Gangliosides are essential in the protection of inflammation and neurodegeneration via maintenance of lipid rafts: elucidation by a series of ganglioside-deficient mutant mice

Gangliosides are considered to be involved in the maintenance and repair of nervous tissues. Recently, novel roles of gangliosides in the regulation of complement system were reported by us. In this study, we compared complement activation, inflammatory reaction and disruption of glycolipid-enriched microdomain (GEM)/rafts among various mutant mice of ganglioside synthases, i.e. GM2/GD2 synthase knockout (KO), GD3 synthase KO, double KO (DKO) of these two enzymes and wild type. Up-regulation of complement-related genes, deposits of C1q, proliferation of astrocytes and infiltration of microglia also showed similar gradual severity depending on the defects in ganglioside compositions. In the expression of inflammatory cytokines such as IL-1 beta and tumor necrosis factor alpha, only DKO showed definite up-regulation. Immunoblotting of fractions from sucrose density gradient ultracentrifugation revealed that lipid raft markers such as caveolin-1 and flotillin-1 tended to disperse from the raft fractions with intensities of DKO > GM2/GD2 synthase KO > GD3 synthase KO > wild type. Decay-accelerating factor and neural cell adhesion molecule tended to disappear from the raft fraction. Phospholipids and cholesterol also tended to decrease in GEM/rafts in GM2/GD2 synthase KO and DKO, although total amounts were almost equivalent. These results indicate that destruction of GEM/rafts is caused by ganglioside deficiency with gradual intensity depending on the degree of defects of their compositions.