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PubMed1986

Effects of chronic alcohol consumption in weanling rats on brain gangliosides.

Chronic ingestion of ethyl alcohol in pre-weanling rats can decrease whole-brain levels of sialic acid (SA), an acidic sugar that serves as terminal groups on glycolipids (gangliosides) and glycoproteins. Because SA occurs in both classes of membrane-bound chemicals, the alcohol effect could be on either or both parent compounds. We examined the effects of alcohol on gangliosides by measuring levels of six specific ganglioside species in post-weanling rats that were fed liquid alcohol diet for 35 days. We found no major effect on any of the ganglioside species in the alcohol-fed rats compared with their pair-fed littermates. These data suggest that alcohol may have acute effects on membrane gangliosides, but during chronic exposure in more mature animals, the membrane may adapt and maintain near-normal ganglioside composition. Thus, gangliosides may reflect mechanisms of membrane tolerance; they could also be involved in mediating metabolic dependencies in neuronal membranes, a possibility that needs testing.

Age Factors↗
PubMed1996

Anti-GM3 (II3Neu5Ac-lactosylceramide) ganglioside antibody labels human fetal Purkinje neurons during the critical stage of cerebellar development.

The ganglioside GM3 (II3Neu5Ac-lactosylceramide) represents a minor ganglioside in normal human brain compared to major gangliosides with gangliotetraose-backbone. In this study the presence of GM3 in three 23 and 24 weeks of gestation old human cerebella was demonstrated by immunostaining extracted gangliosides on thin-layer chromatography plate as well as by immunohistochemical analysis of cerebellar cryosections. During this stage of brain development GM3 was found to be dominantly expressed on cells corresponding to Purkinje neurons. Delipidation of histological sections with chloroform/methanol caused significant reduction of anti-GM3 immunostaining, thus confirming the prevalent ganglioside nature of this antigen. These results give evidence that (1) GM3 ganglioside is associated with a specific subset of human fetal cerebellar neurons during the critical development stage, and (2) a definite ganglioside in general is distributed to a specific subset of cells in normal human brain.

Antibody Specificity↗
PubMed1992

Generation of one set of monoclonal antibodies specific for a-pathway ganglio-series gangliosides.

We established five murine monoclonal antibodies (MAbs) specific for a-pathway ganglio-series gangliosides by immunizing C3H/HeN mice with these purified gangliosides adsorbed to Salmonella minnesota, followed by fusion with mouse myeloma cells. The binding specificities of these MAbs were determined by enzyme-linked immunosorbent assay and immunostaining on thin-layer chromatogram. These five MAbs, designated GMR6, GMB28, GMB16, GMR17, and GMR11 reacted strongly with the gangliosides GM3, GM2, GM1, GD1a, and GT1a, respectively, that were used as immunogens. Three MAbs, GMB28 (anti-GM2), GMB16 (anti-GM1), and GMR11 (anti-GT1a) showed highly restricted binding specificities, reacting only with the immunizing ganglioside. None of the other various authentic gangliosides or neutral glycolipids was recognized. On the other hand, the other two MAbs, GMR6 (anti-GM3) and GMR17 (anti-GD1a) exhibited broader specificities. MAb GMR6 cross-reacted with GM4, GM1b, GD1a, GT1b, and IV3NeuAc alpha-nLc4Cer. MAb GMR17 also reacted with GM1b and GT1b. Neither GMR6 nor GMR17 reacted with other gangliosides or neutral glycolipids tested. Using these MAbs, we determined the expression of these gangliosides, especially GM1, GD1a, and GT1a on mouse, rat and human leukemia cells. GM1 and GD1a were expressed on some leukemia cells, whereas GT1a was not detected in these cells.

Animals↗
PubMed1986

Systematic position of fish species and ganglioside composition and content.

The ganglioside content in brain of cartilaginous and bony fishes studied varies from 110 to 581 and from 104 to 595 micrograms sialic acid per g of wet weight respectively. A high degree of alkali lability and the predominance of C18-sphingosine and N-acetylneuraminic acid are typical of fish brain gangliosides. A high content of oligosialogangliosides with four and more residues of sialic acid and the predominance of gangliosides with gangliotetraosyl carbohydrate chain are characteristic for teleost brain. No pronounced difference was revealed in ganglioside composition and content of clupeomorphs and percomorphs. Gangliosides with short (lactosyl and gangliotriaosyl) carbohydrate chain predominate in brain of all cartilaginous fishes studied. A statistically significant difference was found in ganglioside content, relative oligosialoganglioside content and ganglioside fatty acid composition of squalomorphs and rajiformes, on one hand, and dasyatiformes and galeomorphs, on the other hand.

Animals↗
PubMed1991

Developmental change in ganglioside expression in primary culture of rat neurons.

Developmental changes in ganglioside levels and patterns were investigated in neuronal cells dissociated from 17-day-old fetal rat hemispheres for up to 7 days of culture. Increases in ganglioside contents and the onset of GM3 synthesis, which is associated with proliferation of glial cells, were observed as the neuronal network was established in cell cultures. The distribution of gangliosides in developing neurons was monitored by the indirect immunofluorescent technique using three anti-ganglioside antibodies. Anti-GM1 antibody showed immunofluorescence only on the cell soma 1 and 3 days after plating and additional binding between cell aggregates by 7 days in culture. GD3 ganglioside, the predominant species in embryonic neurons, was not detected on the neuronal cell surface, whereas the number of positively stained non-neuronal cells was increased at 7 days. Monoclonal A2B5 antibody suggested that polysialogangliosides play a role in neuronal network formation. In 1-day-old culture, however, all antibodies bound poorly to cell surface antigens and strongly to cells, the membranes of which were permeabilized with acetone. These results suggest that a substantial amount of gangliosides are retained, transformed within the cell to more complex gangliosides, and translocated to the cell surface following neurite outgrowth and morphological changes.

Animals↗
PubMed1989

Age and cell density dependent changes of gangliosides in human diploid fibroblasts.

The gangliosides in human diploid fibroblasts--TIG-1, TIG-7, and IMR-90--were analysed at different cell densities at early and late passages to clarify the relationship between age and cell density dependent changes of the gangliosides. In early passages, the ganglioside concentrations increased with increase in cell density. At late passages, however, the concentrations were lower than those at the early passages either in the growing or confluent phase, and slightly increased with increase in cell density. The pattern of ganglioside compositions were apparently different between early and late passage cells either in growing or confluent state. In the early passages, GM3 and GD3 were major constituents, and GM2, GD1a, or the other more complex gangliosides were detected as minor components. With increase in cell density, the content of GM3 decreased, whereas GD3 and the others increased. At the late passages, however, GM3 was the major component, and GD3, GM2, or GD1a were minor, but the others were hardly detectable. The ganglioside pattern did not change with increase in cell density. Thus, the age-dependent changes of gangliosides could be distinguished from the cell density dependent alterations.

Cell Count↗
PubMed2005

A method for profiling gangliosides in animal tissues using electrospray ionization-tandem mass spectrometry.

Gangliosides are critical in many functions of mammalian cells but present as a minor lipid component with many molecular species of subtle differences. Conventional strategies for profiling gangliosides suffer from poor reproducibility, low sensitivity, and low-throughput capacity. Prior separation of gangliosides by thin-layer chromatography and/or high-performance liquid chromatography not only was laborious and tedious but also could introduce uneven losses of molecular species. We developed a new strategy of using electrospray ionization-tandem mass spectrometry (ESI-MS/MS) to profile gangliosides with high-throughput potential. This strategy involves three new findings: (i) collision-induced fragmentation of gangliosides gave rise to a common ion of m/z 290, a derivative of N-acetylneuraminic acid; (ii) phospholipids exert a profound suppression of ganglioside detection in ESI-MS/MS to prevent a direct detection in total cellular lipid extracts; and (iii) enrichment of gangliosides in the aqueous phase from total cellular lipid extracts eliminates the damping effect of phospholipids and permits direct precursor scan.

Animals↗
PubMed2005

Gangliosides activate the phosphatase activity of the erythrocyte plasma membrane Ca2+-ATPase.

The previous studies showed that gangliosides modulated the ATPase activity of the PMCA from porcine brain synaptosomes [Yongfang Zhao, Xiaoxuan Fan, Fuyu Yang, Xujia Zhang, Arch. Biochem. Biophys. 427 (2004) 204-212]. The effects of gangliosides on the hydrolysis of p-nitrophenyl phosphate (pNPP) catalyzed by the erythrocyte plasma membrane Ca(2+)-ATPase, which was characterized as E(2) conformer of the enzyme, were studied. The results showed that pNPPase activity was stimulated up to seven-fold, depending upon the different gangliosides used with GD1b>GM1>GM2>GM3 approximately Asialo-GM1. Under the same conditions, the ATPase activity was also activated, suggesting that gangliosides should modify both E(1) and E(2) conformer of the enzyme. The Ca(2+), which drove the enzyme to E(1) conformation, inhibited the pNPPase activity, but with the similar half-maximal inhibitory concentrations (IC(50)) in the presence and the absence of gangliosides. Moreover, the pNPPase activity was also inhibited by the raise in ATP concentrations. Gangliosides caused a large increase in V(max), but had no effect on the apparent affinity (K(m)) of the enzyme for pNPP. The kinetic analysis indicated that gangliosides could modulate the erythrocyte PMCA through stabilizing E(2) conformer.

4-Nitrophenylphosphatase↗
PubMed2006

Immunogenic gangliosides in human ovarian carcinoma.

Ganglioside signatures of four poorly and three moderately differentiated ovarian epithelial cancer (OEC) cell lines reveal the presence of GM3, GM2, GD2, O-AcGD2, GD1a and GM1b. The expression of GM3, presence of GD1a and GM1b in the ascitic fluid and plasma, together with a positive correlation in the total-gangliosides levels between ascitic fluid and plasma of OEC patients support the earlier contention that the tumor-gangliosides may be released (or shed) into the tumor-microenvironment. The immunogenicity of OEC-gangliosides is determined by comparing anti-ganglioside-IgM titers in ascitic fluid (n = 14) and plasma (n = 23) of OEC-patients and age-matched healthy (n = 14). The titers were measured by ELISA. Strikingly, the level of anti-GD1a-IgM is significantly higher in ascitic fluid and plasma of patients than in the plasma of healthy volunteers. Paired sample analysis of ascitic fluid and plasma from the same patients confirmed the significant expression of anti-GD1a IgM in OEC patients, while no such difference was observed with other anti-ganglioside IgMs among different groups. The significance of the endogenous IgM response to GD1a may be to eliminate this immunosuppressive-ganglioside from the tumor-microenvironment.

Ascitic Fluid↗
PubMed1997

Multivalent ganglioside and sphingosine conjugates modulate myelin protein kinases.

Gangliosides, added exogenously at concentrations of 10-100 microM, inhibit intrinsic protein kinase activities in purified rat brain myelin. Multivalent neoganglioproteins--gangliosides covalently attached, via their lipid moieties, to bovine serum albumin--were much more potent, inhibiting myelin protein phosphorylation half-maximally at a concentration of 100 nM. Different ganglioside conjugates varied 10-fold in inhibitory potency; GT1b-conjugates being the most potent and GM3-conjugates being the least. Conjugates of ganglioside oligosaccharides, lacking the lipid moiety, did not inhibit myelin protein phosphorylation, whereas conjugates of sphingosine inhibited nearly as potently as GT1b conjugates. Conjugate-mediated inhibition of myelin protein phosphorylation was due to inhibition of a protein serine kinase activity rather than activation of a phosphatase activity. We conclude that (i) clustered gangliosides or sphingosine are potent myelin protein kinase inhibitors, and (ii) sphingolipid metabolism is not required for myelin protein kinase inhibition. In contrast to their effects on myelin protein phosphorylation, ganglioside conjugates stimulated phosphorylation of a presumptive axon membrane protein. The data support the conclusion that gangliosides and other sphingolipids, when appropriately clustered, are potent modulators of central nervous system protein phosphorylation.

Animals↗
PubMed2001

Characterization of cytosolic sialidase from Chinese hamster ovary cells: part II. Substrate specificity for gangliosides.

Cytosolic Chinese hamster ovary (CHO) cell sialidase has been cloned as a soluble glutathione S-transferase (GST)-sialidase fusion protein with an apparent molecular weight of 69 kD in Escherichia coli. The enzyme has then been produced in mg quantities at 25-L bioreactor scale and purified by one-step affinity chromatography on glutathione sepharose (Burg, M.; Müthing, J. Carbohydr. Res. 2001, 330, 335-346). The cloned sialidase was probed for desialylation of a wide spectrum of different types of gangliosides using a thin-layer chromatography (TLC) overlay kinetic assay. Different gangliosides were separated on silica gel precoated TLC plates, incubated with increasing concentrations of sialidase (50 degreesU/mL up to 1.6 mU/mL) without detergents, and desialylated gangliosides were detected with specific anti-asialoganglioside antibodies. The enzyme exhibited almost identical hydrolysis activity in degradation of GM3(Neu5Ac) and GM3(Neu5Gc). A slightly enhanced activity, compared with reference Vibrio cholerae sialidase, was detected towards terminally alpha(2-3)-sialylated neolacto-series gangliosides IV3-alpha-Neu5Ac-nLc4Cer and VI3-alpha-Neu5Ac-nLc6Cer. The ganglio-series gangliosides G(D1a), G(D1b), and G(T1b), the preferential substrates of V. cholerae sialidase for generating cleavage-resistant G(M1), were less suitable targets for the CHO cell sialidase. The increasing evidence on colocalization of gangliosides and sialidase in the cytosol strongly suggests the involvement of the cytosolic sialidase in ganglioside metabolism on intracellular level by yet unknown mechanisms.

Animals↗
PubMed1986

Mouse liver gangliosides.

The major gangliosides from mouse liver were purified and characterized by t.l.c., g.l.c., sialidase treatment, and a methylation study. GM3(NeuAc), GM3(NeuGc), GM2(NeuGc), GM1(NeuGc), and GDla(NeuGc, NeuGc) were identified. The structural identification of three of the gangliosides, GM2(NeuGc), GM1(NeuGc), and GDla(NeuGc, NeuGc), was supported by the results of 1H-n.m.r. analysis, and the structures of GM3(NeuGc), GM2(NeuGc), and GM1(NeuGc) were further confirmed by negative-ion fast-atom bombardment mass spectrometry. Ganglioside mapping showed that there was polymorphic variation of gangliosides in the liver of inbred strains of mice and that the major gangliosides were GM3(NeuGc) in WHT/Ht, GM2(NeuGc) in BALB/c and C3H/He, and GM2(NeuGc), GM1(NeuGc), and GDla(NeuGc, NeuGc) in ICR mice. Gangliosides containing N-acetylneuraminic acid, except for GM3(NeuAc), were not detected as major gangliosides in the strains of mice we analyzed.

Animals↗
PubMed2002

Cryosurgical ablation of liver tumors in colon cancer patients increases the serum total ganglioside level and then selectively augments antiganglioside IgM.

Cryosurgical ablation (CSA) of tumors induces disruptive necrosis. Necrosis may release tumor gangliosides into circulation and they may augment serum antiganglioside antibodies depending on the nature of gangliosides released. The hypothesis is tested by determining the level of serum total gangliosides (STG) and their antibody titers in the sera of colon cancer patients with cryoablated liver tumors. As controls, we examined the sera of patients who underwent radiofrequency ablation (RFA) and regular surgery (RS), none of which cause disruptive necrosis. The STG level (expressed as lipid-bound sialic acids, LBSA) is higher (p(2)<0.001) in 35 patients (stage IV) than in 38 healthy case-controls (median 23.48 mg/dL, Q-range 7.1 vs 16.04 mg/dL, Q-range 4.5). The mean STG level increased significantly to 31.2+/-6.0mg/dL (p(2)<0.03) after CSA. Concomitantly, the IgM titer against colon cancer-associated gangliosides (GM(2), GD(1a), GT(1b)), increased significantly, but no increase was observed against normal tissue gangliosides (GM(3) or GM(1)). Also after RFA and RS, no such increase was observed either in the level of STG or in IgM titer against tumor gangliosides. The results suggest that CSA-induced necrosis might have acted as an adjuvant, because purified gangliosides without exogenous adjuvants even after repeated immunization failed to elicit antibody response. The post-CSA decline in the STG level correlated with the increase in the antibodies, suggesting a homeostatic role of the antibodies.

Adenocarcinoma↗
PubMed1988

Improved method for large-scale purification of brain gangliosides by Q-sepharose column chromatography. Immunochemical detection of C-series polysialogangliosides in adult bovine brains.

A new chromatographic method for separation of bovine brain gangliosides has been developed using Q-Sepharose. Gangliosides were separated based not only on their sialic acid numbers but also on the sialic acid molecular species and chain lengths of the skeletal oligosaccharide portions. The following results indicate that this column chromatography has practical advantages in separating mixtures of gangliosides, especially positional isomers and molecular species with N-acetyl- or N-glycolylneuraminic acid. (1) the loading capacity of Q-Sepharose for gangliosides was very high; (2) most major gangliosides such as GM1, GD1a, GD1b, GT1b and GQ1b were isolated in a single step; (3) these major gangliosides were clearly separated from gangliosides containing, N-glycolylneuraminic acid when examined using Hanganutziu-Deicher antibody; (4) polysialogangliosides that have four or more sialic acid residues were isolated efficiently. It was shown by the combination of Q-Sepharose column chromatography with thin-layer chromatography/enzyme immunostaining that adult bovine brains possess C-series polysialogangliosides as minor components which are known as embryonic molecules in avian and mammalian brains.

Animals↗
PubMed2003

Longitudinal changes of anti-ganglioside antibodies before and after Guillain-Barré syndrome onset subsequent to Campylobacter jejuni enteritis.

Anti-ganglioside antibodies frequently are present in sera from patients with Guillain-Barré syndrome (GBS) during the acute phase, but no patients in whom anti-ganglioside antibodies were tested before the onset of the syndrome have been reported. We describe the first case of GBS subsequent to Campylobacter jejuni infection, in which longitudinal changes in anti-ganglioside antibody titers were measured before and after the onset of limb weakness. Serum antibody titers against GM1 (IgM/IgG), GM1b (IgM/IgG), GalNAc-GD1a (IgM/IgG), and GD1b (IgG) were highest on the day of onset, but negative before onset. Anti-C. jejuni IgG and IgA antibody titers paralleled those of the anti-ganglioside antibodies, indicative that C. jejuni infection triggered anti-ganglioside antibody production. Press et al. [J. Neurol. Sci. 190 (2001) 41] reported that anti-ganglioside antibody titers peaked during the recovery phase, but our findings are counter to theirs. We speculate that anti-ganglioside antibodies are the primary effectors of nerve damage in GBS.

Antibodies↗
PubMed2003

Is there a decrease in Guillain-Barré syndrome incidence after bovine ganglioside withdrawal in Italy? A population-based study in the Local Health District of Ferrara, Italy.

There have been many reports of cases of Guillain-Barré syndrome (GBS) after therapeutic injection of bovine ganglioside preparations with the result that they were withdrawn in Italy in December 1993. As the relationship between bovine gangliosides and GBS has not yet been established, a further epidemiological investigation in the Local Health District (LHD) of Ferrara, Italy, was carried out in the years 1994-2001 to verify whether the incidence of GBS had changed after ganglioside withdrawal. The other aim of this investigation was to update the incidence of GBS in this area since the two previous investigations we carried out showed an increase in incidence from the years 1981-1987 to the years 1988-1993. The cases of GBS were identified prospectively. To guarantee completeness of case ascertainment, an intensive retrospective survey of all possible sources of cases for the entire study period was performed. The mean annual crude incidence rate in the years 1994-2001 (based on 26 new cases) was 1.97 per 100,000 population (95% CI 1.29-2.89), whereas it had been 1.87 per 100,000 population (95% CI 1.35-2.52) in the years 1981-1993 (based on 43 cases) when gangliosides were available. The age-adjusted rates were almost identical (1.66 and 1.65 per 100,000 population, respectively). Although ganglioside administration could have triggered, on the basis of an individual susceptibility, an immunologic reaction which produced GBS, the incidence of GBS in the study area did not change after ganglioside withdrawal. In the whole period 1981-2001, a temporal pattern of incidence was reported with an increase towards a peak in 1990-1992 and a progressive decline thereafter. This temporal pattern did not seem related to ganglioside withdrawal, and no definite explanation for it was found which could imply that the disease incidence is less stable than it was deemed.

Adolescent↗
PubMed2001

Excitotoxicity induces changes in rat brain gangliosides.

The patterns of major gangliosides in the rat hippocampi and olfactory bulbs was examined in vivo after microinjections of Ibotenic acid and L-BOAA (NMDA and AMPA receptor agonists, respectively) which were given under free-movement conditions. The excitotoxicity induced by injections of Ibotenic acid promoted transient ganglioside changes in olfactory bulbs and permanent changes in hippocampus. Four days after injections, the amount of gangliosides in the hippocampus increased significantly for GQ1b, GT1b and GD1b and decreased in the olfactory bulb for GQ1b, GT1b, GD1b, GD1a and GM1 compared to normal ganglioside levels. The alterations of gangliosides were minimal 1 day after injections. After 5 weeks, the amounts of GQ1b, GT1b and GD1b dramatically decreased in the hippocampus while in the olfactory bulbs gangliosides recovered to normal levels. The results obtained with L-BOAA 4 days after injections strengthen the results observed in the experiments using Ibotenic acid and corroborate our suggestion that gangliosides have an active role in the compensatory mechanism to maintain the number of glutamate receptors during the excitotoxicity.

Amino Acids, Diamino↗
PubMed2001

Brain gangliosides: functional ligands for myelin stability and the control of nerve regeneration.

Gangliosides, sialylated glycosphingolipids which are the predominant glycans on vertebrate nerve cell surfaces, are emerging as components of membrane rafts, where they can mediate important physiological functions. Myelin associated glycoprotein (MAG), a minor constituent of myelin, is a sialic acid binding lectin with two established physiological functions: it is involved in myelin-axon stability and cytoarchitecture, and controls nerve regeneration. MAG is found selectively on the myelin membranes directly apposed to the axon surface, where it has been proposed to mediate myelin-axon interactions. Although the nerve cell surface ligands for MAG remain to be established, evidence supports a functional role for sialylated glycoconjugates. Here we review recent studies that reflect on the role of gangliosides, sialylated glycosphingolipids, as functional MAG ligands. MAG binds to gangliosides with the terminal sequence 'NeuAc alpha 3Gal beta 3GalNAc' which is found on the major nerve gangliosides GD1a and GT1b. Gangliosides lacking that terminus (e.g., GM1 or GD1b), or having any biochemical modification of the terminal NeuAc residue fail to support MAG binding. Genetically engineered mice lacking the GalNAc transferase required for biosynthesis of the 'NeuAc alpha 3Gal beta 3GalNAc' terminus have grossly impaired myelination and progressive neurodegeneration. Notably the MAG level in these animals is dysregulated. Furthermore, removal of NeuAc residues from nerve cells reverses MAG-mediated inhibition of neuritogenesis, and neurons from mice lacking the 'NeuAc alpha 3 Gal beta 3GalNAc' terminus have an attenuated response to MAG. Cross-linking nerve cell surface gangliosides can mimic MAG-mediated inhibition of nerve regeneration. Taken together these observations implicate gangliosides as functional MAG ligands.

Animals↗