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.