Gangliosides in axon stability and regeneration

Gangliosides, sialylated glycosphingolipids, are major glycans on the surfaces of vertebrate nerve cells. All mammals express the same four major brain gangliosides, GM1, GD1a, GD1b, and GT1b, which together comprise 94 % of brain gangliosides in mice and men alike. Among their functions, brain gangliosides GD1a and GT1b on neuronal axons are complementary binding partners for myelin-associated glycoprotein (MAG), which functions in axon-myelin stability and the control of axon regeneration. Human congenital disorders of ganglioside biosynthesis and related mouse genetic models reveal that complex gangliosides are required for long-term axon survival; loss of gangliosides results in paraplegia in humans and similar progressive motor neuropathy in mice. In addition to stabilizing axons, axon-myelin interactions restrict axon regeneration after injury in adults. MAG on residual myelin that persists at sites of central nervous system injury contributes to axon outgrowth inhibition by binding to gangliosides, thereby signaling axons to halt outgrowth. Modulating ganglioside structures on living nerve cells in vitro and in animal models attenuates inhibition and enhances anatomical and motor behavioral outcomes after axonal injury. Knowledge of ganglioside functions in the brain contributes to a more complete understanding of glycosciences in axon-related physiology and pathology.