An intestinal sphingolipid promotes neuronal health across generations

Maternal diet and environment can influence the neuronal health of offspring. Here, we report that diet-induced intestinal sphingolipid biosynthesis reduces adult-onset neurodegeneration intergenerationally in Caenorhabditis elegans. Feeding C. elegans with ursolic acid (UA), a natural plant product, provides neuroprotection by enhancing maternal provisioning of sphingosine-1-phosphate (S1P) - a bioactive sphingolipid. S1P promotes neuronal health across generations by upregulating transcription of the acid ceramidase-1 (asah-1) gene in the intestine. Intergenerational intestine-to-oocyte S1P transfer is essential for promoting neuronal health and is dependent on the lipoprotein yolk receptor RME-2 (Receptor-Mediated Endocytosis-2). Spatially regulating sphingolipid biosynthesis is critical, as inappropriate asah-1 neuronal expression causes developmental axon outgrowth defects. Our results reveal that sphingolipid homeostasis impacts the development and intergenerational health of the nervous system. One-Sentence SummaryAn intestinal lipid prevents neurodegeneration across generations.