The Relationship Between Gangliosides and Nervous System Development

Gangliosides (GA) are a class of glycosphingolipids (GSLs) containing sialic acid, which are widely distributed in tissues and body fluids, and are most abundant in the nervous system, where their expression accounts for 10 % ~ 12% of the total lipids in nerve cell membranes.

Gangliosides are mainly enriched in plasma membranes, endoplasmic reticulum membranes, mitochondrial membranes, and nuclear membranes of nerve cells, and together with proteins, sphingomyelin, and cholesterol, they form active microdomains of cell membranes—lipid rafts. They participate in intercellular interactions, regulate neurotrophic factor receptors and neurotransmitter receptors, regulate nerve cell proliferation and differentiation, affect nerve and synapse generation, nerve remodeling and other important biological functions.

In Vivo Synthesis and Metabolism of Gangliosides

Gangliosides consist of a lipophilic ceramide lipid chain and a hydrophilic oligosaccharide chain with one or more sialic acid groups. The lipophilic ceramide lipid chain is less polar and anchored in the cell membrane lipid bilayer, which can enhance the lateral crosslinking and stabilize the lipid bilayer structure.

The hydrophilic oligosaccharide chain connected to ceramide serine is negatively charged and polar because it is connected with several polyhydroxy sugar groups and sialic acid groups. When exposed to the extracellular environment, it can interact with lipid raft inner membrane protein Lateral interactions occur, affecting the function of plasma membrane proteins and regulating signal transduction. Oligosaccharide chains can also participate in intercellular interactions, cell adhesion, migration and growth through glycosynapse. Based on the number of sugar groups and sialic acid and the different connection sites, it can be divided into tetraglycosyl monosialoganglioside (GM1), tetraglycosyl disialoganglioside (GD1) and tetrasaccharide Trisialyl ganglioside (GT1) and so on.

In Vivo Synthesis of Gangliosides
The synthesis of gangliosides mainly occurs in the endoplasmic reticulum and Golgi apparatus, and then transported to the plasma membrane of the cell. Its synthesis begins in the endoplasmic reticulum, completes the synthesis of ceramide (Cer) by the endoplasmic reticulum membrane, and then transports it to the Golgi apparatus for structural expansion by the ceramide transporter (CERT). Ceramide reacts with glucose uridine diphosphate to form glucosylceramide (GlcCer) under the catalysis of Golgi glucotransferase (Glc-T).

The latter, under the catalysis of galactosyltransferase (Gal-T), connects a molecule of galactose to the glucose group to synthesize lactosylceramide (LacCer). Using this as a precursor substance, under the action of a series of sialyltransferases (ST-I, ST-II, etc.) and N-acetylgalactosamine transferase (GalNac-T), galactosyltransferase (Gal-T) Further synthesis of different types of gangliosides. Among them, GM3 is the ganglioside with the simplest structure, and together with LacCer, GD3, and GT3, it serves as the precursor synthetic substance of complex gangliosides (asialo-series, a-series, b-series, c-series), controlling Synthesis of complex gangliosides.

In Vivo Metabolism of Gangliosides
Exogenous gangliosides can enter the blood circulation after intestinal absorption or injection, and accumulate in large quantities in viscera. Studies have shown that gangliosides absorbed or injected through the gut can pass through the blood brain barrier and the placental barrier to enter the central nervous system, thereby affecting the content of gangliosides in the brain.

The intracellular degradation of gangliosides mainly occurs in endosomes and lysosomes, but there are also sialidases (Neu1, Neu3) and glycosyltransferases, glycosidases, and timely Degrades or modifies the oligosaccharide chains of gangliosides. Catabolism requires the intracellular environment to meet various conditions, such as the presence of specific glycosidases, lipid transporters, appropriate pH, and ganglioside membrane domains. Disorders of catabolism can cause high accumulation of gangliosides in the lysosomes of brain and visceral tissues, leading to gangliosidosis, such as Tay-Sachs disease.

Biological Functions of Gangliosides

Gangliosides have rich biological functions and play important roles in the nervous system and immune system. Its diverse structure allows it to act as a cell surface receptor and participate in signal transduction to regulate a variety of membrane processes. It can act as an ion channel regulator to participate in the regulation of calcium ion balance, and then regulate the release of neurotransmitters. In addition, it participates in cell recognition and adhesion, cell proliferation and differentiation, apoptosis, immunity, and the transport of intracellular lipid raft components. Gangliosides can also promote the recruitment of calcium ions by regulating the activity of membrane proteins, membrane receptors, and ion channels, thereby participating in more cell signal transduction reactions.

The possible mechanisms are as follows: 1. Gangliosides participate in protein-protein interaction and receptor trafficking by recruiting or reducing receptors and ion channels in GSL-enriched membrane microdomains; 2. Gangliosides interact with receptors specifically Regulating membrane receptors; 3. Ganglioside may act as a co-receptor to promote the interaction between ligand and receptor. In addition, its glycosyl chain can also be used as an antigen cluster to bind to the receptors of various viruses, bacteria, and bacterial toxins, and participate in the occurrence of diseases. Gangliosides are also related to the myelination of nerve fibers. GM1, GD1a, and GT1b on the surface of the axon membrane can have an affinity with MAG in the inner layer of the myelin sheath, improving the long-term stability of the axon and myelin sheath. The interaction between the two It plays an important role in the realization of myelin stability and axon function.