Design, synthesis and neurite outgrowth activity of novel ganglioside GM1 derivatives by remodeling of the fatty acid moiety

Ganglioside GM1 is a glycosphingolipid found on mammalian cell membranes, and it is involved in ischemic encephalopathy, spinal cord injury and neurodegenerative diseases. Fatty acids, as a structure module of GM1, have been reported to affect its physiological function and neurite growth activity. Due to the limitation of preparation methods, the function of GM1 derivatives containing different fatty acids in nerve cells has not been systematically studied. To discover novel GM1 derivatives as nerve growth-promoting agents, we developed an efficient SA_SCDase enzymatic synthetic system of GM1 derivatives, yielding twenty GM1 derivatives with unsaturated fatty acid chains in high total yields (16-67%). Subsequently, the neurite outgrowth activities of GM1 derivatives were assessed on Neuro2a Cells. Among all the GM1 derivatives, GM1 (d18:1/C16:1) induced demonstrably neurite outgrowth activity. The subsequent RNA-sequencing (RNA-seq) and Western blot analysis was then performed and indicated that the mechanism of nerve cells growth involved cholesterol biosynthesis regulation by up-regulating SREBP2 expression or ERBB4 phosphorylation to activate the PI3K-mTOR pathway.

Automated summary

In this study, an efficient enzymatic synthetic system was developed to prepare various GM1 derivatives, and one derivative GM1 (d18:1/C16:1) was found to promote neurite outgrowth. Further analysis revealed that the promotion of nerve cell growth by GM1 (d18:1/C16:1) may involve the regulation of cholesterol biosynthesis and activation of the PI3K-mTOR pathway.