Neutral sphingomyelinase increases and delocalizes in the absence of Toll-Like Receptor 4: A new insight for MPTP neurotoxicity
Neutral sphingomyelinase increases and delocalizes in the absence of Toll-Like Receptor 4: A new insight for MPTP neurotoxicity
复制标题
DOI：
10.1016/j.prostaglandins.2019.03.004
复制
发表时间：
2019-06-01
影响因子：
2.9
通讯作者：
Conte, Carmela
中科院分区：
文献类型：
--
作者：
Albi, Elisabetta;Cataldi, Samuela;Conte, Carmela
鞘磷脂酶和Toll样受体4(TLR4)都与神经退行性疾病有关。然而，这两个分子之间的关系仍然不清楚。本研究利用WT和TLR4缺陷小鼠，用1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)治疗或不治疗，研究TLR4与中脑中性鞘磷脂酶(NSMase)的关系。我们发现，TLR4的缺失导致了中脑nSMase蛋白表达和酶活性的增加，以及细胞膜的明显离位。这导致鞘磷脂(SM)种类减少，神经酰胺水平上升。我们发现，TLR4缺陷小鼠暴露在MPTP中，通过增加饱和/不饱和SM比例来减少不饱和SM种类。饱和脂肪酸使SM变得更加僵硬，可能有助于降低神经的可塑性。在这项研究中，我们发现，缺乏TLR4还导致了重神经丝和胶质纤维酸性蛋白(GFAP)的减少，并且小鼠对MPTP的注射表现出更高的敏感性。我们推测nSMase-TLR4复合体与MPTP中脑损伤之间可能存在关联。综上所述，我们的发现首次提供了TLR4在SM代谢改变中在MPTP神经毒性中的作用的迹象。
Both sphingomyelinase and Toll-Like Receptor 4 (TLR4) are implicated in neurodegenerative diseases. However, the relationship between the two molecules remains unclear. In this study, using WT and TLR4-deficient mice, treated or not with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), we aimed to investigate the relation between TLR4 and neutral sphingomyelinase (nSMase) in the midbrain. We found that the lack of TLR4 caused increase in nSMase protein expression and enzyme activity in the midbrain, as well as a marked delocalization from the cell membranes. This provoked a decrease in sphingomyelin (SM) species and an increase in ceramide levels. We found that exposure of TLR4-deficient mice to MPTP reduces unsaturated SM species by increasing saturated/unsaturated SM ratio. Saturated fatty acid make SM more rigid and could contribute to reducing neural plasticity. In this study we showed that the absence of TLR4 also induced reduction of both heavy neurofilaments and glial fibrillary acidic protein (GFAP) and mice exhibited higher sensitivity to MPTP administration. We speculated about the possible association between nSMase-TLR4 complex and MPTP midbrain damage. Taken together, our findings provide for the first time indications about the role of TLR4 in change of SM metabolism in MPTP neurotoxicity.