engleski

GD3 synthase deficient mice exhibit altered cholesterogenic genes expression in the brain

Gangliosides are sialic acid-containing glycosphingolipids that are expressed in the outer leaflet of the plasma membrane and they are especially abundant in the central nervous system (CNS). They are particularly involved in brain development and maturation and thought to play a role in memory formation and neuritogenesis. Cholesterol and gangliosides aggregate into highly organized microdomains termed lipid rafts, which are being attributed a multitude of functions: intracellular sorting of proteins, membrane trafficking, signal transduction, etc. In this study the expression of cholesterogenic genes was investigated in GD3 synthase (Siat8a) knockout mice which lack b-series of gangliosides (GD3, GD2, GD1b and GT1b). The aim was to see whether changed ganglioside profile has an effect on cholesterol metabolism due to the redistribution of membrane lipids. Using quantitative real-time PCR (qRT-PCR) the expression of several genes (HMG-CoA synthase (Hmgcs), HMG-CoA reductase (Hmgcr), lanosterol 14-alpha demethylase (Cyp51), sterol regulatory element binding protein 2 (Srebf2), LDL-receptor (Ldlr) and VLDL receptor (Vldlr)) was compared between knockout and wild type animals in different brain regions: frontal cortex, cerebellum, hippocampus and brain stem. The most distinct difference in gene expression between knockout and wild type mice was observed in hippocampus, where higher expression was found in knockout animals. When comparing genes, the difference was most prominent for Cyp51 and Hmgcr (for the hippocampus). Relative mRNA expression for Cyp51 was increased more than 2-fold in the hippocampus of knockout mice than in hippocampus of wild type mice. The results indicate that there is a perturbance of gene expression level for genes involved in cholesterol biosynthesis in brains where b-series of gangliosides is depleted. Altered ganglioside profile, in conjucture with changed cholesterol metabolism can lead to alterations in signalling pathways and changes in normal brain development.

GD3 synthase; cholesterogenic genes; brain

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