明神经酰胺毒性可能介导少突胶质细胞变性。为了解释神经酰胺积累的来源，在诱导实验性自身免疫性脑脊髓炎 (EAE) 后，对 Lewis 大鼠的总鞘脂谱进行了研究，同时还对培养的人少突胶质细胞进行了研究。EAE 脊髓中观察到神经酰胺间歇性增加，随后神经酰胺积累，同时丝氨酸棕榈酰转移酶 (SPT) 活性受到刺激。在 EAE 大鼠的腰椎脊髓中鉴定出细胞凋亡，这是最突出的脱髓鞘区域。TNFα 和 IFNγ 刺激培养中的少突胶质细胞也导致神经酰胺积累，同时升高神经酰胺。鞘氨醇的升高被 SPT 抑制剂 myriocin 和 FTY720 大大阻断。myriocin 处理还可防止细胞因子介导的少突胶质细胞凋亡或程序性细胞死亡。因此，我们提出神经酰胺毒性可能导致 EAE 和 MS 中的脱髓鞘，EAE 中的间歇性神经酰胺积累至少部分是通过 SPT 激活介导的，这是一个以前没有报道过的新发现。
