engleski

Brain ganglioside biosynthesis and function

Gangliosides, sialylated glycosphingolipids, are the major sialoglycans in the brain. The same four ganglioside structures, GM1, GD1a, GD1b and GT1b, comprise most of the brain gangliosides in mammals (~97% in humans). The functions of brain gangliosides are not fully known. Two major brain gangliosides, GD1a and GT1b, are implicated in myelin-axon interactions based on their ability to act as receptors for the brain lectin MAG (myelin-associated glycoprotein). These two gangliosides share the same terminal MAG-binding determinant, NeuAc(α 2-3)Gal(β 1-3)GalNAc. GD1a and GT1b are synthesized from GM1 and GD1b (respectively) by addition of terminal α 2-3-linked sialic acid. We used mouse genetics to block sialylation of GM1 and GD1b in vivo. Gangliosides were extracted from brains of mice engineered to lack each of four different α 2-3 sialyltransferase genes: St3gal1, St3gal2, St3gal3 and St3gal4. A significant, but partial (~50%) block of GD1a and GT1b synthesis was found only in St3gal2-null mice. However, expression of GD1a and GT1b was robustly blocked in St3gal2 and Stgal3 double null mice, with commensurate increases in their precursors, GM1 and GD1b. Impaired GD1a and GT1b expression was confirmed in St3gal2 and Stgal3 double null mice by thin layer chromatography, multi-dimensional mass spectroscopy and ganglioside immunohistochemistry. Preliminary phenotypic characterization indicates that these animals are runted, short-lived, and have early motor deficits reflected by impaired hind limb reflexes. These data identify St3gal2 and St3gal3 as the key sialyltransferase genes responsible for terminal ganglioside sialylation, and further implicate GD1a and GT1b in nervous system function.

gangliosides; sialyltransferase; brain

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