Characterization of some minor gangliosides in Tay-Sachs brains

The ganglioside distribution of Tay-Sachs brain was re-examined in detail. In both the gray and white matter, the levels of lipid-bound sialic acid were increased 6- and 10-fold, respectively, over normal infant brain, and approximately 90% of the total ganglioside was G_M2. The level of G_M2 was increased about 90 times in gray matter and 220 times in white matter in comparison with that in normal controls. The level of G_D1a-GaINAc was increased 19 times and 10 times in gray and white matter, respectively. The concentration of G_D2 was increased about 4-fold in Tay-S-Sachs white matter. In addition, the G_M3 level was increased 2.7 and 3.5 times and the G_D3 level 2 and 2.4 times over normal gray and white matter, respectively. However, the levels of other complex gangliosides such as G_M1, G_D1a, G_D1b, G_T1b and G_Q1b decreased remarkably. Since G_M2, G_D2, G_D1a-GalNAc and a recently characterized ganglioside G_M1b-GalNAc possess a common N-acetylgalactosaminyl terminal structure, their accumulation in Tay-Sachs brains is therefore consistent with the known hexosaminidase A deficiency. However, the accumulation of hexosamine-free G_M3 and G_D3 is not. The in vitro incorporation of N-acetylgalactosamine into G_M3 to form G_M2 was examined in a rat brain microsomal fraction in the presence of large amounts of other glycolipids. Acidic glycolipids were slightly stimulating and then became increasingly inhibitory when the molar ratio of lipid to substrate G_M3 exceeded 10 to 1. Neutral glycolipids and the phospholipid, phosphatidylcholine, were inhibitory at all levels tested. The data suggest that the accumulation of G_M3 and G_D3 in Tay-Sachs brains could be due to an inhibition of N-acetylgalactosaminyl-transferas by high levels of glycolipids, and the inhibition is not due to chelation of the obligate divalent cation necessary for the activity of this enzyme. The inhibition of this enzyme may also be responsible for the decreased levels of other complex gangliosides.