Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
School of Pharmacy, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Cell Rep. 2021 Apr 13;35(2):108972. doi: 10.1016/j.celrep.2021.108972.
Disruption of sphingolipid homeostasis is known to cause neurological disorders, but the mechanisms by which specific sphingolipid species modulate pathogenesis remain unclear. The last step of de novo sphingolipid synthesis is the conversion of dihydroceramide to ceramide by dihydroceramide desaturase (human DEGS1; Drosophila Ifc). Loss of ifc leads to dihydroceramide accumulation, oxidative stress, and photoreceptor degeneration, whereas human DEGS1 variants are associated with leukodystrophy and neuropathy. In this work, we demonstrate that DEGS1/ifc regulates Rac1 compartmentalization in neuronal cells and that dihydroceramide alters the association of active Rac1 with organelle-mimicking membranes. We further identify the Rac1-NADPH oxidase (NOX) complex as the major cause of reactive oxygen species (ROS) accumulation in ifc-knockout (ifc-KO) photoreceptors and in SH-SY5Y cells with the leukodystrophy-associated DEGS1 variant. Suppression of Rac1-NOX activity rescues degeneration of ifc-KO photoreceptors and ameliorates oxidative stress in DEGS1-carrying cells. Therefore, we conclude that DEGS1/ifc deficiency causes dihydroceramide accumulation, resulting in Rac1 mislocalization and NOX-dependent neurodegeneration.
鞘脂代谢平衡的破坏已知会导致神经紊乱，但特定鞘脂种类调节发病机制的机制仍不清楚。从头合成鞘脂的最后一步是二氢神经酰胺去饱和酶（人类 DEGS1；果蝇 Ifc）将二氢神经酰胺转化为神经酰胺。Ifc 的缺失导致二氢神经酰胺积累、氧化应激和光感受器变性，而人类 DEGS1 变体与白质营养不良和神经病有关。在这项工作中，我们证明了 DEGS1/ifc 在神经元细胞中调节 Rac1 的区室化，并且二氢神经酰胺改变了活性 Rac1 与细胞器模拟膜的结合。我们进一步将 Rac1-NADPH 氧化酶 (NOX) 复合物鉴定为 ifc 敲除 (ifc-KO) 光感受器和携带白质营养不良相关 DEGS1 变体的 SH-SY5Y 细胞中活性氧 (ROS) 积累的主要原因。抑制 Rac1-NOX 活性可挽救 ifc-KO 光感受器的变性，并改善携带 DEGS1 的细胞中的氧化应激。因此，我们得出结论，DEGS1/ifc 的缺乏导致二氢神经酰胺的积累，从而导致 Rac1 的定位错误和依赖 NOX 的神经退行性变。
