Glycosphingolipids in the Regulation of the Nervous System

Abstract

The highest expression of gangliosides, sialic acid-containing glycosphingolipids (GSLs), is found in the nervous tissue of vertebrates. Changes in the profiles of gangliosides during the development of nervous tissues indicate that they are involved in the regulation of neurogenesis and synaptogenesis. Their distinct distribution patterns support the suggestion that they are involved in both the differentiation and function of neural cells. In addition to results of studies of GSLs done using biochemical, histopathological, and cell biological approaches, recent progress in the genetic engineering of glycosyltransferase genes has resulted in novel findings and concepts about their roles in the nervous system. Roles of GSLs in the regulation of signaling that determine cell fates in membrane microdomains such as lipid rafts have been extensively studied. In particular, gene targeting of glycosyltransferases in mice has enabled investigation of the in vivo functions of GSLs. The majority of abnormal phenotypes exhibited by knockout (KO) mice may reflect an abnormal structure and a resultant altered function of lipid rafts caused by alterations in their GSL composition. Generally speaking, abnormal phenotypes found in most KO mice were milder than expected, suggesting that the remaining GSLs compensate for the functions of those lost. There are also functions that cannot be replaced by the remaining GSLs. Thus, there may be two modes of function of GSLs: one is nonspecific and can be carried out by multiple GSLs, the second mode is that in which the function of the missing GSL(s) cannot be compensated by others. Identification of natural ligands for individual GSLs is crucial in order to clarify the functions of each structure.

Sphingolipids: membrane microdomains in brain development, function and neurological diseases

“…Overexpression of the GD3 synthase also leads to an increase in GD1b and GT1b, while the level of GM1 decreases indicating that GD1b and GT1b might also be involved in regulating TrkA signalling. Surprisingly, overexpression of the GM1 synthase (B3GALT4) in PC12 cells prevents NGF-induced activation of TrkA, which is probably due to significant changes in the intracellular localization of the receptor [71]. Thus, balancing the level of GM1, as well as GD1b and GT1b, is important in controlling the TrkA signalling response in neuronal polarization.…”

Glycosphingolipid metabolic reprogramming drives neural differentiation

“…The most important example of developmental GSL remodelling is that operating in neural differentiation (Furukawa et al, 2014). Nevertheless, metabolic channelling mechanisms are exploited during development where the GSL synthetic flux is switched from one metabolic direction to another.…”

FLAGS: A Flexible and Adaptive Association Test for Gene Sets Using Summary Statistics

“…The third-ranked gene set "glycosphingolipid biosynthesisglobo series" produces glycosphingolipids (GSLs) that are especially abundant in the nervous system. Mounting evidence supports regulatory roles of GSLs in neurogenesis and signal transduction in the developing human brain (Furukawa et al 2014). FLAGS also identified another significant gene set, "gap junction," which is consistent with its important roles in the nervous system.…”