Wang Guanghu, Bieberich Erhard
Department of Physiology, University of Kentucky, Lexington, KY, USA.
Department of Physiology, University of Kentucky, Lexington, KY, USA.
Adv Biol Regul. 2018 Dec;70:51-64. doi: 10.1016/j.jbior.2018.09.013. Epub 2018 Sep 22.
For many decades, research on sphingolipids associated with neurodegenerative disease focused on alterations in glycosphingolipids, particularly glycosylceramides (cerebrosides), sulfatides, and gangliosides. This seemed quite natural since many of these glycolipids are constituents of myelin and accumulated in lipid storage diseases (sphingolipidoses) resulting from enzyme deficiencies in glycolipid metabolism. With the advent of recognizing ceramide and its derivative, sphingosine-1-phosphate (S1P), as key players in lipid cell signaling and regulation of cell death and survival, research focus shifted toward these two sphingolipids. Ceramide and S1P are invoked in a plethora of cell biological processes participating in neurodegeneration such as ER stress, autophagy, dysregulation of protein and lipid transport, exosome secretion and neurotoxic protein spreading, neuroinflammation, and mitochondrial dysfunction. Hence, it is timely to discuss various functions of ceramide and S1P in neurodegenerative disease and to define sphingolipid metabolism and cell signaling pathways as potential targets for therapy.
几十年来，与神经退行性疾病相关的鞘脂研究主要集中在糖鞘脂的变化上，尤其是糖基神经酰胺（脑苷脂）、硫脂和神经节苷脂。这似乎很自然，因为许多这些糖脂是髓鞘的组成成分，并在糖脂代谢酶缺乏导致的脂质贮积病（鞘脂贮积症）中积累。随着认识到神经酰胺及其衍生物鞘氨醇-1-磷酸（S1P）是脂质细胞信号传导以及细胞死亡和存活调节的关键参与者，研究重点转向了这两种鞘脂。神经酰胺和S1P参与了大量与神经退行性变相关的细胞生物学过程，如内质网应激、自噬、蛋白质和脂质转运失调、外泌体分泌和神经毒性蛋白传播、神经炎症以及线粒体功能障碍。因此，及时讨论神经酰胺和S1P在神经退行性疾病中的各种功能，并将鞘脂代谢和细胞信号通路定义为潜在的治疗靶点是很有必要的。
