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PubMed1990

The influence of gangliosides on the hydrophilic pore edge line tension and monolayer fusion of lipid membranes.

It is shown that inclusion of gangliosides into planar phospholipid bilayers leads to an essential suppression of their monolayer fusion. In contrast to phospholipid lysoforms, the gangliosides do not cause an associative decrease of the specific energy of the hydrophilic pore edge determined in the experiments on the electrical breakdown of membranes. This phenomenon depends on the effective size of the polar headgroup of the gangliosides. It is supposed that the effect of gangliosides on the parameters mentioned is based on the fact that they have large hydrated polar headgroups which create steric hindrances, which prevent (i) the membranes to come into contact during monolayer fusion; (ii) the gangliosides to take part in hydrophilic pore formation.

Cerebrosides↗
PubMed1990

Characterization of the binding epitope of the monoclonal antibody DMAb-1 to ganglioside GM2.

Several derivatives of ganglioside GM2 were synthesized for mapping of the binding epitope of a monoclonal antibody raised against this ganglioside. The GM2 ganglioside was modified in both the hydrophobic and the hydrophobilic part of the molecule. The synthesized derivatives were characterized with fast atom bombardment mass spectrometry (FAB-MS). Affinity of the monoclonal antibody for the GM2 derivatives was determined by enzyme-linked immunosorbent assay (ELISA) on microtitre plates or by TLC immunostaining. Modifying the GM2 sialic acid by deacetylation or blocking of the carboxyl moiety abolished the binding to the monoclonal antibody while the cleaving of the glycol group on the sialic acid tail led to a 70% reduced binding affinity. Removal of the fatty acid (lyso-GM2) eliminated the binding to the antibody. GM2 derivatives with fatty acid moieties of 8 carbon atoms or less showed almost no reactivity. GM2 with saturated fatty acids 16:0, 18:0 and 20:0 had binding affinity similar to natural GM2, while the 24:0 fatty acid had only half the binding affinity. The results demonstrate the importance of ganglioside fatty acid composition with regard to ligand binding between the monoclonal antibody and its specific ganglioside antigen. Thus, caution must be shown in the application of immunaffinity methods with monoclonal antibodies for the quantitative determination of glycosphingolipids from different tissues.

Antibodies, Monoclonal↗
PubMed1987

Inhibition by gangliosides of the specific binding of lipopolysaccharide (LPS) to human monocytes prevents LPS-induced interleukin-1 production.

In a previous work we have reported that gangliosides inhibit interleukin 1 (IL-1) release by human monocytes stimulated with lipopolysaccharides (LPS). In the present study we extend this work to IL-1 production and we correlate these observations with the capacity of gangliosides to inhibit the binding of radiolabeled LPS to its specific receptor on human monocytes. Preincubation of 3H-LPS with crude bovine brain gangliosides, as well as purified human brain mono, di, and trisialogangliosides (GM1, GD1a, and GT1b, respectively), led to an inhibition of the specific binding of LPS to the cell surface. Neither ceramide nor N-acetyl neuraminic acid, two constituents of gangliosides, was able by itself to inhibit the specific binding. A strict parallelism was observed with respect to inhibition on LPS-induced IL-1 production and release. Asialoganglioside (asialo-GM1) was inactive in both assays, suggesting that the N-acetyl neuraminic acid plays a role within the ganglioside molecule, with respect to inhibitory activity. We conclude that LPS-induced production and release by human monocytes is not due to a signal triggered by nonspecific absorption and/or intercalation of LPS into cell membrane which occur through hydrophobic interaction mediated by the lipid A region. Addition of exogenous sialogangliosides which blocked LPS-induced IL-1 production and release, did not modify significantly the nonspecific binding of 3H-LPS, whereas it did inhibit the specific binding which is mediated by the polysaccharide moiety of the LPS molecule. These results establish a relationship between the specific endotoxin receptor on monocytes and a LPS-induced cellular function.

Binding, Competitive↗
PubMed1995

Spontaneous transfer of GM3 ganglioside between vesicles.

The spontaneous transfer between membranes of GM3, a ganglioside present in a vesicular form of aggregation instead of micellar form like the majority of gangliosides in aqueous medium, has been studied. Upon incubation of GM3 in the presence of dipalmitoylphosphatidylcholine (DPPC) large unilamellar vesicles at 50 degrees C, mixed GM3/DPPC vesicles are formed. The maximum amount of GM3 that can be inserted into vesicles is about 8%. The temperature dependence of the kinetics has been followed by the excimer formation technique, using the fluorescent analogue pyrenyldodecanoyl-GM3. The transfer of ganglioside from its vesicles to DPPC vesicles depends on the physicochemical characteristics of both the donor and of the acceptor vesicles and increases with the temperature (k = 0.006 0.012, 0.037 at 30, 41 and 50 degrees C, respectively), with a major break point at 41 degrees C and a minor one at 35 degrees C. These temperatures correspond to the gel- to liquid-crystalline transition of DPPC (Tm = 41.3 degrees C), and to a temperature transition displayed by GM3 ganglioside. Similar experiments performed with erythrocyte ghosts yielded a rate constant of 0.04 at 37 degrees C. For the transfer of ganglioside from DPPC (donor) to DMPC (acceptor) the rate constants were 0 at 15 degrees C (both phospholipids in the gel phase), 0.005 at 37 degrees C (donor in the gel phase, acceptor in the fluid phase) and 0.04 at 50 degrees C (both phospholipids in the fluid phase).(ABSTRACT TRUNCATED AT 250 WORDS)

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1991

Determination of gangliosides and sulfatide in human cerebrospinal fluid with a microimmunoaffinity technique.

An immunostaining procedure has been developed for the assay of the gangliotetraose gangliosides and sulfatide in cerebrospinal fluid. Gangliosides of the gangliotetraose series were individually determined with cholera toxin B-subunit (CT-B) and an anti CT-B monoclonal antibody after chromatography and sialidase hydrolysis to GM1 on high performance thin-layer plates. Sulfatide was determined by thin-layer chromatography using an anti-sulfatide antibody. The method was applied to normal cerebrospinal fluid from 20 adults and 30 children. The concentration of the gangliotetraose series gangliosides in adults varied from 100-300 nmol/l with a mean value of 230 +/- 56 nmol/l. Corresponding values for sulfatide were 30-225 nmol/l and 140 +/- 46 nmol/l. The values for gangliosides and sulfatide in children increased during development. The major gangliosides in cerebrospinal fluid of adults were GT1b and GD1b and in children GD1a and GT1b.

Adolescent↗
PubMed1990

Extensive precursor-product relationship between gangliosides formed from exogenous glucosylceramide in rat liver.

Glucosylceramide, radiolabelled on the glucose residue, was administered to rats and the radioactive gangliosides formed at different time points were chemically characterized. They were identified as GM3, GM1, GD1a and GD1b, each one carrying only radioactive glucose. The time course of each individual ganglioside showed that the simpler gangliosides were formed earlier but were consumed earlier than the more complex ones, resulting in radioactivity patterns that were different at each time point. Only 30 h after injection did it resemble that of endogenous rat liver gangliosides. These results indicate that an extensive precursor-product relationship actually exists in the course of ganglioside biosynthesis.

Animals↗
PubMed1988

Gangliosides suppression of murine lymphoproliferation and interleukin 1 production.

Studies were carried out to determine whether inhibition of gangliosides on lymphoproliferation was related to interleukin (IL)-1. The results showed that gangliosides, GM1 and GT1b were able to inhibit the proliferation of spleen lymphocytes from C57BL/6J mice in dose-dependent fashion, whereas asialo-GM1 was not inhibitory. However, gangliosides, GM1 and asialo-GM1 did not suppress the production of IL-1 in Salmonella typhosa lipopolysaccharide (LPS)-induced peritoneal adherent cells. Various types of LPS including S. enteritidis, S. minnesota and Escherichia coli 055:B5 were used to stimulate the production of IL-1 in adherent cell cultures. The IL-1 production was not affected by gangliosides, GD1a and GD1b. Although GT1b suppressed IL-1 production of human monocytes to 82% of control level it did not, however, affect the IL-1 production of murine adherent cells. Thus, the inhibitory mechanism of gangliosides on murine immune cells remains unclear, and warrants further study.

Animals↗
PubMed1989

Anti-GM1 ganglioside antibodies with differing fine specificities in patients with multifocal motor neuropathy.

Antibodies to gangliosides were detected in sera from three of 19 patients with chronic inflammatory polyneuropathy (CIP) by a thin-layer chromatogram overlay technique. All three of the patients fell into a clinical subset of the group that had multifocal motor neuropathy, and in all three patients the antibodies reacted with GM1 ganglioside. However, the fine specificities of the antibodies differed as demonstrated by cross-reactivity with different gangliosides in each of the three patients. The antibodies in patient 1 reacted with GM1, GD1b, and asialo-GM1 suggesting that the terminal Gal(beta 1-3)GalNAc moiety that is common to these three glycolipids is an important part of the epitope(s). This was confirmed by showing reactivity of the antibodies with Gal(beta 1-3)GalNAc conjugated to bovine serum albumin. Patient 2 had antibodies that did not react with GD1b, but cross-reacted with GM2 ganglioside suggesting that the epitope(s) involved the inner portion of the oligosaccharide moiety that is shared between GM1 and GM2. Patient 3 had antibodies that reacted with GM1 and asialo-GM1, but they did not cross-react with either GD1b or GM2. These results provide further evidence for a relationship between motor nerve syndromes and anti-GM1 antibodies and also suggest that GM1 could be a principal target antigen since other reactive gangliosides differed among the patients. However, the possible pathogenic effects of anti-GM1 antibodies on motor nerves remain to be established.

Antibodies↗
PubMed1989

Changes in ganglioside composition and morphological features during the development of cultured astrocytes from rat brain.

Changes in ganglioside content over a period of days were examined in astrocytes obtained via cell passage from rat cerebral cortex. Thin-layer chromatography revealed that, in the astrocytes, ganglioside GM1 was absent, the predominant ganglioside being GM3. Also, an increased GD3 content in long-term astrocyte cultures was detected. The morphological features of astrocytes were also studied using immunoperoxidase staining. Astroglial features were characterized by high levels of glial fibrillary acidic protein (GFAP) and vimentin, which are the major intermediate-filament proteins present in astrocytes at an early culture stage. In long-term-cultured (greater than 7 months) astrocytes, vimentin and GFAP were increased in process-bearing cells. Ganglioside GD3 recognized by R24 monoclonal antibody was also expressed in these cells. These results suggest that the increase of ganglioside GD3 in long-term-cultured astrocytes may be related to the appearance of multistellate cells showing strong reactivity against GFAP and vimentin during development over a specified period in culture.

Animals↗
PubMed1992

Cell surface distribution of endogenous and effects of exogenous gangliosides on neuronal survival, cell shape and growth in vitro.

In vitro immunostaining of neurons from spinal cord or brain of embryonic chicken by means of monoclonal anti-ganglioside antibodies (Q211, D21b) revealed a fluorescence-labeling of c-polysialogangliosides and GD1b evenly distributed over the entire neuronal surface including filopodia at the growth cones. On electronmicroscopical level the gold-stained ganglioside-antigens were found more or less densely packed in small adjacent areas suggesting a concentration in local "domains". Survival in serum-free or serum-containing medium of embryonic spinal cord motoneurons, which normally died if not cultivated in muscle conditioned medium or in contact to myotubes, was remarkably improved in the presence of a ganglioside mixture (10 microM) from bovine brain. If embryonic neurons from optic lobes were cultivated at low Ca(2+)-concentration (< 20 microM) they developed flat, broad cell bodies with many filopodia and only a few flat-shaped short processes. A very weak cytoskeleton-staining by means of rhodamine-linked phalloidine indicated that polymerization of actin was impaired in these neurons. At the same low Ca(2+)-concentration of < 20 microM but in the presence of ganglioside GM1 (up to 100 microM) most of the neurons developed a "normal" cell shape with rounded perikarya and thin neurites with "normal" shaped growth cones. In this case rhodamine-linked phalloidine revealed a much more intense staining mainly concentrated within the growing tips. The morphology and growth of the ganglioside-treated neurons resembled that of neurons cultivated at a higher Ca(2+)-concentration of at least 600 microM.

Animals↗
PubMed1979

Changes in brain ganglioside composition of normothermic and hibernating golden hamsters (Mesocricetus auratus).

1. Brain ganglioside patterns of normothermic and hibernating golden hamsters (Mesocricetus auratus) and laboratory mice had been investigated. 2. The ganglioside pattern of normothermic golden hamsters in comparison to that of mice is characterized by an unusual high amount of the polar trisialoganglioside GT1. 3. In the hibernating golden hamster in contrast to normothermic counterparts the brain gangliosides are more polar (polysialization-effect). 4. The results are discussed with regard to the hypothesis that neuronal membranes provided with more polar gangliosides at lower environmental temperatures might be more efficient with respect to the high complexation ability of gangliosides with Ca2+-ions.

Animals↗
PubMed2005

Membrane redistribution of gangliosides and glycosylphosphatidylinositol-anchored proteins in brain tissue sections under conditions of lipid raft isolation.

Sphingolipids, glycosylphosphatidylinositol (GPI)-anchored proteins, and certain signaling molecules segregate from bulk membrane lipids into lateral domains termed lipid rafts, which are often isolated based on their insolubility in cold nonionic detergents. During immunohistological studies of gangliosides, major sphingolipids of the brain, we found that cold Triton X-100 solubility is bidirectional, leading to histological redistribution from gray to white matter. When brain sections were treated with > or =0.25% Triton X-100 at 4 degrees C, ganglioside GD1a, which is normally enriched in gray matter and depleted in white matter, redistributed into white matter tracts. Incubation of brain sections from knockout mice lacking GD1a with wild-type sections in the presence of cold Triton X-100 resulted in GD1a redistribution from wild-type gray matter to knockout white matter. GM1, which is normally enriched in white matter, remained in white matter after cold detergent treatment and did not migrate to knockout mouse brain sections. However, when gray matter gangliosides were enzymatically converted into GM1 in situ, the newly formed GM1 transmigrated to knockout mouse brain sections in the presence of cold detergent. When purified GD1a was added to knockout mouse brain sections in the presence of cold Triton X-100, it preferentially incorporated into white matter tracts. These data demonstrate that brain white matter is a sink for gangliosides, which redistribute from gray matter in the presence of low concentrations of cold Triton X-100. A GPI-anchored protein, Thy-1, also transmigrated from wild-type to Thy-1 knockout mouse brain sections in the presence of detergent at 4 degrees C, although less efficiently than did gangliosides. These data raise technical challenges for using nonionic detergents in certain histological protocols and for isolation of lipid rafts from brain tissue.

Animals↗
PubMed2006

Gangliosides of the stroma layer participate in the interferon-gamma receptor-dependent controls of myelopoiesis.

Stroma-mediated myelopoiesis depends upon growth-factors and an appropriate intercellular microenvironment, whose polarity is relevant for granulocyte-macrophage colony stimulating factor (GM-CSF) mediated myeloid cell proliferation. Here we have studied qualitative and quantitative aspects of ganglioside participation in controls of the microenvironment required to sustain myelopoiesis. We analysed ganglioside synthesis, expression and shedding by two primary liver stromal cell cultures isolated from wild type and interferon-gamma (IFNgamma) receptor knockout mice. The latter one has a higher capacity to sustain myelopoiesis. FDC-P1 myeloid growth factor-dependent cell line was used as the reporter system, monitoring the cell survival and proliferation that reflect the bio-availability and the activity of GM-CSF. Although the two stromal cells synthesised the same gangliosides their relative content was quite different. FDC-P1 proliferation decreased in cultures in which ganglioside synthesis was inhibited in the stroma, as well as in presence of stroma cell supernatants in which GM3 was neutralised by the anti-GM3 monoclonal antibody. Addition of exogenous GM3 reverted the inhibition and sustained proliferation of FDC-P1 cells. FDC-P1 cells do not accumulate GM3, but they are able to take up the stroma-produced sphingolipids. Thus, stroma has a double role in sustaining myelopoiesis, providing both growth factor(s) and ganglioside(s) required for the optimal stimulation of the myeloid cell proliferation, and the IFNgamma mediated stroma-dependent controls of myelopoiesis are determinant for this cell interaction.

Animals↗
PubMed1986

Electrokinetic and electrostatic properties of bilayers containing gangliosides GM1, GD1a, or GT1. Comparison with a nonlinear theory.

We formed vesicles from mixtures of egg phosphatidylcholine (PC) and the gangliosides GM1, GD1a, or GT1 to model the electrokinetic properties of biological membranes. The electrophoretic mobilities of the vesicles are similar in NaCl, CsCl, and TMACl solutions, suggesting that monovalent cations do not bind significantly to these gangliosides. If we assume the sialic acid groups on the gangliosides are located some distance from the surface of the vesicle and the sugar moieties exert hydrodynamic drag, we can describe the mobility data in 1, 10, and 100 mM monovalent salt solutions with a combination of the Navier-Stokes and nonlinear Poisson-Boltzmann equations. The values we assume for the thickness of the ganglioside head group and the location of the charge affect the theoretical predictions markedly, but the Stokes radius of each sugar and the location of the hydrodynamic shear plane do not. We obtain a reasonable fit to the mobility data by assuming that all ganglioside head groups project 2.5 nm from the bilayer and all fixed charges are in a plane 1 nm from the bilayer surface. We tested the latter assumption by estimating the surface potentials of PC/ganglioside bilayers using four techniques: we made 31P nuclear magnetic resonance, fluorescence, electron spin resonance, and conductance measurements. The results are qualitatively consistent with our assumption.

Egg Yolk↗
PubMed1998

Intensive extrusion and occlusion of water in ganglioside micelles with thermal reversibility.

By using a shell-modeling analysis for small-angle scattering data of ganglioside micellar dispersion, we recently reported that the elevation of temperature induces a significant shrinkage of the hydrophilic region of the ganglioside micelle, suggesting that the oligosaccharide chains with sialic acid residues of ganglioside molecules change the conformation, sensitively responding to a change in temperature (Hirai et al., 1996. Biophys. J. 70:1761-1768; J. Phys. Chem. 100:11675-11680). We have carried out further analyses of the temperature dependence of the structural parameters reported previously, and we have found clear evidence of reversible extrusion and occlusion of a large amount of water in the hydrophilic region of the ganglioside micelle in the physiological temperature range of 6-60 degrees C. The present results suggest a remarkable function of ganglioside molecules: they change the hydrophilicity of the cell surface locally as a response to variations in temperature. This phenomenon might be involved in various surface events, such as cell-cell interaction and cell surface-protein interaction.

Animals↗
PubMed2005

Glucosamine induces cell-cycle arrest and hypertrophy of mesangial cells: implication of gangliosides.

Alterations in proliferation and hypertrophy of renal mesangial cells are typical features of diabetic nephropathy. The HP (hexosamine pathway) has been proposed as a biochemical hypothesis to explain microvascular alterations due to diabetic nephropathy; however, involvement of HP in the regulation of mesangial cell growth or hypertrophy has been poorly studied. Although gangliosides are known to regulate cell proliferation, their potential role in mesangial cell-growth perturbations has hardly been explored. In the present study, we investigated the effects of the HP activation, mimicked by GlcN (glucosamine) treatment, on mesangial cell growth and hypertrophy and the potential implication of gangliosides in these processes. Our results indicate that GlcN induced hypertrophy of mesangial cells, as measured by an increase in the protein/cell ratio, and it caused cell-cycle arrest by an increase in the expression of cyclin-dependent kinase inhibitor p21(Waf1/Cip1). Furthermore, GlcN treatment resulted in a massive increase in the levels of gangliosides G(M2) and G(M1). Treatment of cells with exogenous G(M2) and G(M1) reproduced the effects of 0.5 mM GlcN on p21(Waf1/Cip1) expression, cell-cycle arrest and hypertrophy, suggesting that gangliosides G(M2) and G(M1) are probably involved in mediating GlcN effects. These results document a new role of the HP in the regulation of mesangial cell growth and hypertrophy. They also suggest a potential new mechanism of action of the HP through modulation of ganglioside levels.

Animals↗
PubMed1975

Interaction of cholera toxin and membrane GM1 ganglioside of small intestine.

Ganglioside GM1 was isolated from the small intestinal mucosa of man, pig, and beef and amounted to 0.1, 2.0, and 43 nmol per g fresh weight, respectively. These differences in GM1 content were associated with a quantitatively differing ability of the mucosal cells to bind cholera toxin. Human cells bound about 15,000 toxin molecules when saturated with the toxin, porcine cells 120,000, and bovine cells 2,600,000 molecules. The association constant (KA) of the cholera toxin binding was, for cells of all three species, about 10(9) liters/mol. Exogenously added GM1 ganglioside was incorporated in intestinal mucosal cells as well as in intact rabbit small bowel. The increment in GM1 was associated with a correspondingly increased number of binding sites for cholera toxin, whereas KA was unchanged. GM1 incorporation increased the sensitivity of the rabbit small bowel to the diarrheogenic action of cholera toxin. Vibrio cholerae sialidase hydrolyzed isolated intestinal diand trisialogangliosides to GM1. However, the enzyme did not change the ganglioside pattern of intestinal mucosa, had very little influence on the number of toxin binding sites on intestinal cells, and did not alter the sensitivity of the small bowel to the diarrheogenic action of the toxin. These results demonstrate a relationship in the intestinal mucosa between the GM1 ganglioside concentration, the number of binding sites for cholera toxin, and the sensitivity to the biologic action of the toxin. Thus, the study strongly supports the concept that the GM1 ganglioside is the intestinal binding receptor for cholera toxin.

Animals↗
PubMed1983

Ganglioside GM2 as a human tumor antigen (OFA-I-1).

A monospecific antibody produced in vitro by a B-lymphoblastoid cell line transformed with Epstein-Barr virus has been shown to recognize a membrane antigen (OFA-I-1) on human tumors and fetal brain. This study identifies the chemical nature of OFA-I-1. The glycolipid fraction of antigen-rich spent medium of an OFA-I-1-positive melanoma cell line, M14, was extracted by chloroform/methanol/water, 4:8:3 (vol/vol), and was separated into fractions of neutral glycolipids and gangliosides by DEAE-Sephadex followed by base treatment and Bio-sil A column elution. OFA-I-1 antigens were found exclusively in the ganglioside fraction when assayed with monospecific anti-OFA-I-1 by an immune adherence inhibition test. The results obtained from thin-layer chromatography of the antigenic M14 ganglioside and sequential glycosidase digestion suggested that the antigen was a ganglioside GM2, GalNAc beta 1 leads to 4(NeuAc alpha 2 leads to 3)Gal beta 1 leads to 4Glc leads to Cer. These results were further supported by testing various authentic gangliosides and neutral glycolipids for OFA-I-1 antigenicity. Only GM2 showed positive reactivity.

Adult↗