Major biosynthesis pathway of brain gangliosides catalyzed by UDP glucose:ceramide glucosyltransferase (Ugcg).
© dkfz.de

Membranes of all mammalian cells contain - in addition to phosphoglycerolipids and cholesterol - substantial amounts of sphingolipids: i.e. ceramides (Cer), sphingomyelins (SM) and glycosphingolipids (GSL). These sphingolipids are expressed in a cell type- and differentiation stage- specific manner. GSL influence neuronal, metabolic and immune functions. Interactions between glycoproteins and GSLs are pivotal to stabilize the brain.
For example, the gangliosides GM1a and GD1a serve on axonal membranes as ligand for the myelin associated glycoprotein (MAG) in order to establish cell-to-cell contacts. Loss of neuronal gangliosides therefore is not compatible with normal life.
In muscle cells, the ganglioside GM3 influences the activity of the insulin receptor (IR) and GM3-deficiency in mice leads to hypersensitivity of IR.
Alpha galactosylceramide is a potent stimulator of natural killer Tcells.

Glycosphingolipids and organ function

The basic enzyme necessary for the synthesis of almost all GSLs isglucosylceramide synthase (Ugcg). To investigate the function of GSL, mice with cell-specific deletion of Ugcg were generated.

Brain

A specific GSL knockout in neuroepithelial stem cells led to a complete loss of gangliosides in the brain. Animals died shortly after birth and isolated neurons showed retardation of dendritic extensions and underwent early pruning.

Neurons, isolated from hippocampus. Neurons lacking GSLs show reduced dendritic processes and early pruning (right slide).
© dkfz.de

Glucosylceramide synthase - a regulator of neurons

Imbalances in neuronal ganglioside homeostasis have been associated with the development of neurodegeneration in lipid storage diseases and Alzheimer’s disease. The contribution of the membrane lipid microenvironment to pathological processes is a major research focus of our group.
Our group could recently demonstrate with the help of inducible cell specific gene deletion that neuronal Ugcg expression is required for central nervous system regulation of energy homeostasis. Ugcg-derived gangliosides are suggested to participate in physiological processes of differentiated neurons, such as electrical transmission, ion channel function, and neurotransmitter release. These regulatory aspects of gangliosides in neural stem cells and differentiated neurons are currently under investigation.

left: Ganglioside GD1a immunofluorescence in mouse hippocampus.

right: Overweight Ugcg f/f//CamKCreERT2 mice
harbouring a central nervous system defect in ganglioside homeostasis.

© dkfz.de

Skin

In skin, loss of GSL led to hyperkeratosis and to a disruption
of the epidermal barrier, causing severe dehydration and death of mice. GSL are therefore essential for the viability of organs and the whole organism. Experiments are in progress to dissect the in vivo molecular mechanisms which enable GSL to influence cellular differentiation.

Control mouse and mouse with specific deletion of GSL in epidermis. Compared to control skin, KO mice are characterized by extreme hyperkeratosis and loss of regular keratinocyte differentation accompanied with a disruption of the skin barrier.

© dkfz.de








Immune system

Recognition of lipid antigens plays a major role in immune control of tuberculosis caused by the lipid rich bacterium Mycobacterium tuberculosis and in autoimmune diseases such as multiple sclerosis. Sphingolipids and glycosphingolipids are relevant lipid antigens, stimulating natural killer Tcells. Our group has generated mice deficient for those sphingolipids assumed to influence the interaction between dendritic cells (antigen presenting cells) and natural killer Tcells. Experiments are done to address the function of these neutral glycosphingolipids in bacerial infections.

The glycosphingolipid alpha-galactosylceramide leads to a significant increase in blood of different cytokines.
© dkfz.de

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