Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

Abstract

Gangliosides, which are sialylated glycosphingolipids, are the major class of glycoconjugates on neurons and carry the majority of the sialic acid within the central nervous system (CNS). To determine the role of ganglioside synthesis within the CNS, mice carrying null mutations in two critical ganglioside-specific glycosyltransferase genes, Siat9 (encoding GM3 synthase) and Galgt1 (encoding GM2 synthase), were generated. These double-null mice were unable to synthesize gangliosides of the ganglio-series of glycosphingolipids, which are the major ganglioside class in the CNS. Soon after weaning, viable mice developed a severe neurodegenerative disease that resulted in death. Histopathological examination revealed striking vacuolar pathology in the white matter regions of the CNS with axonal degeneration and perturbed axon-glia interactions. These results indicate that ganglioside synthesis is essential for the development of a stable CNS, possibly by means of the promotion of interactions between axon and glia.glycosphingolipid ͉ neurodegeneration ͉ glycosyltransferase

Cell-specific deletion of glucosylceramide synthase in brain leads to severe neural defects after birth

“…Observations, comparable to GalNAcT Ϫ͞Ϫ , have been described recently in mice with deleted GalNAcT͞sialyltransferase 9 genes that were unable to synthesize ganglio-series gangliosides (28). Perhaps as compensation, these mice synthesize lacto-series gangliosides and increased amounts of SM3 in the brain, leading to a higher life expectancy (Ͼ5 months), as compared with our Ugcg-deficient animals.…”

Gangliosides as apoptotic signals in ER stress response

“…Histopathologic analyses of the CNS revealed striking vacuolization of the white matter regions, axonal degeneration, and perturbed axon-glia interactions. 50 Overall, these studies underscore the crucial role of gangliosides in stabilizing the developing CNS.…”

“…7,47 Progress toward this endeavor has been made by generating mice with targeted disruptions of key genes that encode glycosyltransferases or glycosylhydrolases, the enzymes that control the synthesis and degradation of gangliosides. [48][49][50] Although no human diseases have yet been identified in which pathogenesis is attributed to genetic deficiency of any glycosyltransferase, the analyses of these genetically engineered null mice are beginning to identify the functions of complex gangliosides in development and cell differentiation. For instance, deficiency of glucosylceramide synthase gene (Ugcg), which eliminates the major pathway of ganglioside synthesis, 51 does not adversely affect growth rate, and differentiation in vitro, but impairs embryonic development and differentiation of some tissues in vivo.…”

“…Considerably more severe phenotypes have been demonstrated in mice carrying mutations in two crucial ganglioside-specific glycosyltransferase genes, Siat9, that encodes GM3 synthase (CMP-Nacetylneuraminic acid : LacCer a-2,3-sialyltransferase) and Galgt1 that encodes GM2/GD2 synthase (UDP-N-acetyl-Dgalactosamine : GM3/GM2/GD2 synthase), also known as GalNAcT. 50 These mice are unable to synthesize gangliosides of the a-, b-, or c-series. Soon after weaning, viable mice develop a severe neurodegenerative disease that results in premature death.…”

Neuromuscular synaptic function in mice lacking major subsets of gangliosides

“…This shows that gangliosides are not a general prerequisite for synaptic function. However, such absence of a biological role for gangliosides in mammals is rather unlikely in view of the presence of such a highly organized ganglioside synthesis system and, furthermore, the demonstrated severe neurodegeneration in transgenic mice lacking all gangliosides including GM3 (Yamashita et al, 2005) and the severe neurological symptoms in human babies with loss-of-function mutated GM3-synthase (Simpson et al, 2004). Therefore, it would be of interest to investigate synaptic transmission in GM3-synthase null-mutant mice.…”