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Gangliosides



1.  Sialic acids and Gangliosides

The name ganglioside was first applied by the German scientist Ernst Klenk in 1942 to lipids newly isolated from ganglion cells of brain. They were shown to be oligoglycosylceramides derived as a first step from lactosylceramide and containing a sialic acid residue, i.e. carbohydrates with a nine-carbon backbone and a carboxylic acid group, such as N-acetylneuraminic acid (‘NANA’ or ‘SA’ or 'Neu5Ac' or 'NeuAc'). Less often the sialic acid component is N-glycolyl-neuraminic acid (Neu5Gc), which differs by only one oxygen atom at the C-5 N-acetyl group, or it can be a Neu5Ac analogue in which the amide group is replaced by OH (3-deoxy-D-glycero-D-galacto-nonulosonic acid, given the abbreviation ‘KDN’). The sialic acids are joined via α-glycosidic linkages to one or more of the monosaccharide units, i.e. via the hydroxyl group on position 2, or to another sialic acid residue. The polar head groups of the lipids carry a net-negative charge at pH 7.0 and they are acidic. Gangliosides are not found outwith the animal kingdom.

Formulae for sialic acids

NeuAc is the biosynthetic precursor of NeuGc, which is a component of gangliosides from most animal species, including mice, horse, sheep and goats. However, NeuGc is not synthesised in humans, although it is present in other primates such as the great apes, and indeed anti-NeuGc antibodies are produced normally in healthy humans (and especially after injection of NeuGc-containing glycoconjugates). The absence or irreversible inactivation of a number of relevant genes both for sialo-lipids and peptides in humans suggests that this may have been a major biochemical branch-point in human evolution. It may even be a factor in the superior performance of the human brain as overexpression of Neu5Gc in the brains of transgenic mice resulted in abnormal development. However, some NeuGc is presumably obtained from the diet and may be incorporated into human gangliosides to a limited extent, especially in fetal tissues and some cancers.


2.  Structure and Occurrence of Gangliosides

Most of the common range of gangliosides are derived from the ganglio- and neolacto-series of neutral oligoglycosphingolipids, and they should be named systematically in the same way with the position of the sialic acid residue(s) indicated as for branched structures. However, they are more conveniently defined by a short-hand nomenclature system proposed by Svennerholm in which M, D, T and Q refer to mono-, di-, tri- and tetrasialogangliosides, respectively, and the numbers 1, 2, 3, etc refer to the order of migration of the gangliosides on thin-layer chromatography. For example, the order of migration of monosialogangliosides is GM3 > GM2 > GM1 (sometimes defined by subscripts, e.g. GM1 or GM1). To indicate variations within the basic structures, further terms are added, e.g. GM1a, GD1b, etc. Although alternatives have been proposed that are more systematic in structural terms, the Svennerholm nomenclature is that approved by IUPAC-IUB. Ganglio-series glycosphingolipids having 0, 1, 2,and 3 sialic acid residues linked to the inner galactose unit are termed asialo- (or 0-), a-, b- and c-series gangliosides, respectively, while gangliosides having sialic acid residues linked to the inner N-galactosamine residue are classified as α-series gangliosides.

As of 2009, 188 gangliosides with variations in the carbohydrate chain had been characterized in vertebrates alone. One of the most studied monosialo-gangliosides (ganglioside GM1a or Neu5Acα2-3(Galβ1-3GalNAcβ1-4)Galβ1-4Glcβ1Cer) is illustrated -

Structural formula of ganglioside GM1a

It can also be depicted as -

Structural formula of ganglioside GM1 - short form)

An alternative nomenclature uses the Ganglio (Gg) root structure (see the web page on neutral oligoglycosylceramides) with Roman numerals to designate each hexose unit and the location of the Neu5Ac along the carbohydrate chain and with Arabic superscripts to designate the hydroxyl group to which this is linked. By this system, GM1a is defined as II3-α-Neu5Ac-Gg4Cer.

Gangliosides can amount to 6% of the weight of lipids from brain, where they constitute 10 to 12% of the total lipid content (20-25% of the outer layer) of neuronal membranes, for example. Aside from this, they are synthesised and are present at low levels (1-2%) in all animal tissues, where like the neutral oligoglycosphingolipids they are concentrated in the outer leaflet of the plasma membrane in the subdomains known as 'rafts'.

The brain contains as much as 20 to 500 times more gangliosides than most non-neural tissues, with three times as much in grey as in white matter. As the brain develops, there is an increase in the content of gangliosides and in their degree of sialylation. There are large differences between species and tissues. For example, during embryogenesis and the postnatal period in the human central nervous system, the total amount of gangliosides increases approximately threefold, while that of GM1 and GD1a increases 12 to 15-fold. During the same period the hemato-series gangliosides, GM3, GD3, and 9-OAc-GD3, which lack a hexosamine residue, are the predominant ganglioside species, but they are present in much lower amounts in adults and then in some areas of the brain only. In mouse brain, the total amount of gangliosides is almost 8-fold greater in adults than in embryos, with a similar shift in composition from simple to more complex gangliosides. There is no doubt that gangliosides play a crucial role in neuronal function and brain development, especially during infancy when there is high nutrient demand as the brain undergoes rapid restructuring.

The main gangliosides (~95%) of adult mammalian brain are GM1, GD1a, GD1b and GQ1b, while lactosyl series gangliosides such as GM3 (sialyllactosylceramide) are found mainly in the extra-neural tissues. The remaining ~5% consists of minor components in brain include GM4, GM3, GD3, GM2, GD2, Fuc-GM1, Fuc-GD1b, GT1a and GP1c, the proportions of which vary depending on species. On the other hand, modern mass spectrometric methodology has revealed a much higher degree of sialylation than was previously known, including a complete series from mono- to octasialylated gangliosides in fetal frontal lobe. The content and composition of gangliosides in brain also change with ageing, with a substantial fall in the content of lipid-bound sialic acid but an increase in the proportion of the more complex ganglioside forms in the elderly.

Among the extraneural tissues, lactosyl series gangliosides such as GM3 (sialyllactosylceramide) tend to predominate. Relatively high concentrations of ganglioside GD1a are present in erythrocytes, bone marrow, testis, spleen and liver, while GM4 is more abundant in kidney, GM2 in bone marrow, GM1 in erythrocytes and GM3 in intestine. Stage-specific embryonic antigen-4 (SSEA-4), a globo-series ganglioside, is a specific component of human embryonic stem cells. Gangliosides can cross the placental barrier into the fetus and those in milk (mainly GD3 and GM3), which are derived from the apical plasma membrane of secretory cells of the mammary gland, may be of nutritional importance for the newborn. Unfortunately, they are poorly characterized and quantified in foods in general.

Scottish thistleA 5-N-deacetylated form of ganglioside GM3 has been detected in human melanoma tumors. In addition, O-acetylation or lactonization of the sialic acid residue adds to the potential complexity. Gangliosides containing O-acetylated sialic acids, such as 9-OAc-GD3, occur in certain tumors and may protect them from apoptosis. This is also found in the retina and cerebellum of adult rats, but not other brain regions. It is possible that they are even more widespread, but they are missed when gangliosides are isolated after treatment with mild alkali, a common analytical practice. A further complexity is the occurrence of gangliosides with sulfate groups, and these have been isolated from human, mouse and monkey kidney cells. KDN-containing gangliosides are minor components of egg, ovarian fluid, sperm and testis of fish and of some mammalian tissues

Gangliosides from marine invertebrates (echinoderms) are very different in structure from those in vertebrates, and do not have a shorthand nomenclature. They include forms with sialic acids within the oligosaccharide chain or with glycosyl inositol-phosphoceramide structures, while the mollusc, Aplysia kurodai, lacks gangliosides but produces complex oligoglycosylceramides with 2-aminoethylphosphonic acids and/or phosphoethanolamine groups attached that may serve as ganglioside surrogates.

In general, the ceramide structures of gangliosides tend to be relatively simple. Sphingosine is usually the main sphingoid base, accompanied by the C20 analogue in gangliosides of the central nervous system. Stearic acid (18:0) can be 80 to 90% of the fatty acid constituents, accompanied by small amounts of 16:0, 20:0 and 22:0, but with little or no polyunsaturated or 2-hydroxy acids, other than in some exceptional circumstances (e.g. some carcinomas). On the other hand, 2-hydroxylated fatty acids are relatively abundant in gangliosides from intestine, liver and kidney. There are also differences in the composition of the base and fatty acid components in different cells or regions of the brain. During development, the nature and concentrations of these constituents change markedly, and for example, the ratio of C20/C18-sphingosine in ganglioside GD1a of cerebellum increases 16-fold from 8-day-old to 2-year-old rats. In gangliosides outwith the nervous system, C20-sphingosine is barely detectable, and there is often a much wider range of fatty acid constituents (C14 to C24).

The nature of the ceramide component is relevant to the biological function of gangliosides, and changing the fatty acid component to α-linolenic acid by synthetic means alters the biological activity of gangliosides dramatically in vitro. However, it is the carbohydrate moiety that has the primary importance for most of their functions, and detailed discussion of these structures would take us into realms of chemistry best left to carbohydrate experts (see the reading list below). In any given cell type, the number of different gangliosides may be relatively small, but their nature and compositions may be characteristic and in some way related to the function of the cell. It is noteworthy that some terminal glycan structures of gangliosides are also present in glycoproteins of membranes.


3.  Biosynthesis

There is evidence that the pool of glucosylceramide and thence of lactosylceramide that is utilized for ganglioside biosynthesis is different from that for the other neutral oligoglycosylceramides, discussed in a separate web page. This may explain some of the differences in the fatty acid and sphingoid base components between the two groups. How the precursors for ganglioside biosynthesis enter the Golgi is an open question, but it appears that the regulation of intracellular sphingolipid traffic may be as important as the control of enzyme expression and activity in determining the final compositions of the various glycosphingolipid types. GM4 or NeuAcα2,3Gal-Ceramide, a major component of myelin, is the exception in that galactosylceramide is its precursor.

Thereafter, the pathways for the biosynthesis of the common series of gangliosides of the ganglio-series, for example, involve sequential activities of distinct sialyltransferases and glycosyltransferases as illustrated below for the four main 0-, a-, b- and c-series of gangliosides. The required enzymes are bound to the membranes of the Golgi apparatus in a sequence that corresponds to the order of addition of the various carbohydrate components. Thus, the sialyltransferase that catalyses the synthesis of the relatively simple ganglioside GM3 is located in the cis-region of the Golgi, while those that catalyse the terminal steps of ganglioside synthesis are located in the distal or trans-Golgi region. The GM3 synthase in particular, which catalyses the transfer of NeuAc from cytidine monophosphate (CMP)-NeuAc onto the terminal galactose residue of lactosylceramide, has a unique specificity.

The simple ganglioside GM3 is synthesised by addition of sialic acid to lactosylceramide by CMP:LacCer α2-3 sialyltransferase (or GM3 synthase), before GD3 and GT3 are produced in turn by the action of appropriate synthases. Subsequently, GM3, GD3 and GT3 serve as precursors of more complex gangliosides by the action of further glycosyl- and sialyl-transferases. An alternative theory with some supporting evidence proposes that a multiglycosyl-transferase complex is responsible for the synthesis of each individual ganglioside rather than a series of individual enzymes. Further sialylation of each of the a, b and c series and in different positions in the carbohydrate chain can occur to give an increasingly complex and heterogeneous range of products, such as the α-series gangliosides with sialic acid residue(s) linked to the inner N-acetylgalactosamine residue (not illustrated). Finally, the newly synthesised gangliosides are transferred to the external leaflet of the plasma membrane via the lumenal surface of transport vesicles.

Ganglioside biosynthesis

The changes that occur in ganglioside compositions of brain and other tissues in the embryonic and post-natal stages are governed mainly by changes in the expression level and activity of the glycosyl- and sialyl-transferases. In addition, the presence of distinctive sialidases that differ from the catabolic lysosomal enzymes (see below) in raft-like regions of the plasma membrane bring about further changes in the composition of the cell surface gangliosides, causing a shift from poly-sialylated species involving a decrease of GM3 and formation of GM2 then GM1 by hydrolysis of terminal sialosyl residues linked either α2‑8 on another sialic acid or α2‑3 on galactose. As GM1 is resistant to most sialidases, it tends to increase in concentration relative to oligosialo species as developmental and other GM1-requiring processes come into play. This may have consequences for important cellular events, such as neuronal differentiation and apoptosis. Conversely, sialylation may occur in some neuronal membranes, increasing the proportions of poly-sialylated species. In particular, a CMP-NeuAc:GM3 sialyltransferase is able to sialylate GM3.

Ganglioside lactones have been detected as minor components in brain tissues. As the process of lactonization profoundly influences the shape and biological properties of the original ganglioside, it is possible that lactonization-delactonization in a membrane might be a trigger for specific cellular reactions. Similarly, GD3 ganglioside can undergo O-acetylation at C9 of the outer sialic acid with important metabolic implications.

Gangliosides added to many types of cell preparations in vitro are rapidly taken up by the cells, while gangliosides injected into animals in vivo are rapidly internalized by tissues. They can cross the blood-brain barrier, and via the placenta they can enter the foetus. Similarly, dietary gangliosides are absorbed intact by intestinal cells and remodelled in the enterocyte prior to export and transport in plasma to the brain and other tissues. Indeed, there is some experimental evidence with animals and humans that dietary gangliosides may improve cognitive functions.


4.  Ganglioside Function

In their natural biological environment, gangliosides have a negative charge because of the presence of sialic acids, which also add to the hydrophilicity of the polysaccharide constituent. This is balanced somewhat by the hydrophobic character of the ceramide moiety, so that over all the molecules are amphiphilic in nature, but very different from the glycerophospholipids, which are essential for the formation of membrane bilayers. Indeed, a ganglioside such as GM1 is soluble in water, where it can form aggregates though hydrophilic effects. The nature of the ceramide unit with its capacity to form hydrogen bonds with glycerophospholipids is important in ensuring that gangliosides are inserted in a stable manner into the outer layer of the plasma membrane.

Thus, gangliosides are anchored in membranes with their sialoglycan components extending out from the cell surface, where they can participate in intermolecular interactions by hydrogen bonding mainly. They function as antigens or receptors by recognizing specific molecules (lectins) at the cell surface and by modulating the charge density at the membrane surface; they also regulate the activities of proteins within the plasma membrane. All gangliosides, but especially the simplest GM3 or Neu5Acα2-3Galβ1-4Glcβ1Cer, have a structural role, and they are segregated together with other sphingolipids and cholesterol into raft micro-domains, where the very large surface area occupied by the oligosaccharide chain imparts a strong positive curvature to the membrane. For example, molecules of GM3 and other gangliosides are present as clusters on the surface of lymphocytes of human peripheral blood, and there is evidence that the density of these clusters in membranes governs their reactivity as antigens. Many of the biological functions of rafts are mediated through the location of gangliosides in these domains or in a subset, the caveolae. Gangliosides are also important constituents of nuclear membranes.

However, there are also suggestions that gangliosides and other oligoglycosylceramides cluster together through hydrogen donor-acceptor (cis) interactions because of the presence of hydroxyl and acetamide groups to form glycosynaptic domains, which are functionally distinct from raft signalling platforms (with lower cholesterol concentrations). These glycosynaptic domains and their ganglioside components may have specialized functions in cell adhesion, growth and motility through interactions with specific proteins and signal transduction pathways. For example, the phosphorylation state and activity of insulin receptors in caveolae and thence the insulin resistance of cells is controlled by the concentration of GM3, which is the main ganglioside in plasma and other extraneural tissues in vertebrates.

Scottish thistleOne of the first examples of a ganglioside influencing a signalling event to be studied in some detail concerns the epidermal growth factor receptor (EGFR), which upon binding to Epidermal Growth Factor (EGF) stimulates the transition of the receptor from an inactive monomeric to an active homodimeric form and in turn triggers receptor auto-phosphorylation and activation of a signalling cascade that promotes cell proliferation. GM3 ganglioside binds to EGFR via a protein-carbohydrate interaction involving its terminal N-acetylneuraminic acid and a lysine residue in the transmembrane domain of the receptor and also via by a carbohydrate-carbohydrate interaction, thereby maintaining the latter in its inactive monomeric state. In contrast, the neutral oligoglycosphingolipid Gb4 exerts the opposite effect on EGFR by interacting directly with it to potentiate its auto-phosphorylation with activation of the downstream cascade.

The techniques of molecular biology such as targeted gene deletion, which enable specific enzymes to be eliminated from experimental animals, are now leading to a better understanding of the function of each ganglioside. It is evident that they are essential to central myelination, to maintain the integrity of axons and myelin, and for the transmission of nervous impulses. These effects may be mediated by interactions of the negatively charged sialic acid residues of gangliosides with calcium ions, which are critical for neuronal responses. By stabilizing neuronal circuits, gangliosides have a function in memory, and conversely, disturbances in ganglioside synthesis can lead to neurodegenerative disorders (see below). In particular, mice that express GM3 primarily and are devoid of the typical complex gangliosides of brain suffer weight loss, progressive motor and sensory dysfunction, and deterioration in spatial learning and memory with aging.

Changes in ganglioside composition can be induced by nerve stimulation, environmental factors or drug treatments. The various interconvertible ganglioside types in the plasma membrane of neurons are particularly important for its development in that they regulate such processes as axonal determination and growth, signalling and repair. In addition, gangliosides are believed to be functional ligands for maintenance of myelin stability and the control of nerve regeneration by binding to a specific myelin-associated glycoprotein. The occurrence of gangliosides in cell nuclei suggests a possible involvement of gangliosides in the expression of genes relevant to neuronal function. For example, the monosialoganglioside GM1 has been shown to promote the differentiation of various neuronal cell lines in culture. Within membrane rafts, this ganglioside has key roles in several signalling systems through association with specific proteins that have glycolipid-binding domains, including those that modulate mechanisms such as ion transport, neuronal differentiation, G protein-coupled receptors (GPCRs), immune system reactivities and neuroprotection. It is important for Ca2+ and Na+ homeostasis in the nucleus and plasma membrane and in regulating the effects of platelet-derived growth factor. GD1a is sometimes considered to be a reserve pool for GM1.

The ganglioside GD3 is essential for the process of apoptosis by blocking the activation of specific transcription factors and thence disabling the induction of antiapoptotic genes. Deletion of the GM2/GD2 synthase lead to infertility in male mice and production of a novel fucosylated ganglioside containing very-long-chain polyunsaturated fatty acids.

Cell–cell interactions occur by sialoglycans on one cell binding to complementary binding proteins (lectins) on adjacent cells, bringing about adhesion of cells and enabling regulation of intracellular signalling pathways. Thus, in experimental systems, gangliosides have been shown to be cell-type specific antigens that control growth and differentiation of cells. In particular, they have key functions in immune defence. They act as receptors of interferon, epidermal growth factor, nerve growth factor and insulin and in this way may regulate cell signalling. While intact gangliosides inhibit growth by rendering cells less sensitive to stimulation by epidermal growth factor, removal of the N-acetyl group of sialic acid enhances this reaction and stimulates growth.


5.  Catabolism

The principles of catabolism of glycolipids in general are discussed in the web page dealing with monoglycosylceramides. In relation to gangliosides, sialidases (neuraminidases) and exoglycohydrolases remove individual sialic acid and sugar residues sequentially from the non-reducing terminal unit with the eventual formation of ceramide, which is then split into long-chain base and fatty acids by ceramidases. This degradation occurs through the endocytosis-endosome-lysosome pathway with a requirement for an acidic pH inside the organelle. In addition to the sialidases and exoglycohydrolases, the various reactions require effector molecules, termed ‘sphingolipid activator proteins‘, including saposins and the specific GM2-activator protein. Anionic lipids in the membranes stimulate ganglioside degradation while cholesterol is inhibitory. This process constitutes a salvage mechanism that is important to the overall cellular economy since a high proportion of the various hydrolysis products are re-cycled for glycolipid biosynthesis. By generating ceramide and sphingosine, it may also be relevant to the regulatory and signalling functions of these lipids. In addition, some partial hydrolysis of gangliosides occurs in the plasma membrane as part of a biosynthetic remodelling process discussed above. Defects in catabolism lead to the gangliosidoses discussed next.


6.  Gangliosides and Disease

Bacterial toxins and viruses: Some gangliosides bind specifically to viruses and to various bacterial toxins, such as those from botulinum, tetanus and cholera, and they mediate interactions between microbes and host cells during infections, with NeuAc as the main recognition module. The best known example is cholera toxin, which is an enterotoxin produced by Vibrio cholerae where the specific cell surface receptor is ganglioside GM1. Interestingly, the subsequent metabolism of the ganglioside-toxin complex is dependent on the nature of the fatty acid components of the ganglioside. It is believed that toxins utilize the gangliosides to hijack an existing retrograde transport pathway from the plasma membrane to the endoplasmic reticulum. For example, the passage of the cholera toxin through the epithelial barrier of the intestine is mediated by GM1, possibly by endocytosis of the toxin-GM1 complex via caveolae into the apical endosome and thence into the Golgi/endoplasmic reticulum, where the complex dissociates. The consequence is persistent activation of adenylate cyclase by the toxin and continuous production of cAMP that leads to the severe fluid loss typical of cholera infections.

Similarly, ganglioside GM2 binds to a toxin secreted by Clostridium perfringens. Influenza viruses have two glycoproteins in their envelope membranes, hemagglutinin, which binds to cellular receptors such as gangliosides, and sialidase (neuraminidase), which cleaves the sialic acid from the receptors. The carbohydrate moiety of gangliosides is essential for initial binding of viruses, but the lipid moiety is believed to be important for controlling their intracellular transport.

Gangliosidoses and other neurodegenerative diseases: As with the neutral oligoglycosylceramides, a number of unpleasant lipidoses have been identified that involve storage of excessive amounts of gangliosides in tissues because of failures in the catabolic mechanism. The most important of these are the GM2 gangliosidoses, i.e. Tay-Sachs disease (and the similar Sandhoff disease), a fatal genetic disorder found mainly in Jewish populations in which harmful quantities of ganglioside GM2 accumulate in the nerve cells in the brain and other tissues. A modified GM2 derivative that contains taurine in amide linkage to the sialic acid carboxyl group has been identified in the brain of such patients. As infants with the most common form of the disease develop, the nerve cells become distended and a relentless deterioration of mental and physical abilities occurs. The condition is caused by insufficient activity of a specific enzyme, β-N-acetylhexosaminidase, which catalyses the degradation of gangliosides.

Scottish thistleIn addition, a generalized GM1 gangliosidosis has been characterized in which ganglioside GM1 accumulates in the nervous system leading to mental retardation and enlargement of the liver. The condition is a consequence of a deficiency of the lysosomal β-galactosidase enzyme, which hydrolyses the terminal β-galactosyl residues from GM1 ganglioside, glycoproteins and glycosaminoglycans. It appears that storage of substantial amounts of unwanted lipids in the lysosomal system leads to a state of cellular starvation, so that essential elements such as iron are depleted in brain tissue.

The Guillain–Barré syndrome is an acute inflammatory disorder, usually triggered by a severe infection, which affects the peripheral nervous system. Antibodies to gangliosides are produced by the immune system, leading to damage of the axons, which can result in paralysis of the patient. Impaired ganglioside metabolism is also relevant to Alzheimer’s disease, as complexation with ganglioside GM1 causes aggregation of the amyloid β-protein deposits that characteristically accumulate in brain. Similarly, Huntington’s disease is believed to involve disruption of the metabolic pathways between glycosylceramides and gangliosides, and there is a human autosomal recessive infantile-onset epilepsy syndrome caused by a mutation to a sialyl transferase. In contrast, gangliosides are believed to have a neuroprotective role in certain types of neuronal injury, Parkinsonism, and some related diseases. The therapeutic properties of ganglioside GM1, the most accessible species, and derived molecules are under clinical investigation.

Cancer: Gangliosides are involved in pathological states such as cancer in that certain distinctive gangliosides are expressed at much higher levels in tumours than in normal healthy tissue, mainly by altered glycosyltransferase and glycohydrolase activities. Indeed, they can be shed from the surface of tumour cells into the local environment, where they can influence interactions between cancer cells, including the transition of tumours from a dormant to a malignant state (angiogenesis). For example, gangliosides GD2, GD3 and GM2 are present at much higher concentrations in cancer cells, especially melanomas and neuroblastomas. Aberrant sialylation is found in many malignant cancers, where the levels of neuraminidases are key factors for metastasis and survival of cancer cells, and there can be a significant accumulation of unusual gangliosides containing N-glycolyl sialic acid in some cancers.

Increased synthesis of 9-O-acetyl-GD3 occurs in malignant melanomas and this appears to limit apoptosis. In contrast, metastatic melanoma cells have high levels of GD3 in comparison to poorly metastatic cells or the normal counterpart, suggesting that GD3 may promote metastasis possibly by suppressing the anti-tumor immune response. Similarly, the 5-N-deacetylated form of GM3 is expressed in metastatic melanomas, but not in healthy tissue or even in primary melanomas; it is considered to be a specific marker for the metastatic condition and a target for potential therapy. N-Glycolyl-GM3, normally absent from human tissues, is present in all stage II breast cancers, and it is accompanied by a number of other less common complex gangliosides. A unique fucosyl-GM1 in which the terminal galactose is α-1,2-fucosylated at the non-reducing end is found in a number of cancers, but rarely in normal tissue, and is also considered to be a potential marker for cancer and a candidate for immunotherapy. Indeed, clinical trials with antibodies to GD2 and fucosyl-GM1 are underway against the childhood cancer neuroblastoma.

Other diseases: Aberrant production of the ganglioside GM3 has been linked to pathophysiological changes associated with obesity, metabolic disorders and type 2 diabetes mellitus through its effects upon insulin receptors.


7.  Analysis

Gangliosides are not the easiest of lipids to analyse as they are most 'un-lipid-like' in many of their properties. For example, in the conventional Folch method for extraction of lipids from tissues, the gangliosides partition into the aqueous layer rather than with the conventional lipids in the chloroform layer. Nonetheless, methods have been devised for quantitative extraction, and gangliosides can then be sub-divided into the various molecular forms by high-performance thin-layer chromatography or high-performance liquid chromatography. Mass spectrometry is the main method for structural analysis, including identification and sequencing of the carbohydrate chains, with invaluable assistance from nuclear magnetic resonance spectroscopy. Conversion of individual gangliosides to ceramide derivatives for detailed analysis of molecular species is a useful ancillary technique.


Recommended Reading


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