Sanofi, Rare and Neurologic Disease, 350 Water Street, Cambridge, MA, USA.
Sanofi, Precision Medicine and Computational Biology, 350 Water Street, Cambridge, MA, USA.
Commun Biol. 2024 Nov 30;7(1):1597. doi: 10.1038/s42003-024-07231-0.
Ceramides are lipids that play vital roles in complex lipid synthesis, membrane function, and cell signaling. Disrupted ceramide homeostasis is implicated in cell-death and several neurologic diseases. Ceramides are often analyzed in tissue, but this approach fails to resolve cell-type differences in ceramide homeostasis that are likely essential to understanding cell and non-cell autonomous contributions to neurodegeneration. We show that human iPSC-derived neurons and glia differ in their rate of ceramide synthesis, ceramide isoform composition, and responses to altered ceramide levels. RNA-sequencing of cells treated to increase or decrease ceramides revealed connections to inflammation, ER stress, and apoptosis. Moreover, introducing labeled sphinganine showed that glia readily synthesize ceramide de novo and that neurons are relatively more sensitive to ceramide toxicity. Our findings provide a framework for understanding neurologic diseases with sphingolipid alternations and insights into designing therapeutics that target ceramide for treating them.
神经酰胺是在复杂脂质合成、膜功能和细胞信号转导中发挥重要作用的脂质。神经酰胺稳态的破坏与细胞死亡和几种神经疾病有关。神经酰胺通常在组织中进行分析，但这种方法无法解决神经酰胺稳态中的细胞类型差异，而这些差异对于理解细胞和非细胞自主对神经退行性变的贡献可能至关重要。我们表明，源自人类 iPSC 的神经元和神经胶质细胞在神经酰胺合成率、神经酰胺同型组成以及对神经酰胺水平变化的反应方面存在差异。用增加或减少神经酰胺的药物处理细胞的 RNA 测序显示与炎症、内质网应激和细胞凋亡有关。此外，引入标记的神经酰胺表明神经胶质细胞很容易从头合成神经酰胺，而神经元对神经酰胺毒性相对更敏感。我们的发现为理解具有神经酰胺改变的神经疾病提供了框架，并为设计针对神经酰胺的治疗方法提供了见解。
