Dihydroceramide desaturase 1 (DEGS1) converts dihydroceramide (dhCer) to ceramide (Cer) by inserting a C4-C5 trans (∆4E) double bond into the sphingoid backbone. Low DEGS activity causes accumulation of dhCer and other dihydrosphingolipid species. Although dhCer and Cer are structurally very similar, their imbalances can have major consequences both in vitro and in vivo. Mutations in the human DEGS1 gene are known to cause severe neurological defects, such as hypomyelinating leukodystrophy. Likewise, inhibition of DEGS1 activity in fly and zebrafish models causes dhCer accumulation and subsequent neuronal dysfunction, suggesting that DEGS1 activity plays a conserved and critical role in the nervous system. Dihydrosphingolipids and their desaturated counterparts are known to control various essential processes, including autophagy, exosome biogenesis, ER stress, cell proliferation, and cell death. Furthermore, model membranes with either dihydrosphingolipids or sphingolipids exhibit different biophysical properties, including membrane permeability and packing, thermal stability, and lipid diffusion. However, the links between molecular properties, in vivo functional data, and clinical manifestations that underlie impaired DEGS1 function remain largely unresolved. In this review, we summarize the known biological and pathophysiological roles of dhCer and its derivative dihydrosphingolipid species in the nervous system, and we highlight several possible disease mechanisms that warrant further investigation.

二氢神经酰胺去饱和酶 1 (DEGS1) 通过将 C4-C5反式(Δ4E) 双键插入鞘氨醇主链，将二氢神经酰胺 (dhCer) 转化为神经酰胺 (Cer) 。低 DEGS 活性会导致 dhCer 和其他二氢鞘脂种类的积累。尽管 dhCer 和 Cer 在结构上非常相似，但它们的不平衡可能在体外和体内产生重大后果。已知人类DEGS1基因突变会导致严重的神经缺陷，例如髓鞘形成性脑白质营养不良。同样，在果蝇和斑马鱼模型中抑制 DEGS1 活性会导致 dhCer 积累和随后的神经元功能障碍，这表明 DEGS1 活性在神经系统中发挥着保守且关键的作用。已知二氢鞘脂及其去饱和对应物可控制各种重要过程，包括自噬、外泌体生物发生、内质网应激、细胞增殖和细胞死亡。此外，含有二氢鞘脂或鞘脂的模型膜表现出不同的生物物理特性，包括膜渗透性和堆积、热稳定性和脂质扩散。然而，DEGS1 功能受损的分子特性、体内功能数据和临床表现之间的联系在很大程度上仍未得到解决。在这篇综述中，我们总结了 dhCer 及其衍生物二氢鞘脂在神经系统中的已知生物学和病理生理学作用，并重点介绍了几种值得进一步研究的可能疾病机制。