Intergenerational Neuroprotection by an Intestinal Sphingolipid in Caenorhabditis elegans

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 (UA), a natural plant product, reduces adult-onset neurodegeneration intergenerationally. UA provides neuroprotection by enhancing maternal provisioning of sphingosine-1-phosphate (S1P) - a bioactive sphingolipid. Intestine-to-oocyte S1P transfer is required for intergenerational neuroprotection and is dependent on the RME-2 lipoprotein yolk receptor. S1P acts intergenerationally by upregulating transcription of the acid ceramidase-1 (asah-1) gene in the intestine. Spatially regulating 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. Comparative gene expression profiling analysis of RNA-seq data for Ursolate treated vs untreated C. elegans