Gangliosides

The name "ganglioside" was coined by the German biochemist Klenk (1896-1971) and assigned to a group of acidic GSLs that he isolated from ganglion cells (Klenk E (1942) and from the brains of patients suffering from the so-called amaurotic idiopathy. Sialic acid was first isolated from submaxillary mucin in 1936. Its structure was elucidated by various groups in the 1950s, and it was found to be identical to N-acetylneuraminic acid isolated by Klenk and Faillard. The first structure of a ganglioside was elucidated by Kuhn and Wiegandt in 1963. The nomenclature of brain gangliosides that is still valid today goes back to Svennerholm (Svennerholm L 1963).

Gangliosides are a group of related acidic glycosphingolipids that contain a ceramide chain incorporated into the lipid bilayer of the plasma membrane. The carbohydrate components are located on the cell surface and are available for recognition by antibodies. Gangliosides are also present on neoplastic cells and on some non-neoplastic cells (especially in nervous tissue). The various gangliosides differ in their expression on tumor cells and normal tissue and in their intrinsic immunogenicity.

Gangliosides are sialic acid-containing glycosphingolipids (GLS) and make up a large portion of the cell surface glycans on neuronal cells. Glycosphingolipids are lipids that contain a sphingoid base and one or more sugar residues. Together with glycoproteins and glycosaminoglycans, glycosphingolipids (GSL) contribute to the glycocalyx that covers eukaryotic cell surfaces. Sialic acids are nine-carbon sugars formed biosynthetically from N-acetylmannosamine and phosphoenolpyruvate. With an average pK A of about 2.6, they are more acidic than most carboxylic acids and negatively charged at most physiological pH values. Among the sialic acids, N-acetylneuraminic acid is the most abundant sialic acid in humans, but N-glycolylneuraminic acid is also abundant in many other species. In total, > 50 different sialic acids have been described. They can be O-acetylated at positions 4, 7, or 9, but can also be N-deacetylated, O-methylated, sulfated, or modified by lactonization (Kohla G et al. (2005).

Gangliosides are particularly abundant in the brain, where their occurrence in gray matter is about five times higher than in white matter. In adult human brain regions, levels range from 2 to 14 μg lipid-bound sialic acid/mg protein (Kracun I et al. (1984). In the brain, ganglioside expression correlates with neurogenesis, synaptogenesis, synaptic transmission, and cell proliferation (Wang B 2009). In cultured mouse hippocampal neurons, axonogenesis, but not dendritogenesis, is accompanied by an increase in the formation of complex gangliosides (Hirschberg K et al 1996). In extraneural tissues, ganglioside content is one to two orders of magnitude lower than in the brain; relatively high concentrations of gangliosides of the ganglia series are found in bone marrow, erythrocytes, intestine, liver, spleen, and testis, GM4 in kidney, and SSEA-4 in embryonic stem cells.

Cellular gangliosides sometimes form complex glycan patterns that are cell type and tissue specific. These are not temporally stable but change with physiological and pathophysiological processes such as cell growth, differentiation, viral transformation, ontogenesis, oncogenesis, embryogenesis (Kwak DH et al. 2011), lactation or tumor progression (Hakomori SI 1996). Gangliosides of the ganglionic series are mainly found in the nervous system, where they account for 10-12% of lipid content. During brain development, the ganglioside pattern changes from the prevalence of the simple gangliosides GM3 and GD3 to more complex ganglioside molecules (e.g. GD1a and GT1b). Ganglioside content and brain composition also change during aging: for example, the amount of lipid-bound sialic acid decreased from 1070 μg/g wet weight in a 25-year-old healthy subject to 380 μg/g wet weight in an 85-year-old individual. Nevertheless, concentrations of GQ1b, GT1b and GD1b increase with age at the expense of GM1 and GD1a (Senn H J et al 1989). Changes in ganglioside composition with age also occur in the liver. There is only evidence of the functional consequences of such changes (Ando S 2012).

Gangliosides are also found in serum. There, GM3, GD3, GD1a, GM2, GT1b, sialylneolactotetraosylceramide, GD1b and GQ1b are mainly present, about 98% of which are transported by serum lipoproteins, mainly LDL (66%), followed by HDL (25%) and VLDL (7%) (Senn H J et al 1989).

Ganglioside degradation: Constitutive degradation of gangliosides occurs in endosomes and lysosomes. In addition, the plasma membrane-associated sialidase Neu3, can also degrade gangliosides and is highly expressed on melanoma cells, for example (Miyata M et al 2011). The nuclear envelope also contains sialidases, with Neu3 located in the inner nuclear membrane and Neu1 in the outer nuclear membrane. Lysosomal ganglioside degradation occurs after endocytosis of portions of the plasma membrane at intraendosomal and intralysosomal membranes and associated lipid aggregates. This requires the presence of appropriate glycosidases, appropriate pH, in some cases lipid transfer proteins, and appropriate composition of ganglioside-containing membranes.

Hereditary diseases: the biochemical defects underlying the diseases:

• GM1 gangliosidosis
• Tay-Sachs disease
• Sandhoff disease

were discovered as early as the 1960s by Sandhoff and others.

Acquired neurological diseases: In addition to these inherited diseases, ganglioside levels may also be altered in several acquired diseases. For example, gangliosides play a role in neurological diseases such as Alzheimer's disease, Parkinson's disease, and Huntington's disease (Yanagisawa K (2011).

Tumor diseases: Ganglioside expression may also be altered in tumor cells in malignant tumor diseases, affecting signal transduction and tumor-host interactions. GM3, GD2, GD3, GM2 and FucosylGM1 are considered tumor-associated antigens (Heimburg-Molinaro J et al 2011) and are targets for oncogenic immunotherapy.

Ganglioside antibodies: Several neuropathies, including variants of Guillain-Barré and Miller-Fisher syndrome, are caused by serum antibodies to gangliosides (Uncini A 2012). They are also encountered in diabetic neuropathy, amyotrophic lateral sclerosis, SLE. In diabetes mellitus , they may give clues to autoimmune insulinitis.

Therapeutic approaches: Gangliosides can be used for both passive and active immunotherapy, although their use as targets for passive immunotherapy has not shown consistent laboratory or clinical responses. In the past, gangliosides isolated from bovine brain have been studied and also used in human patients to enhance nerve repair and treat stroke. Direct application of ganglioside GM1 in the brain of patients with Alzheimer's disease has also been studied. Indirect functions include inhibition of ganglioside biosynthesis to treat insulin resistance.

Since gangliosides are not proteins that are degraded and expressed in the context of MHC, but rather cell surface molecules, active specific immunotherapy should elicit a humoral response. The best studied ganglioside vaccine is the GM2 vaccine in melanoma. Ganglioside GM2 is expressed in a large percentage of melanoma cells, whereas it is rarely found in normal tissue. Approximately 5% of melanoma patients have naturally occurring anti-GM2 antibodies.

1. Ando S (2012) Neuronal dysfunction with aging and its amelioration. Proceedings of the Japan Academy B 88:266-282.
2. Hakomori SI (1996) Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism. Cancer Research 56:5309-5318.
3. Hirschberg K et al. (1996) Ganglioside synthesis during the development of neuronal polarity: major changes occur during axonogenesis and axon elongation, but not during dendrite growth or synaptogenesis. The Journal of Biological Chemistry 271:14876-14882
4. Heimburg-Molinaro J et al (2011) Cancer vaccines and carbohydrate epitopes. Vaccine 29:8802-8826.
5. Klenk E (1942) On the gangliosides, a new group of sugar-containing brain lipoids. Hoppe-Seyler's Journal of Physiological Chemistry 273:76-86.
6. Kohla G et al. (2005) Sialic acids in gangliosides: origin and function. Neuroglycobiology Oxford University Press
7. Kracun I et al. (1984) Topographical atlas of the gangliosides of the adult human brain. Journal of Neurochemistry. 43:979–989.
8. Kwak DH et al. (2011) Roles of gangliosides in mouse embryogenesis and embryonic stem cell differentiation. Experimental and Molecular Medicine 43:379-388.
9. Miyata M et al. (2011) Membrane sialidase NEU3 is highly expressed in human melanoma cells promoting cell growth with minimal changes in the composition of gangliosides. Cancer Science 102:2139-2149.
10. Senn H J et al. (1989) Ganglioside in normal human serum. Concentration, pattern and transport by lipoproteins. European Journal of Biochemistry 181:657-662.
11. Svennerholm L (1963) Chromatographic separation of human brain gangliosides. Journal of Neurochemistry. 10:613–623.
12. Uncini A (2012) A common mechanism and a new categorization for anti-ganglioside antibody-mediated neuropathies. Experimental Neurology 235:513-516.
13. Yanagisawa K (2011) Pathological significance of ganglioside clusters in Alzheimer's disease. Journal of Neurochemistry 116:806-812.
14. Wang B (2009) Sialic acid is an essential nutrient for brain development and cognition. Annual Review of Nutrition 29:177-222.