Glycosphingolipids, found in eukaryotic plasma membranes, are comprised of a ceramide backbone that has a glycan covalently bound to it. It is thought that glycosphingolipids act to modulate membrane-protein function, as well as playing a role in cell-cell communication.
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Glycosphingolipids are also thought to play a role in cell differentiation. Furthermore, it is thought that glycosphingolipids play a role in the development of immune cells, as well as modulating the development of Amyotrophic Lateral Sclerosis (ALS).
Glycosphingolipids; a class of glycolipids
Glycosphingolipids are a class of glycolipids and are comprised of a ceramide backbone linked by a β-glycosidic bond to complex glycans. They are well characterized in vertebrates and are typically amphipathic.
Given that there are variations seen in both ceramide and glycans, the structures of glycosphingolipids are diverse; it is estimated that there are more than 400 glycan residues that have been linked to ceramide, utilizing 12 different sugars with are unlinked or linked with up to 19 other sugar units. The most common sugars seen in glycosphingolipids are galactose, N-acetylglucosamine, glucose, fucose and N-acetylneuraminic acid.
Generally, glycosphingolipids are divided into two groups, based on whether the ceramide core is galactosylated or glucosylated. They are then further divided into four series; asialo, ganglio, globo, and lacto. These base structures are further modified to create molecules such as gangliosides.
What are the functions of glycosphingolipids?
While cells do not strictly require glycosphingolipids, they are vital in multi-cellular organisms. It is thought that individual cells show variation in the glycosphingolipid content based on the environment and stage of development.
What can mouse models tell us about the function of glycosphingolipids?
The gene GlcCer synthase is one that is involved in the synthesis of glucosylceramide and when this is knocked-out the resulting embryos die during gastrulation. A similar situation is also seen with B4G ALT-V, which produces lactosylceramide, in that its knock-out results in embryonic death at 10.5 days.
Lactosylceramide is produced downstream of glucosylceramide, thus these studies indicate that glucosylceramide and glycosphingolipids produced downstream of glucosylceramide are required for embryonic development.
Knock-out of ST3GAL5, a gene involved in the formation of the glycosphingolipid GM3, has been linked to increased insulin sensitivity, compromised neuropsychological behavior and hearing loss. Knock-out of genes downstream of ST3GAL5 leads to primarily neuronal defects.
Knock-out of GA2/GM2/GC2 synthase leads to male infertility, axonal degeneration, myelin defects, motor deficits and Parkinson’s like symptoms. Knock-out of GC3 synthase leads to hyperalgesia, mechanical allodynia and reduced neurodegeneration, which all use gangliosides, which are molecules comprised of glycosphingolipids.
Consequently, knock-out of GM3 synthase and GA2/GM2/GC2 synthase induces severe neurodegeneration, while knock-out of GC3 synthase and GA2/GM2/GC2 synthase are thought to be responsible for lethal audiogenic seizures and peripheral nerve degeneration. Therefore, it is likely that these glycosphingolipids play a significant role in neuropsychological function.
What influence does glycosphingolipid have on cell fate specification?
As stated previously, glycosphingolipids are highly diverse. Embryognesis utilizes this diversity, and certain glycosphingolipids are produced during specific stages of embryo development.
Pluripotent stem cells, for example, produce globo and lacto series glycosphingolipids, but when they start the differentiation process to neuronal progenitor cells the levels of these glycosphingolipids decrease while levels of GD3, GM3, GM1 and GD1 increase. In cells that differentiate into the definitive endoderm, there is a shift in glycosphingolipid composition where Gb4 becomes the dominant glycosphingolipid.
How do glycosphingolipids influence the function of immune cells?
Activation and differentiation of immune cells require membrane organization, and glycosphingolipids are known to play a role in membrane organization. A well-characterized example is in T-cells; when the T-cell receptor is activated, it is brought into proximity of GM1 enriched microdomains.
This is thought to play a crucial role in T-cell signaling – in fact, disrupting glycosphingolipid enriched microdomains in the T-cell membrane has been shown to impact T-cell activation. A similar story has been observed in B-cells.
Glycosphingolipids can also act as signal transducers in immune cells; lactosylceramide enriched microdomains interact with the kinase Lyn in neutrophils, however, the activation of Lyn is dependent on the length of the fatty acid chain of the glycosphingolipids, with activation being triggered by 24 carbon fatty acid chain. Activation of Lyn results in the production of superoxide in neutrophils.
Is there a link between glycosphingolipid and Amyotrophic Lateral Sclerosis (ALS)?
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that leads to the progressive loss of motor neurons within the central nervous system. Since studies had shown that glycosphingolipid metabolism is involved in neuromuscular diseases, Dodge et al. decided to investigate whether glycosphingolipids played a role in ALS.
They found that patients with ALS showed higher levels of glycosphingolipids in their spinal cords; these include glucosylceramide, galactosylceramide, lactosylceramide, globotriaosylceramide, GM3 and GM1.
Further, the authors found that enzymes involved in the hydrolysis of glycosphingolipids were also elevated in ALS patients. This indicates that glycosphingolipids could be playing a crucial role in the development of ALS, and could potentially be a target for treatment.
D’Angelo, G. et al. (2013) Glycosphingolipids: synthesis and functions FEBS Journal doi:10.1111/febs.12559
Dodge, J. C. et al. (2015) Glycosphingolipids are modulators of disease pathogenesis in amyotrophic lateral sclerosis PNAS https://doi.org/10.1073/pnas.1508767112
Russo, D. et al. (2018) Glycosphingolipid metabolism in cell fate specification Journal of Cell Science doi: 10.1242/jcs.219204
Zhang, T. et al. (2019) The Role of Glycosphingolipids in Immune Cell Functions Frontiers in Immunology https://doi.org/10.3389/fimmu.2019.00090