An intestinal sphingolipid confers intergenerational neuroprotection

作者：Wenyue Wang, Tessa Sherry, Xinran Cheng, Qi Fan, Rebecca Cornell, Jie Liu, Zhi‐Cheng Xiao, Roger Pocock · 发表于：Nature Cell Biology · 年份：2023 · DOI：10.1038/s41556-023-01195-9 · 被引用次数：25 · 研究领域：Lysosomal Storage Disorders Research、Sphingolipid Metabolism and Signaling、Birth, Development, and Health

In animals, maternal diet and environment can influence the health of offspring. Whether and how maternal dietary choice impacts the nervous system across multiple generations is not well understood. Here we show that feeding Caenorhabditis elegans with ursolic acid, a natural plant product, improves axon transport and reduces adult-onset axon fragility intergenerationally. Ursolic acid provides neuroprotection by enhancing maternal provisioning of sphingosine-1-phosphate, a bioactive sphingolipid. Intestine-to-oocyte sphingosine-1-phosphate transfer is required for intergenerational neuroprotection and is dependent on the RME-2 lipoprotein yolk receptor. Sphingosine-1-phosphate acts intergenerationally by upregulating the transcription of the acid ceramidase-1 (asah-1) gene in the intestine. Spatial regulation of sphingolipid metabolism is critical, as inappropriate asah-1 expression in neurons causes developmental axon outgrowth defects. Our results show that sphingolipid homeostasis impacts the development and intergenerational health of the nervous system. The ability of specific lipid metabolites to act as messengers between generations may have broad implications for dietary choice during reproduction.