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Annals of Clinical & Laboratory Science 34:3-13 (2004)
© 2004 Association of Clinical Scientists

Review

Glycosphingolipids in Health and Disease

Xinbo Zhang and Frederick L. Kiechle
Department of Clinical Pathology, William Beaumont Hospital, Royal Oak, Michigan

Address correspondence to Frederick L. Kiechle, M.D., Ph.D., Department of Clinical Pathology, William Beaumont Hospital, 3601 West Thirteen Mile Road, Royal Oak, MI 48073-6769, USA; tel 248 551 8020; fax 248 551 3694; e-mail fkiechle{at}beaumont.edu.


   Abstract
Top
 Abstract
Classification and Nomenclature
 Analysis of Glycosphingolipids
 Function of Glycosphingolipids
 Glycosphingolipid-Related...
 Glycosphingolipids and Apoptosis
 Acknowledgements
 References
 
Glycosphingolipids are ubiquitous membrane constituents that are subdivided in neutral or acidic fractions (gangliosides and sulfatides). Their analysis requires extraction and separation by thin-layer chromatography or high-performance liquid chromatography. Ganglioside composition changes occur in response to variations in cellular morphology and function. Glycosphingolipids are implicated in the pathogenesis of various diseases, including glycosphingolipidoses, peripheral neuropathies caused by anti-ganglioside antibodies, and secretory diarrhea. Gangliosides play a role in the induction of apoptosis. For example, ceramide-induced apoptosis is associated with increased synthesis of a ganglioside, GD3. Gangliosides are also potential diagnostic markers and therapeutic targets for cancer.

(received 10 November 2003; accepted 15 November 2003)

Keywords: Glycosphingolipids, gangliosides, sulfatides, glycosphingolipidosis, Tay-Sachs disease, Sandhoff disease, peripheral neuropathies, bacterial toxin receptor, apoptosis


   Classification and Nomenclature
Top
 Abstract
 Classification and Nomenclature
Analysis of Glycosphingolipids
 Function of Glycosphingolipids
 Glycosphingolipid-Related...
 Glycosphingolipids and Apoptosis
 Acknowledgements
 References
 
Glycosphingolipids (GSLs) were discovered and named by Ernst Klenk after their isolation from brain tissue in 1942 [1]. The heterogeneity of the brain ganglioside fraction was demonstrated in 1956 by Svennerholm [2]. GSLs are ubiquitous membrane constituents, which are embedded in the cell plasma membrane. The term, GSLs, applies to compounds that contain at least one monosaccharide and a sphingoid. They have been subdivided into neutral GSLs and acidic GSLs. Acidic GSLs consist of two groups: the sialosylglycosylsphingolipids or gangliosides and the sulfoglycosylsphingolipids or sulfatides [3]. GSLs may also be classified as ganglio-series, globo-series, lacto-series type 1, and lacto-series type 2 based on the core structure of oligosaccharides (Table 1Go). Gangliosides are derived not only from the ganglio-series, but also from the globo-series and lacto-series of neutral GSLs [4,5]. Fig. 1Go indicates the structure of ganglioside GM1 and the abbreviations for gangliosides introduced by Svennerholm [6].


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  		Table 1. Classification of GSLs according to their core structure of oligosaccharides.
 


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  		Fig. 1. The structure of ganglioside GM1 (panel A) and Svennerholm’s nomenclature for gangliosides (panel B). G stands for ganglioside, M for monosialo-, D for disialo-, and T for trisialo-ganglioside. The number (n = 1, 2, 3, or 4) indicates the number of carbohydrate units and the sequence of migration of gangliosides on thin layer chromatograms.

 

   Analysis of Glycosphingolipids
Top
 Abstract
 Classification and Nomenclature
 Analysis of Glycosphingolipids
Function of Glycosphingolipids
 Glycosphingolipid-Related...
 Glycosphingolipids and Apoptosis
 Acknowledgements
 References
 
GSLs are difficult to purify and analyze since they are most "un-lipid-like" in many properties. For example, in the conventional Folch method [7] and the di-isopropyl ether/1-butanol method [8,9] for extraction of lipids from tissues, the gangliosides partition into the aqueous layer rather than with the conventional lipids in the chloroform layer or di-isopropyl ether/1-butanol layer. This section summarizes the basic methods for isolation, separation, and analysis of GSLs.

Isolation of GSLs.  There are two kinds of methods for isolation and purification of gangliosides that are widely used: partition in solvents (Folch partition and di-isopropyl ether/1-butanol/50 mM NaCl partition) [7–9] or ion exchange chromatography [10]. Di-isopropyl ether/1-butanol/50 mM NaCl partition is a simple and rapid method for the purification of gangliosides from the total lipid extract of plasma, cells, or tissues [9]. If Sep-Pak C18 cartridge is used for desalting instead of Sephadex G-50 gel filtration, the efficiency and speed of the di-isopropyl ether/1-butanol/50 mM NaCl partition method is improved [11]. Neutral GSLs are purified either by an acetylation method developed by Saito and Hakomori [12] or by a non-acetylation method [13].

Separation of GSLs.  There are two methods for separation of individual GSLs: thin-layer chromatography (TLC) [10] or high-performance liquid chromatography [14,15]. TLC is a convenient method for the purification of GSLs that have been previously fractionated by column chromatography. This technique is also well adapted for the study of individual molecular species within total GSLs and for the separation of small quantities of purified compounds required for fatty acid or sugar analyses. Although one-dimensional TLC system has been widely applied, two-dimensional systems are also in use [10]. Fig. 2Go shows thin-layer chromatograms of gangliosides (Fig. 2AGo) and neutral GSLs (Fig. 2BGo) from a human melanoma cell line (HT-144).



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  		Fig. 2. Isolation and purification of GSLs from a human melanoma cell line (HT-144). Panel A: The total gangliosides were isolated by a modified di-isopropyl ether/1-butanol method [11], and separated by TLC. The plate was developed in CH3Cl/CH3OH/0.25% CaCl2 (50/45/10, by volume) and stained with resorcinol-HCl reagent. Lane S, bovine brain gangliosides + canine red blood cell GM3 purchased from Sigma (St Louis, MO); Lane M, total gangliosides from a human melanoma cell line (HT-144). Panel B: Total neutral GSLs, isolated according to Cooling et al [13], were separated by TLC. The plate was developed in CH3Cl/CH3OH/water (65/35/8, by volume) and stained with orcinol-H2SO4 reagent. CMH, galactocerebroside; CDH, lactosylceramide; CTH, globotriaosylceramide; CXH, polyhexosylceramide. Lane S, standard neutral GSLs purchased from Matreya, Inc. (Pleasant Gap, PA); Lane M, total neutral GSLs from a human melanoma cell line (HT-144).

 
Analysis of sugar and fatty acids of GSLs.  Methods for analysis of sugar and fatty acids of GSLs include gas-liquid chromatography [10,16,17], mass spectrometry [17,18], and nuclear magnetic resonance spectroscopy [19]. Today, mass spectrometry is the primary method for structural analysis, with the assistance of nuclear magnetic resonance spectroscopy for identifying and sequencing the carbohydrate chains.


   Function of Glycosphingolipids
Top
 Abstract
 Classification and Nomenclature
 Analysis of Glycosphingolipids
 Function of Glycosphingolipids
Glycosphingolipid-Related...
 Glycosphingolipids and Apoptosis
 Acknowledgements
 References
 
Specific changes in the composition and metabolism of GSLs occur during cell proliferation [20,21], cell cycle phases [22], brain development [23,24], differentiation [25–29], and neoplasia in various cell types [30–36], indicating that the ganglioside composition responds to changes in the morphology and function of cells. For example, neuronal survival is crucial during the embryonic period because about half of the proliferative neurons and glial cells die by apoptosis between gestational day E12 and E18 [37]. This gestational phase is coincident with a synthetic switch from simple gangliosides GM3 and GD3 to complex gangliosides or the b-series complex gangliosides of the type GD1b, GT1b, and GQ1b in developing brain tissue at days E14-E16. This same synthetic switch has been observed during neuronal differentiation of teratocarcinoma-derived embryonic stem cells [23,24].

The major ganglioside component isolated from diploid human melanocytes is sialosyllactosyl-ceramide (GM3, 86–91% of total sialic acid), with ganglioside GD3 as a minor component (2–6% of total sialic acid). In human melanoma cells, GD3 is the predominant ganglioside component (48–63% of total sialic acid) [31]. These findings indicate that ganglioside synthesis in melanoma cells shifts from the a-series to the b-series [38], suggesting that sialyltransferase II in melanoma cells is activated. In Fig. 2Go, the GSL profile of a human melanoma cell line (HT-144) demonstrates that the major ganglio-side components are a-series gangliosides (eg, GM1, GM2 and GM3) and GM4 (Fig. 2AGo), and neutral GSLs (galactocerebroside, lactosyl ceramide and globotriaosyl ceramide) (Fig. 2BGo). There is no shift of ganglioside biosynthesis from the a-series to the b-series in HT-144 cells, as reported for human neoplastic melanoma cells by Carubia et al [31]. In HT-144 cells, the a-series gangliosides are more abundant and a new component, ganglioside GM4, is present. Our recent results indicate that the GSL composition of human promyelocytic leukemia cell line HL-60 cells and human melanoma cells (HT-144) is changed after Hoechst 33342-induced apoptosis when compared with untreated cells [39,40]. These findings suggest that ganglioside composition is unique to cell or tissue type, and that this specificity may play a functional role in adhesion and/or intracellular signal transduction characteristic of specific cell types.

GSLs form "microdomains" or "rafts" within the cell membrane, which move within the fluid bilayer as platforms for the attachment of proteins during signal transduction and cell adhesion. Although the majority of glycoproteins are separated from GSL rafts, some functional glycoproteins such as growth factor receptors associated with intrinsic tyrosine kinases are often found within GSL domains and display clear interaction with and functional susceptibility to gangliosides [41]. Specific gangliosides interact with key transmembrane receptors or signal transducers involved in cell adhesion and signaling to regulate cell growth, proliferation, and differentiation. Examples include: (1) modulation of growth factor receptors with intrinsic tyrosine kinases [42–45]; (2) modulation of integrin function [46] by complex formation with tetraspanin CD9 [47]; (3) interaction with and activation of cytoplasmic signal transducers such as Src family kinases and small G proteins present in microdomains [48–51]; and (4) GM1 ganglioside acts as a functional coreceptor for the transmembrane receptor, fibroblast growth factor 2 [52].

The interaction of gangliosides with glyco-proteins is dependent on specific posttranslational modification of the transmembrane glycoproteins. This structural specificity may explain why only a minority of functional glycoproteins bind tightly with GSLs. For example, GM3 binding to epidermal growth factor and GM3-dependent inhibition of its receptor tyrosine kinase are observed only when N-glycans are fully processed to a complex-type structure. Therefore, the GM3 interaction with N-glycosylated epidermal growth factor leads to down-regulation of its receptor-associated tyrosine kinase [53]. Immunoblot analysis reveals an unusually tight association of GM1 with the sodium-calcium exchanger in the nuclear envelope but not with the same exchanger in the plasma membrane [54].

GSLs interact with growth factor receptors to modulate cell growth, for example, by the inhibition of receptor-associated tyrosine kinases. However, gangliosides, particularly GM1, mimic or potentiate the neuritogenic actions of neurotrophins. For instance, GM1 and other gangliosides enhance formation of neurites in cultures of neuroblastoma cells and primary neurons. GM1 stimulates the biochemical development and survival of dopaminergic and gabaergic neurons in cultures of mouse mesencephalic cells. Exogenous GM1 given alone mimics the effects of nerve growth factor (NGF) in preventing cell death of cholinergic neurons after cortical damage and promotes hippocampal regeneration after partial transection of the fimbriafornix. GM1 administration improves the recovery and survival of specific CNS cell populations after various types of brain lesions [55]. The molecular mechanism by which GM1 protects neurons from degeneration is associated with the following observations: (1) activation of the tyrosine kinase receptor (Trk) NGF receptor, a pathway that may be used by other neurotrophic growth factors [56]; (2) activation of mitogen-activated protein kinases and cAMP-response element-binding protein in the retina with axotomized nerve [57]; and (3) stimulation of the dimerization of neurotrophic factor receptor tyrosine kinases, thus mimicking the action of their corresponding ligands [55]. These results demonstrate that gangliosides play an important role in cell growth, proliferation, adhesion, and differentiation by regulating the activities of transmembrane receptors and signal transduction pathways.


   Glycosphingolipid-Related Diseases
Top
 Abstract
 Classification and Nomenclature
 Analysis of Glycosphingolipids
 Function of Glycosphingolipids
 Glycosphingolipid-Related...
Glycosphingolipids and Apoptosis
 Acknowledgements
 References
 
GSLs have been implicated in the pathogenesis of various diseases. Table 2Go lists the 3 principal types of GSL-related diseases, their etiologies, and major clinical manifestations. Inherited metabolic disorders involving GSL pathway enzymes cause glycosphingolipidoses. In these disorders, a deficiency of an enzyme blocks the degradation of specific GSLs in lysosomes. Glycosphingolipidoses are the most prevalent subgroup of the lysosomal storage disorders and are characterized by accumulation of one or multiple GSLs [58]. Since GSLs are abundantly expressed in the central nervous system, glycosphingolipidoses frequently present with progressive neurodegenerative course (Table 2Go) [58,59]. For example, Tay–Sachs and Sandhoff diseases represent members of a subcategory called the GM2 gangliosidoses that are so named because GM2 ganglioside accumulates in cells secondary to hexosaminidase deficiency [60].


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  		Table 2. Glycosphingolipid-related diseases and their pathogenesis.
 
The primary enzyme deficiences are ß-hexosaminidase A in Tay–Sachs disease and ß-hexosaminidases A and B in Sandhoff disease. Since only ß-hexosaminidase A degrades GM2 ganglio-side, the substrate accumulates in both diseases. Affected individuals with either disease exhibit a virtually identical clinical course of neurodegeneration leading to death in early childhood. Apoptosis of neurons is detected in patient specimens and in mouse models [61,62]. Although it is clear that a primary insult to neurons is the accumulation of the ganglioside substrates, the exact molecular mechanisms that translate the primary insult into neuronal death have not been identified.

Microdomians of GSLs within the plasma membrane function as a binding site or receptor for bacterial toxins [63–65]. For example, cholera toxin and heat-labile toxin type I are the most important virulence factors produced by Vibrio cholerae and toxigenic Escherichia coli, which lead to massive secretory diarrhea. Cholera toxin and heat-labile toxin type I consist of five identical B-subunits (11 kDa) and a single A-subunit with two domains termed the A1- and A2-peptides. The pentameric B-subunit (55 kDa) binds with high affinity to GM1 at the apical cell surface [66,67]. To induce secretory diarrhea, the toxin must first bind ganglioside GM1 at the apical surface of polarized intestinal epithelial cells, enter the cell by endocytosis, and travel retrograde through the Golgi cisternae to the endoplasmic reticulum, where the A1-peptide (22 kDa) is enzymatically activated. Activated A1-peptide stimulates adenylyl cyclase to produce cAMP, which catalyzes the ADP-ribosylation of the heterotrimeric GTPase. Stimulatory GTP binding protein, Gs, induces chloride secretion, which is the fundamental transport event responsible for secretory diarrhea [68–73].

GSLs may function as allogeneic antigens in humans (eg, blood group ABH, Lewis, I/I and PP1Pk) or as heterogenetic antigens (eg, Forssman antigen and Gal) [74–76]. Anti-ganglioside antibodies have been detected in a variety of autoimmune diseases, including Guillain-Barré syndrome [77–81], chronic idiopathic ataxic neuropathy [82], multifocal motor neuropathy [77,78], Miller-Fisher syndrome [77–81] and neuropathy with IgM paraproteinemia [77,83]. Guillain-Barré syndrome (GBS), the prototype of postinfectious autoimmune diseases, is characterized by limb weakness and areflexia. The most frequent antecedent pathogen is Campylobacter jejuni from which lipopolysaccharides isolated from GBS patients have ganglioside-like epitopes. GBS subsequent to C jejuni enteritis is associated with a severe, pure motor axonal variant of the disease and production of IgG antibodies against GM1, GM1b, GD1a, or GalNAc-GDla, which are gangliosides expressed in human peripheral nerves. Cytomegalo-virus (CMV) is the most common viral antecedent infection associated with the demyelinating variant of GBS. CMV-infected fibroblasts express the GM2 epitope. Patients with GBS related to a recent CMV infection have severe sensory deficits and produce anti-GM2 IgM antibodies [82]. Fisher syndrome is a GBS variant associated with anti-GQ1b IgG antibody production [77–81]. Although the role of anti-GSL antibodies in the pathogenesis of neuropathies is not fully understood, the following are some mechanisms by which anti-GSL antibodies may cause neuropathies: (1) anti-GSL antibodies cause selective damage to motor neurons or sensory neurons [85]; (2) anti-GSL antibodies disturb the function of ion channels [86]; (3) anti-GSL antibodies to myelin inhibit remyelination [87]; and (4) the binding of anti-GSL antibodies to GSLs results in axonal degeneration and conduction block [88].


   Glycosphingolipids and Apoptosis
Top
 Abstract
 Classification and Nomenclature
 Analysis of Glycosphingolipids
 Function of Glycosphingolipids
 Glycosphingolipid-Related...
 Glycosphingolipids and Apoptosis
Acknowledgements
 References
 
Recent studies have demonstrated that some types of gangliosides are apoptotic inducers, including ganglioside GM1 [89], GM3 [90], and GD3 [91–94]. Ceramide is a mediator of programmed cell death signaling in lymphoid cells and rapidly accumulates after CD95 cross-linking following the hydrolysis of sphingomyelin by acidic sphingomyelinase. In 1997, DeMaria et al [91] reported that the apoptotic signal triggered by CD95 cross-linking increases ceramide, which is followed by an increase in ganglioside GD3 synthesis. GD3 accumulation is rapid, transient, and peaks 15 min after CD95 stimulation in hematopoietic cells. GD3 is a potent mediator of cell death, since its addition to cells in culture damages mitochondria, with consequent dissipation of mitochondrial transmembrane potential ({Delta}{Psi}M), DNA fragmentation and apoptosis in HuT78 cells. None of these effects could be induced by other gangliosides such as GD1a, GM1 or GT1b. Furthermore, CD95-induced GD3 accumulation is dependent upon upstream activation of caspases, since the addition of tetrapeptide caspase inhibitors prevents apoptosis [91].

Recent reports indicate that mitochondria are the immediate downstream target of GD3 [93,94–99]. Rippo et al [93] showed that GD3 directly interacts with mitochondria and reduces the mitochondrial transmembrane potential ({Delta}{Psi}M) with consequent release of cytochrome c, apoptosis-inducing factor, and caspase-9 from mitochondria. Overexpression of the anti-apoptotic protein, Bcl-2, in lymphoid cells demonstrates substantial resistance to GD3-induced apoptosis and marked delay in GD3-induced mitochondrial damage. Colell et al [94] reported that ganglioside GD3-induced apoptosis is associated with suppressing translocation of NF-{kappa}B from the cytosol to the nucleus, suggesting that GD3 blocks the NF-{kappa}B-dependent survival pathway. NF-{kappa}B is a ubiquitously expressed transcription factor which can initiate transcription of anti-apoptotic genes such as Bcl-x to prevent the loss of mitochondrial {Delta}{Psi}M and cytochrome C release [100,101]. Furthermore, the generation of reactive oxygen species is markedly stimulated by ganglioside GD3, which activates caspases that in turn lead to the dissolution of the cell membrane and nuclear components resulting in apoptosis [94,102].

Therefore, the increase in GD3 synthesized after ceramide accumulates secondary to the action of acidic sphingomyelinase on sphingomyelin exerts multiple mechanisms of cell killing, which combine mitochondrial-dependent apoptosome activation, suppression of the NF-{kappa}B-dependent survival pathway, and recruitment of reactive oxygen species such as superoxide and peroxynitric acid. Gangliosides GM3 and GD3, purified from human melanoma tumors, inhibit the phenotypic and functional differentiation of monocyte-derived dendritic cells induced by CD154 in a dose dependent manner. Furthermore, additions of GM3 and GD3 gangliosides not only decrease the viable cell yield and induce significant monocyte-derived dendritic cell apoptosis, but also decrease interleukin-2 (IL-2) and increase interleukin-10 (IL-10) concentration in monocyte-derived dendritic cells. This cytokine pattern may hamper an efficient antitumor immune response [103]. Exogenous ganglioside GM1 induces feline thymocyte apoptosis [89], which involves suppression of NF-{kappa}B, and decrease in IL-2 and interferon-{gamma} production (104). Overexpression of ganglioside GM3 using GM3 synthase gene expression vector induces apoptosis in human bladder tumor cells, but its mechanism is unclear [90].

Since GSLs are an abundant component of the external leaflet of the plasma membrane of cancer cells and anti-GSL antibodies involve pathogenic processes of neurological disorders, GSLs represent a potential target to trigger apoptosis in cancer cells. GM2 is the most immunogenic melanoma ganglioside and is the focus of most clinical research. Initial trials with ganglioside vaccines showed a strong correlation between the presence of GM2 antibodies in serum samples from patients with melanoma and improved disease-free and overall survival [105]. In addition, in vitro studies demonstrated that anti-ganglioside antibodies can induce cancer cell apoptosis. For example, addition of anti-ganglioside GD2 monoclonal antibodies into cell medium results in apoptosis in GD2-expressing human small cell lung cancer cells and reduces activation levels of mitogen-activated protein kinase [106]. Addition of anti-ganglioside GM2 to cell medium induces apoptosis of GM2-positive human lung cancer cells [107].

In contrast to anti-GSL antibodies, some cells, such as tumor cells, synthesize and shed large amounts of gangliosides into their microenvironment, which regulate cell functions through immunosuppression and apoptosis. Kudo et al [108] used a coculture method to demonstrate that renal tumor cells, SK-RC-45, induce apoptosis when cultured with Jurkat cells or normal T lymphocytes. SK-RC-45 cell-induced apoptosis in Jurkat cells or normal T lymphocytes is partially or completely abrogated by the ganglioside synthesis inhibitor, 1-phenyl-2-hexadecanoylamino-3-pyrrolidino-1-propanol, suggesting that shedding gangliosides from SK-RC-45 cells generate the apoptotic response in cocultured Jurkat cells or normal T lymphocytes. This type of ganglioside-induced apoptosis involves a variety of pathways including decreasing lymphocyte expression of Bcl-2 and Bcl-XL, inducing cytochrome C release from mitochondria, and activating caspase 9 and 3. These results suggest that gangliosides may be a key mediator of renal cell carcinoma-induced T-cell apoptosis and contribute to the T-cell dysfunction in the tumor microenvironment [108]. Gangliosides released from mesangial cells function as a growth inhibitor and enhance the apoptotic process adjacent to mesangial cells [109,110]. Over-expression of the anti-apoptotic gene, Bcl-XL, significantly reduced the release of gangliosides from mesangial cells. In addition, ganglioside shedding increased when mesangial cells were exposed to other agents (ie, H2O2 and staurosporin). These findings demonstrate that the gangliosides shed into the tumor microenvironment inhibit specific components of the immune response [111–114], thereby enhancing tumor formation and progression [115–117].

In conclusion, gangliosides are potential diagnostic markers and therapeutic targets for cancer. Enzyme replacement therapy by bone marrow transplantation and somatic gene therapy are potential options for the treatment of glycosphingolipidoses. The effective immunomodulation of autoantibodies to GSLs in immune-mediated motor neuropathies may significantly improve the quality of life in affected patients. Further insights into the survival-promoting effects of GM1 may define a role for GM1 in several therapeutic settings.


   Acknowledgements
Top
 Abstract
 Classification and Nomenclature
 Analysis of Glycosphingolipids
 Function of Glycosphingolipids
 Glycosphingolipid-Related...
 Glycosphingolipids and Apoptosis
 Acknowledgements
References
 
Supported in part by a grant from the William Beaumont Hospital Research Insitute. The authors thank Ms Bassima Georgis for typing this manuscript.


   References
Top
 Abstract
 Classification and Nomenclature
 Analysis of Glycosphingolipids
 Function of Glycosphingolipids
 Glycosphingolipid-Related...
 Glycosphingolipids and Apoptosis
 Acknowledgements
 References
 

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