engleski

Ganglioside deficient mice exhibit altered cholesterogenic genes expression in the hippocampus

Gangliosides are membrane lipids abundant in mammalian central nervous system (CNS) which stabilize the mature CNS by promoting the axon-glia interactions. Cholesterol and gangliosides aggregate into highly organized membrane microdomains - lipid rafts, involved in intercellular communication, membrane trafficking, signal transduction, etc. In this study, the expression of cholesterogenic genes was investigated in two knockout mouse models, Siat8a and Galgt1, whose phenotypes include impaired peripheral nerve regeneration, dysmyelination and axonal degeneration. Siat8a mice lack the enzyme GD3 synthase while Galgt1 mice lack the GM2/GD2 synthase. In consequence, depletion of either the b-series gangliosides (GD3, GD2, GD1b, GT1b) or of complex brain gangliosides replaced by simpler gangliosides (GM3, GD3, O-acetyl-GD3) occurs, respectively. The aim was to see whether changed ganglioside profile has an effect on transcription of selected cholesterogenic genes, which could eventually lead to alteration of cholesterol metabolism and redistribution of the major membrane lipids. Using quantitative real-time PCR (qRT-PCR), the gene expression of 14-alpha demethylase (Cyp51) and brain-specific cholesterol 24-hydroxylase (Cyp46) was analyzed in hippocampi of Siat8a, Galgt1 and matched wild type mice. Siat8a mice showed 2-fold increase in the relative mRNA expression for both Cyp51 and Cyp46 when compared to wild type mice. The change was much more prominent for Galgt1 mice: almost 10-fold change for Cyp51 and even more than 20-fold change for Cyp46. The results indicate that there is a significant alteration of gene expression level for analyzed genes involved in cholesterol biosynthesis as a response to ganglioside depletion. We suggest that altered ganglioside profile, in conjuncture with changed cholesterol metabolism can also lead to alterations in signalling pathways and thus contribute to disturbed neuronal maturation and CNS stability caused by the lack of CNS complex gangliosides.

Gangliosides; cholesterol; hippocampus

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