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PubMed2000

Ganglioside-induced antiganglioside antibodies from a neuropathy patient cross-react with lipopolysaccharides of Campylobacter jejuni associated with Guillain-Barré syndrome.

Antiganglioside serum antibodies from a patient treated with gangliosides were examined for cross-reactivity with lipopolysaccharides (LPSs) of Campylobacter jejuni strains associated with Guillain-Barré syndrome (GBS). The patient had no preceding infection with C. jejuni and developed chronic progressive motor polyneuropathy following parenteral ganglioside treatment. Serum IgG antibodies recognised GM1 and GD1b gangliosides as well as asialo-GM1, and cross-reactivity was observed with LPSs from C. jejuni O:2, O:4, O:19 and O:41. The results give a clear indication that gangliosides and LPSs from C. jejuni serotypes associated with GBS share common epitopes.

Adult↗

PubMed1998

Ganglioside composition of GH3 cells: enhancement of fucoganglioside expression by estradiol, epidermal growth factor and insulin.

The GH3 cell line, a bipotential cell line secreting both prolactin (PRL) and growth hormone (GH), is a useful model for investigating GH/PRL cell lineage differentiation and anterior pituitary adenoma formation. In this study, we investigated the ganglioside composition of GH3 cells and identified two fucogangliosides as the major gangliosides expressed by these cells. Analyses by DEAE-Sephadex A-25 and thin-layer chromatography (TLC) revealed that the GH3 cells contained two major gangliosides, designated FG1 and FG2, respectively. Their structures were identified by fast atom bombardment mass spectrometry and proton nuclear magnetic resonance spectrometry: FG1 is IV2FUc alpha,II3NeuAc-GgOse4Cer and FG2 is IV2FUc alpha,IV3Gal alpha,II3NeuAc-GgOse4Cer. Expression of these fucogangliosides was enhanced by chronic treatment with 17 beta-estradiol (1 nM), epidermal growth factor (10 nM) and insulin (300 nM), which induced differentiation of GH3 cells to normal PRL-secreting cells. Interestingly, immunocytochemistry and flow cytometry revealed that the increased expression of these gangliosides reflected a quantitative change inside the cells but not on the cell surface. These results suggest that the intracellular distribution of fucogangliosides is closely related to the differentiation of GH3 cells.

Animals↗

PubMed2000

Reactivity of monoclonal antibodies with ganglioside antigens in human small cell lung cancer tissues.

Gangliosides on tumor cells have been suggested as potential target antigens for specific immunotherapy in various types of cancer including small cell lung cancer (SCLC). In this study we have compared the expression of three gangliosides that have been described as tumor-associated antigens, FucGM1, GM2 and GD3 in SCLC tissue specimens collected at autopsy, using a double-layer immunofluorescence staining method and specific monoclonal antibodies (Mabs) directed against these ganliosides. We found expression of FucGM1, GD3 and GM2 in (70% (n=20), 60% (n=15) and 40% (n75% of the tumor cells in all lesions from the same patient (five of eight cases). Our results indicate that FucGM1 is a relevant ganglioside antigen in SCLC, and suggest that specific immunotherapy involving more than one ganglioside antigen in SCLC should at least include FucGM1 and GD3.

Antibodies, Monoclonal↗

PubMed1985

Lipid phase separations induced by the association of cholera toxin to phospholipid membranes containing ganglioside GM1.

The interactions of cholera toxin and their isolated binding and active subunits with phospholipid bilayers containing the toxin receptor ganglioside GM1 have been studied by using high-sensitivity differential scanning calorimetry and steady-state and time-resolved fluorescence and phosphorescence spectroscopy. The results of this investigation indicate that cholera toxin associates with phospholipid bilayers containing ganglioside GM1, independent of the physical state of the membrane. In the absence of Ca2+, calorimetric scans of intact cholera toxin bound to dipalmitoylphosphatidylcholine (DPPC) large unilamellar vesicles containing ganglioside GM1 result in a broadening of the lipid phase transition peak and a slight decrease (less than 5%) in the transition enthalpy. In the presence of Ca2+ concentrations sufficient to cause ganglioside phase separation, the association of the intact toxin to the membrane results in a significant decrease of enthalpy change for the lipid transition, indicating that under these conditions the toxin molecule perturbs the hydrophobic core of the bilayer. Calorimetric scans using isolated binding subunits lacking the hydrophobic toxic subunit did not exhibit a decrease in the phospholipid transition enthalpy even in the presence of Ca2+, indicating that the binding subunits per se do not perturb the hydrophobic core of the bilayer. On the other hand, the hydrophobic A1 subunit by itself was able to reduce the phospholipid transition enthalpy when reconstituted into DPPC vesicles. These calorimetric observations were confirmed by fluorescence experiments using pyrene phospholipids.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗

PubMed1999

3'-Azidothymidine significantly alters glycosphingolipid synthesis in melanoma cells and decreases the shedding of gangliosides.

In this report, we establish that 3'-azido-3'-deoxythymidine (AZT) treatment of melanoma cells greatly alters the pattern of glycosphingolipid biosynthesis. In SK-MEL-30 cells, synthesis of the gangliosides GM3 and GD3 was significantly inhibited (60% and 50% of control, respectively) and the production of their precursor, lactosylceramide, was stimulated by 2.5-fold. Control experiments established that phospholipid synthesis was not affected by AZT treatment, consistent with AZT treatment only affecting lipid biosynthetic reactions that involve glycosylation. Likely as a consequence of decreased rates of ganglioside synthesis, AZT treatment of SK-MEL-30 cells also significantly suppressed the amount of gangliosides shed from the membranes of these cells. Since shedding of gangliosides has been proposed to allow melanoma cells to avoid destruction by the immune system and alterations of glycosphingolipid levels are likely important for the malignant cell phenotype, these results may have important implications regarding the potential use of AZT or related glycosylation inhibitors as cancer chemotherapeutics.

Antineoplastic Agents↗

PubMed1997

Ganglioside spinal cord changes in chronic relapsing experimental allergic encephalomyelitis induced in the Lewis rats.

Chronic relapsing experimental allergic encephalomyelitis (CREAE) was induced in Lewis rats by inoculation with guinea-pig myelin and complete Freund's adjuvant followed by treatment with low-dose cyclosporin A. Rats were sacrified at different phases of the disease (just before the onset of clinical signs, during the first clinical episode of CREAE and during the first recovery). Gangliosides were extracted from the spinal cord, analysed after purification by two-dimensional chromatography and quantified densitometrically. An increase of GM 1, the main rat myelin ganglioside, and a decrease of GT1b, suggested to play a role in mediating the interactions between oligodendroglia and axons, were observed during the development of the CREAE. These findings indicating significant ganglioside changes in CREAE give further support to the concept concerning the involvement of gangliosides in autoimmune demyelination.

Animals↗

PubMed2004

Synthesis of ganglioside epitopes for oligosaccharide specific immunoadsorption therapy of Guillian-Barré syndrome.

Guillain-Barré syndrome is a postinfectious, autoimmune neuropathy resulting in neuromuscular paralysis. Auto-antibodies, often induced by bacterial infection, bind to human gangliosides possessing monosialoside and diasialoside epitopes and impair the function of nerve junctions, where these ganglioside structures are highly enriched. Truncated gangliosides representive of GD3, GQ1b and GM2 epitopes have been synthesized as methyl glycosides and as a glycosides of an eleven carbon tether. The synthetic oligosaccharide ligands are structural mimics of these highly complex ganglioside epitopes and via their ability to neutralize or remove auto-antibodies have the potential for therapy, either as soluble blocking ligands administered systemically, or as immuno-affinity ligands for use as extracorporeal immunoadsorbents.

Antibodies, Monoclonal↗

PubMed2006

Gangliosides play an important role in the organization of CD82-enriched microdomains.

Four-transmembrane-domain proteins of the tetraspanin superfamily are the organizers of specific microdomains at the membrane [TERMs (tetraspanin-enriched microdomains)] that incorporate various transmembrane receptors and modulate their activities. The structural aspects of the organization of TERM are poorly understood. In the present study, we investigated the role of gangliosides in the assembly and stability of TERM. We demonstrated that inhibition of the glycosphingolipid biosynthetic pathway with specific inhibitors of glucosylceramide synthase [NB-DGJ (N-butyldeoxygalactonojirimycin) and PPMP (D-threo-1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol.HCl)] resulted in specific weakening of the interactions involving tetraspanin CD82. Furthermore, ectopic expression of the plasma-membrane-bound sialidase Neu3 in mammary epithelial cells also affected stability of the complexes containing CD82: its association with tetraspanin CD151 was decreased, but the association with EGFR [EGF (epidermal growth factor) receptor] was enhanced. The destabilization of the CD82-containing complexes upon ganglioside depletion correlated with the re-distribution of the proteins within plasma membrane. Importantly, depletion of gangliosides affected EGF-induced signalling only in the presence of CD82. Taken together, our results provide strong evidence that gangliosides play an important role in supporting the integrity of CD82-enriched microdomains. Furthermore, these results demonstrate that the association between different tetraspanins in TERM is controlled by distinct mechanisms and identify Neu3 as a first physiological regulator of the integrity of these microdomains.

Animals↗

PubMed2001

Differential functional relevance of a plasma membrane ganglioside sialidase in cholinergic and adrenergic neuroblastoma cell lines.

Gangliosides located in the outer leaflet of the plasma membrane are important modulators of cellular functions. Our previous work has shown that in cultured human SK-N-MC neuroblastoma cells a sialidase residing in the same membrane selectively desialylates gangliosides with terminal sialic acid residues, causing a shift from higher species to GM1 and a conversion of GM3 to lactosylceramide. Inhibition of this sialidase by 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (NeuAc2en) resulted in increased cell proliferation and a loss of differentiation markers. In this study, we examined the occurrence and function of this ganglioside sialidase in other neuronal cells. Subcellular fractionation showed the sialidase to be located in the plasma membrane of all cell lines studied. The presence of the inhibitor NeuAc2en led to a profound decrease in the amount of the differentiation marker 200 kDa/70 kDa neurofilaments and an increase in cell proliferation in the cholinergic SK-N-MC and mixed cholinergic/adrenergic SK-N-FI and SK-N-DZ neuroblastoma lines, but had little or no effect in the human adrenergic SK-N-SH and SK-N-AS and the adrenergic/cholinergic PC12 cells from rat. The influence of the inhibitor on cell behaviour was paralleled by a diminished number of cholera toxin B-binding GM1 sites. The findings demonstrate that the plasma membrane ganglioside sialidase is an important element of proliferation and differentiation control in some, but not all, neuroblastoma cells and suggest that there might be a relationship between plasma membrane sialidase activity and cholinergic differentiation.

Adrenergic Fibers↗

PubMed1981

GM1 ganglioside concentration in the cerebrospinal fluid of hydrocephalic infants and children.

Ventricular fluid taken from 29 children with active hydrocephalus was assayed for GM1 ganglioside level and correlated with gross assessment of intellectual outcome. Normal levels of GM1 ganglioside were consistent with grossly normal intellectual function. Marked elevations of GM1 ganglioside were found in the ventricular fluid of severely retarded children. No definitive pattern of GM1 ganglioside level was found in moderately retarded children.

Cerebrospinal Fluid Shunts↗

PubMed1997

Nanomolar concentrations of gangliosides stimulate primary humoral response.

Exogenous gangliosides act as immunosuppressors when applied at micromolar concentrations corresponding to their average level in human plasma. Here we show that at nanomolar concentrations the gangliosides GD3, GD1a and GM1 can act as immunostimulators markedly enhancing the number of plaque-forming cells in mouse splenocyte culture responding to sheep erythrocytes. At such low concentration these gangliosides as well as GM3 were not able to influence significantly proliferative responses of splenic B and T lymphocytes or of cytotoxic T-cells. Neither did they change significantly the production of IL-1 by antigen- representing cells, or of IL-2 by Con A-induced blasts in the splenocyte culture. It is suggested that the stimulatory effect of low ganglioside concentrations on humoral response is due to their influence on cooperative cell-cell interactions required for the differentiation of B-cells into Ig-secreting cells.

Adjuvants, Immunologic↗

PubMed1999

The distribution of ganglioside-like moieties in peripheral nerves.

GM1 ganglioside has been implicated as a target of immune attack in some diseases of the peripheral nervous system. Anti-GM1 ganglioside antibodies are associated with certain acquired immune-mediated neuropathies. It is not clear how anti-GM1 antibodies cause nerve dysfunction and injury; however, sodium and/or potassium ion channel dysfunction at the node of Ranvier has been implicated. To gain insight into the pathogenesis of these neuropathies, we examined the distribution of GM1 ganglioside and Gal(beta1-3)GalNAc moieties in nerve fibres and their relationship to voltage-gated sodium and potassium (Kv1.1, 1.5) channels at the nodes of Ranvier in peripheral nerves from human, rat and dystrophic mice. Gal(beta1-3)GalNAc moieties were localized via the binding of cholera toxin and peanut agglutinin. As a control for the specificity of these findings, we compared the distribution of GM1 moieties to that of the ganglioside GT1b. Our study provides definitive evidence for the presence of Gal(beta1-3)GalNAc bearing moieties on the axolemmal surface of mature myelinated fibres and on Schwann cells. Gal(beta1-3)GalNAc binding sites did not have an obligatory co-localization with voltage-gated sodium channels or the potassium ion channels Kv1.1 and Kv1.5 and are thus not likely carried by these ion channels. In contrast with Gal(beta1-3)GalNAc, GT1b-like moieties are restricted to the axolemma.

Animals↗

PubMed2001

Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations.

Niemann-Pick disease type C (NPC) is a lethal neurologic storage disorder of children most often caused by a defect in the protein NPC1. To better understand the disease we thoroughly characterized the cellular and morphological alterations occurring in murine, feline, and human NPC. Using immunocytochemistry and filipin histochemistry we show that both gangliosides and unesterified cholesterol are differentially stored in neurons of the cerebral cortex, cerebellum, and hippocampus, as well as in liver. Double fluorescence labeling revealed that GM2 ganglioside and unesterified cholesterol were partially co-localized in vesicular structures, and triple fluorescence labeling utilizing a LAMP-1 antibody identified many of these organelles as part of the late endosomal/lysosomal pathway. These observations, coupled with the proposed role of NPC1 in intracellular cholesterol movement, suggest that GM3 and GM2 gangliosides as well as unesterified cholesterol may be retrogradely cleared from late endosomes/lysosomes by an NPC1-dependent mechanism. Cellular consequences of the NPC metabolic defect as shown by parvalbumin immunocytochemistry and rapid Golgi staining, respectively, revealed characteristic axonal spheroids on GABAergic neurons and ectopic dendritogenesis that followed a species-specific gradient of: mouse < feline < human. These studies suggest that the homeostatic regulation of gangliosides and cholesterol in neurons is mediated by NPC1 and that perturbations in this mechanism cause a complex neuronal storage disorder.

Animals↗

PubMed1978

GM3 ganglioside in various tissues of rabbit. Tissue-specific distribution of N-glycolylneuraminic acid-containing GM31.

Molecular species and concentrations of GM3 ganglioside in rabbit tissues, brain, thymus, lung, liver, stomach, intestine, kidney, testis, muscle, and erythrocytes were determined. The highest concentration was found in lung (431.7 nmol/g wet tissue). With the exceptions of brain, thymus, and erythrocytes, GM3 was the dominant ganglioside and comprised more than 50% of the total gangliosides. In brain and thymus, GM3 composed 0.76% and 17.28% of the total gangliosides, respectively. The sialic acid composition of GM3 was determined by mild methanolysis and neuraminidase treatment combined with either permethylation or trimethylsilylation. N-Glycolylneuraminic acid-containing GM3 was found in thymus, lung, kidney, and intestine in addition to N-acetylneuraminic acid-containing GM3, but N-acetylneuraminic acid was the sole sialic acid of GM3 in the other tissues. Sixty-four percent of the thymus GM3 consisted of N-glycolylneuraminic acid. High concentrations of C-20 sphingosine and stearic acid were characteristic for brain GM3 and the major long chain base of the other tissues was C-18 spingosine. The fatty acid composition of GM3 varied in each tissue. The difference in mobility on a thin-layer plate was due to the difference in its molecular constitution, being derived from a combination of fatty acid, long chain base, and sialic acid.

Animals↗

PubMed1984

Autoradiography of ganglioside antigens separated by high-performance thin-layer chromatography with their antibodies.

An improved method is described for the detection of ganglioside antigens with the antibodies on thin-layer chromatograms. The method involves the following steps: Separation of gangliosides on a high-performance thin-layer chromatographic plate, application of antibody solution, and detection of bound antibody with [125I]staphylococcal protein A. Using specific antibodies against gangliosides GM4, GM1, GD3, and asialo GM1 ganglioside, the method allowed positive identification of these antigens on thin-layer plates. It also provides a convenient means of assessing the specificity of an anti-glycolipid antibody.

Antibodies↗

PubMed1997

Gangliosides enhance KCl-induced Ca2+ influx and acetylcholine release in brain synaptosomes.

Effects of gangliosides GM1 and GQ1b on cholinergic synaptic functions were investigated using synaptosomes prepared from mouse brain cortices. Treatment of synaptosomes with GM1 and GQ1b increased high K(+)-evoked acetylcholine (ACh) release in a bell-shaped dose-dependent manner. The peaks of the effects were found to be at 1-5 microM for GM1 and 5-10 microM for GQ1b. ACh synthesis and the levels of ACh in synaptosomes were not affected by the ganglioside treatment. Both gangliosides enhanced depolarization-induced influx of calcium ions into synaptosomes. These results indicate that GM1 and GQ1b gangliosides increase evoked ACh release by modulating voltage-dependent calcium channels in the synaptic plasma membranes. The effect of GM1 on calcium ion influx remained after repetitive washings, but was almost completely abolished when the bound GM1 was removed by trypsin. This indicates that the fraction of GM1 which was tightly bound to, but not incorporated in synaptic plasma membranes, is responsible for activating the calcium channels.

Acetylcholine↗

PubMed1999

Enhancement of TNF-alpha production by ganglioside GM2 in human mononuclear cell culture.

Some gangliosides have been regarded as autoantigens of immune-mediated neurological disorders such as Guillain-Barré syndrome (GBS), Miller Fisher syndrome and multifocal motor neuropathy. On the other hand, proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), may be important in the pathogenesis of some neuroimmunological disorders. To clarify the interactions between immune cells and gangliosides, we investigated the effects of gangliosides on the production of proinflammatory cytokines in peripheral blood mononuclear cell (PBMC) cultures. We found that ganglioside GM2 markedly enhances the production of TNF-alpha and that TNF-alpha induction by coated GM2 is still more marked. These findings suggest that immune cells, especially monocytes/macrophages, cause inflammation upon encountering GM2.

Cell Adhesion↗

PubMed1988

Detection of gangliosides as N-glycolylneuraminic acid-specific tumor-associated Hanganutziu-Deicher antigen in human retinoblastoma cells.

Gangliosides were shown to bear the tumor-associated N-glycolylneuraminic acid (NeuGc)-specific Hanganutziu-Deicher (HD) antigen expressed in human retinoblastoma cells. HD antigenic gangliosides were detected by thin-layer chromatography/enzyme-immunostaining using affinity-purified chicken antibody against GM3 containing NeuGc and horseradish peroxidase-conjugated anti-chicken IgG. One to four species of the antigenic gangliosides were detected from all of 4 cell lines, Y79, WERI-Rb1, TOTL1, and YK, as well as freshly cultured retinoblastoma cells and isolated tumor tissue. All cases contained GM3(NeuGc) as an HD antigen. No HD antigenic ganglioside was detected in normal retinal tissues by the same procedure.

Antigens, Heterophile↗