Gangliosides are Essential for Brain Development and Function

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(Last Updated On: April 2, 2020)
Cell Membrane With Gangliosides
Cell membrane showing glycocalyx with different components. Image: Cara-Lynne Schengrund, 2015

Glycocalyx and its constituents

The glycocalyx is a covering of the cells that are composed of phospholipid bilayers along with glycoproteins and glycolipids. Carbohydrate moieties present in the glycocalyx are mostly in the form of glycolipids and glycoproteins that play roles varieties of functions such as cell differentiation, cell communication, cell to cell interaction, signal transduction, a receptor to the different invading microbes and in some cases carbohydrate moieties can also serve as an antigen determinant, etc.

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Glycolipids and gangliosides

Cells of the central nervous system are enriched in the carbohydrate moiety containing membrane constituents, including glycoproteins and glycolipids, proteoglycans, etc. Glycolipids can be categorized as phosphoglycolipids and sphingoglycolipids, where both are saponifiable lipids but belong to the different classes. Phosphoglycolipids belong to the glycerol ester lipids whereas sphingoglycolipids belong to the non-glycerol ester lipids.

Gangliosides which belong to the sphingoglycolipids are essential for the normal development and function of the neuronal cells. They are present in the greatest amount in the gray matter of the brain where they play most of the essential roles such as signal transduction, cell communication, cell differentiation and many more.

Structure and metabolism of gangliosides

In gangliosides, carbohydrate moieties are attached to the ceramide unit and gangliosides are named according to the composition of carbohydrate and the presence of the sialic acid. Ceramide is synthesized in the endoplasmic reticulum whereas attachment of the different sugar units to the ceramide to make gangliosides via the action of different glycosyltransferases takes place in the Golgi complex. However, gangliosides are catabolized in the lysosomes, where each of the sugar residues of the carbohydrate moiety is released by the action of glycosidases.

In the plasma membrane, both glycosyltransferases and glycosidases are present where they are involved in the modification of the carbohydrate composition of the gangliosides. As, for example, membrane-associated sialidase can catalyze the removal of terminal sialic acid linked through either α2-8 or α2-3 glycosidic linkage in the carbohydrate moieties.

different types of gangliosides
Different types of gangliosides with their structures: Image: Cara-Lynne Schengrund, 2015

Biological roles of the gangliosides

Not only carbohydrate moiety but also ceramide moiety plays an important role in the arrangement of the gangliosides in the membrane. As, for example, different types of fatty acyl residues, whether unsaturated or saturated linked to the sphingosine constituting a ceramide unit of the gangliosides may help pack the gangliosides in different ways in the plasma membrane and also help to interact with other molecules such as cholesterols and proteins to form domains in the plasma membrane. These domains are rich in molecules that are involved in signal transduction and have an essential role in neuronal signal transmission.

In 2004, it was observed that the failure of the mono-sialoganglioside GM3 results in severe central nervous system deficits. The phenotype was identified as infantile-onset symptomatic epilepsy syndrome in which the gene encoding GM3 synthase was found to be mutated. These findings revealed the importance of the gangliosides to the neuronal developments and maintenance of the normal brain function. Furthermore, it was observed that knockout mutation of both genes encoding GM3 synthase and GM2 synthase leads to the neurodegeneration and eventual death in the mouse.

metabolism of gangliosides
Metabolism of gangliosides. Image: Cara-Lynne Schengrund, 2015

Gangliosides play important roles in neuronal cell development and function

GM3 and GD3 are the main gangliosides that are present in the neural stem cells while during Neuro- and astrocyte- genesis more complex gangliosides such as GM1a, GD1a, GD1b, and GT1b are expressed. With an increase in the age, the composition of the brain gangliosides changes in the proportion of the GD1b, GM3, and GD3 whereas the proportion of GM1 and GD1a decreases. While in old age (>70 years) it has been observed that the total amount of the brain gangliosides decreases significantly.

Furthermore, the amount of GM1 expressed in the brain synaptosome was found to be increased along with the age in comparison with that of the non-synaptosome GM1. This result indicates that GM1 in the brain synaptosome is required for the assembly of the β-amyloid peptide (Aβ) and the decomposition of which can lead to Alzheimer’s disease.

Effect of specific gangliosides

There are some approaches that can be used to study the effects of specific gangliosides on brain development and its function. These approaches are (1) blocking the carbohydrate moiety by the addition of gangliosides specific antibodies (2) altering the expression of different gangliosides by genetically modifying the glycosyltransferase and (3) analysis of their interaction with carbohydrate-binding proteins such as lectins.

The results from the study following these approaches indicate that specific gangliosides play unique roles in brain development and function.  As, for example, an anti-9-O-acetyl GD3 antibody was found to have an inhibitory effect on the migration of the cells in the subventricular zone while, in the peripheral nervous system, anti-GM1 antibodies bind to the GM1 and induce the weakness and eventual paralysis as seen in the Guillan-Barre Syndrome.

Different types of ganglioside binding proteins

There are different types of gangliosides-binding proteins (called as lectins) such as galectins, siglecs, and ficolins, however, lectins of human importance are galectins. There are two types of human galectins; galectins-1 and galectins-3.

Galectins-1 binds to the β-galactosyl residue of the GM1 and can induce the neuroblastoma shifting the cell from proliferation to the differentiation. It can also affect hippocampal learning and memory and enhance the neurological recovery from the contusive spinal cord injuries. While galactin-3 binds to the same ligand but may show different effects.

Siglecs are the immunoglobulin-like lectins present in the microglia that recognizes the sialic acid residues present in the gangliosides of neurons and glia. There are two siglecs; siglec-4 and siglec-11 that recognize the sialic acid residue of gangliosides in the central nervous system.

Siglec-4 recognizes the GD1a and GT1b found on the surface of the neurons and inhibits the axonal regeneration. However, this inhibition can be released by the conversion of GD1a and GT1b to GM1 catalyzed by the plasma membrane-associated sialidases, because GM1 is not a ligand for the siglec-4.

Siglec-11 is found in the microglia where it recognizes the sialic acid residues of the gangliosides and prevents the clearance of the aggregating Aβ plaques. Thus accumulated sialic acid residues associated Aβ plaques acts as an activator of the immunosuppressive siglec-11 receptor and, therefore, acts as an immunosuppressant.

Ficolins are the third class of lectins. There are two ficolins; M-2 and M-3 that are recognized as immune recognition proteins. M-2 recognizes the sialic acid-containing gangliosides such as GM1, fucosyl-GM1, and GD1a while M3 recognizes GM2. However, Ficolins are not present in the nervous system but are found at the surface of the blood monocytes where they recognize glycoproteins released by the pathogens.

Gangliosides and age-related neural problems

Dementia is the most common age-related problem. It is characterized by a progressive loss of memory along with the aging, during with amyloid plaques are deposited in the brains. Amyloid plaques contain Aβ peptide produced by the cleavage of amyloid precursor protein (APP). As mentioned earlier, membrane-associated GM1 is the one that causes accumulation of Aβ peptide released from the enzymatic cleavage of APP and therefore, affecting the production of GM1 ultimately leads to the neuronal problems.

Parkinson’s disease is characterized by the loss of function of dopaminergic neurons and about one-third of the people with Parkinson’s disease are found to have dementia. Analysis of the brain from patients who died of Parkinson’s diseases reveals the presence of Lewy bodies containing an aggregated form of α-synuclein.

About 20 years ago, GM1 was shown to be effective against 1-methyl-4-phenyl-1,2,3,6-tetrahydrophyidine induced Parkinson’s disease in the monkeys. This result supports that GM1 binds to the α-synuclein in the unilamellar vesicles changing the structure of the α-synuclein. In this way, GM prevents the aggregation of the α-synuclein that otherwise may disrupt the normal function of the neurons leading to Parkinson’s disease.

Huntington’s disease is characterized by the autosomal dominant mutation of the Huntington gene. Huntington gene mutation causes an increase in the number of glutamine-encoding codon CAG that leads to an increase in the sequence of polyglutamine in the N-terminal region of the Huntington protein.

People with Huntington’s disease have problems with muscle coordination and experience cognitive decline along with the age. Patients died of Huntington’s disease, it was found that expression of glycosyltransferases was affected and metabolic pathways of glycolipids and gangliosides were disrupted.

Studies in the mice reveal that GM1 levels were reduced in the striatum and cortex in Huntington’s diseases. While the levels of GD1a in the cortex and the levels of GT1b in the striatum were decreased. Moreover, genes encoding GM1/GD1b synthase were also found to be downregulated in that sample of mice.

However, the addition of the GM1 helped to restore the level of gangliosides and cells were survived in the same way as in the normal wide type cells. When GM1 was added externally to the diet, it caused the activation of Ser/Thr-specific protein kinases (AKT) that enhanced the phosphorylation of the mutant Huntington proteins, thereby reducing the toxicity of the mutant protein and increasing cell survival of the Huntington’s diseases.

In conclusion, alteration of the gangliosides and or other lipid components may alter their ability to perform varieties of cellular functions. In diseases like Huntington’s disease, Parkinson’s disease, Alzheimer’s diseases, and age-related dementia, all arise due to changes in the expression level of specific types of gangliosides that are necessary to perform normal function and development of the neuronal cells.

Reference: Trends in Biochemical Sciences

Article DOI: 10.1016/j.tibs.2015.03.007

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