An intestinal sphingolipid confers intergenerational neuroprotection

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Maternal diet and environment significantly influence offspring health.
• The transgenerational impact of maternal dietary choices on the nervous system remains poorly understood.
• Sphingolipids are bioactive molecules with critical roles in cellular function.

Purpose of the Study:

• To investigate the intergenerational effects of maternal ursolic acid consumption on the nervous system in Caenorhabditis elegans.
• To elucidate the molecular mechanisms underlying ursolic acid's neuroprotective effects across generations.

Main Methods:

• Feeding Caenorhabditis elegans with ursolic acid.
• Assessing axon transport and fragility in offspring.
• Investigating the role of sphingosine-1-phosphate and its metabolic pathways, including the RME-2 receptor and acid ceramidase-1 (asah-1) gene.
• Analyzing spatial regulation of sphingolipid metabolism.

Main Results:

• Maternal ursolic acid intake improves axon transport and reduces adult-onset axon fragility in offspring, demonstrating intergenerational neuroprotection.
• Neuroprotection is mediated by enhanced maternal provisioning of sphingosine-1-phosphate (S1P).
• Intestine-to-oocyte S1P transfer, dependent on the RME-2 receptor, is crucial for this effect.
• S1P upregulates asah-1 gene transcription in the intestine, while inappropriate neuronal expression causes axon defects.

Conclusions:

• Maternal dietary ursolic acid confers intergenerational neuroprotection in C. elegans by regulating sphingolipid metabolism.
• Sphingolipid homeostasis and its spatial regulation are critical for nervous system development and health across generations.
• Lipid metabolites can act as intergenerational messengers, highlighting the importance of maternal diet during reproduction.