Brüggen Bianca, Kremser Christiane, Bickert Andreas, Ebel Philipp, Vom Dorp Katharina, Schultz Konrad, Dörmann Peter, Willecke Klaus, Dedek Karin
Neurobiology, University of Oldenburg, 26111, Oldenburg, Germany.
Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
Eur J Neurosci. 2016 Jul;44(1):1700-13. doi: 10.1111/ejn.13260. Epub 2016 Jun 1.
Complex sphingolipids are strongly expressed in neuronal tissue and contain ceramides in their backbone. Ceramides are synthesized by six ceramide synthases (CerS1-6). Although it is known that each tissue has a unique profile of ceramide synthase expression and ceramide synthases are implicated in several neurodegenerative disorders, the expression of ceramide synthase isoforms has not been investigated in the retina. Here we demonstrate CerS1, CerS2 and CerS4 expression in mouse retina and cornea, with CerS4 ubiquitously expressed in all retinal neurons and Müller cells. To test whether ceramide synthase deficiency affects retinal function, we compared electroretinograms and retina morphology between wild-type and CerS1-, CerS2- and CerS4-deficient mice. Electroretinograms were strongly reduced in amplitude in ceramide synthase-deficient mice, suggesting that signalling in the outer retina is affected. However, the number of photoreceptors and cone outer segment length were unaltered and no changes in retinal layer thickness or synaptic structures were found. Mass spectrometric analyses of ceramides, hexosyl-ceramides and sphingomyelins showed that C20 to C24 acyl-containing species were decreased whereas C16-containing species were increased in the retina of ceramide synthase-deficient mice. Similar but smaller changes were also found in the cornea. Thus, we hypothesize that the replacement of very long-chain fatty acyl residues by shorter C16 residues may affect the electrical properties of retina and cornea, and alter receptor-mediated signal transduction, vesicle-mediated synaptic transmission or corneal light transmission. Future studies need to identify the molecular targets of ceramides or derived sphingolipids in light signal transduction and transmission in the eye.
复杂鞘脂类在神经组织中大量表达，其主链含有神经酰胺。神经酰胺由六种神经酰胺合酶（CerS1 - 6）合成。尽管已知每个组织都有独特的神经酰胺合酶表达谱，且神经酰胺合酶与多种神经退行性疾病有关，但视网膜中神经酰胺合酶同工型的表达尚未得到研究。在此，我们证明了CerS1、CerS2和CerS4在小鼠视网膜和角膜中的表达，其中CerS4在所有视网膜神经元和穆勒细胞中普遍表达。为了测试神经酰胺合酶缺乏是否会影响视网膜功能，我们比较了野生型小鼠与CerS1 -、CerS2 -和CerS4 -缺陷型小鼠的视网膜电图和视网膜形态。在神经酰胺合酶缺陷型小鼠中，视网膜电图的振幅大幅降低，这表明视网膜外层的信号传导受到影响。然而，光感受器的数量和视锥细胞外段长度未改变，视网膜层厚度或突触结构也未发现变化。对神经酰胺类、己糖基神经酰胺类和鞘磷脂类的质谱分析表明，在神经酰胺合酶缺陷型小鼠的视网膜中，含C20至C24酰基的物质减少，而含C16的物质增加。在角膜中也发现了类似但较小的变化。因此，我们推测用较短的C十六烷基取代非常长链的脂肪酰基残基可能会影响视网膜和角膜的电学性质，并改变受体介导的信号转导、囊泡介导的突触传递或角膜光传输。未来的研究需要确定神经酰胺或衍生鞘脂类在眼睛光信号转导和传输中的分子靶点。
