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PubMed1985

Separation of gangliosides by anion-exchange chromatography on Mono Q.

A new type of strong anion-exchange resin, Mono Q, has been used in the separation of brain gangliosides. The resin consists of monodisperse particles (9.8 micron) and was used in prepacked columns with a bed volume of 1 ml. The gangliosides were separated into mono-, di-, tri- and tetrasialoganglioside fractions by a discontinuous gradient of potassium acetate in methanol. The separation was complete in a volume of 50 ml. The major advantages of the new procedure compared to conventional methods are the shorter separation time, higher loading capacity and recovery of separated ganglioside fractions in small solvent volumes. The procedure was applied to the separation of gangliosides from normal human and GM2-gangliosidosis brain.

Aged↗

PubMed1980

Gangliosides containing glucosamine and galactosamine in transformed Tay-Sachs disease and normal human brain cell lines.

Human SV-40 transformed brain cell lines derived from Tay-Sachs disease (TSD) and normal fetal cerebra were grown in culture and analyzed for their ganglioside content. Both the TSD and normal cells contained GM3, GM2, and a novel triheoxyl N-acetylglucosamine-containing ganglioside. In order to increase tumorigenicity, the cells were cloned on soft agar. The cloned cells still contained GM3, GM2, and the N-acetylglucosamine-containing ganglioside. The per cent distribution of gangliosides in the TSD and normal SV-40 transformed cell lines was surprisingly similar despite the fact that the TSD transformed cells still lacked hexosaminidase A, the isoenzyme which is required to break down GM2.

Animals↗

PubMed1999

Clinical presentation and outcome of Guillain-Barré and related syndromes in relation to anti-ganglioside antibodies.

We correlated the clinical features of 78 patients with Guillain-Barré syndrome (GBS) or related variants, with the presence of serum antibodies to the gangliosides GM1, GM2, GD1a, GD1b and GQ1b in order to determine whether these antibodies may influence the clinical presentation or outcome of GBS. Sixty-three patients had typical GBS (81%), nine a pure motor form (11%), three a paraparetic form (4%), and three had Miller Fisher syndrome (MFS). IgG or IgM (or both) anti-ganglioside antibodies were found by ELISA in 37% of patients, including 36% with typical, 33% with pure motor and 100% with MFS. Beside the constant occurrence of anti-GQ1b antibodies in patients with MFS (P<0.00001), the other clinical forms were not associated with a specific anti-ganglioside reactivity. Anti-GM1 and anti-GD1a antibodies tended to be associated with a worse disability at 6 month than other or no reactivity and, similarly to anti-GM2 antibodies, with a more frequent respiratory impairment. Anti-GM2 and anti-GD1b antibodies were always associated with typical GBS and, in all but one patient, with a complete recovery; still they were found in only 13 and 3%, respectively, of the patients with this presentation. Anti-GQ1b antibodies, though always associated with ophthalmoplegia and ataxia in both MFS and GBS, were found in only 36 and 26%, respectively, of patients with these symptoms. Even if different anti-ganglioside antibodies tend to be associated with some clinical features possibly suggesting that they may influence the clinical presentation or outcome, with the exception of anti-GQ1b antibodies for ophthalmoplegia and ataxia, they do not permit to predict the clinical presentation or outcome in individual patients.

Adolescent↗

PubMed1987

The GM1 ganglioside hastens the reduction of hyperemotionality after septal lesions.

The purpose of the present study was to assess the effects of ganglioside treatment on changes in emotional, activity, and avoidance behaviors following septal brain damage. Rats were treated with GM1-gangliosides either before and after septal lesions, or only after septal lesions and tested for emotionality on 10 consecutive days beginning on the second day after surgery. The ganglioside treatment decreased the emotionality of rats with septal damage on the first test day, and enhanced their rate of recovery to control levels of emotionality. Septal rats treated with gangliosides had activity, rearing, and avoidance behaviors equivalent to nontreated septal rats; however, lesioned rats treated with GM1 showed reduced intertrial crossings during avoidance conditioning. These results suggest that the changes in emotional behavior of septal rats treated with GM1 occur shortly after the lesion.

Animals↗

PubMed1998

Evaluation of GM1 ganglioside-mediated apoptosis in feline thymocytes.

Cats with inherited GM1 gangliosidosis (GM1 mutant cats) have premature thymic involution characterized by decreased total thymocytes primarily affecting the CD4+ CD8+ subpopulation. While GM1 mutant cats have increased cell surface GM1 gangliosides, as determined by cholera toxin B binding, on both thymocytes and peripheral lymph node cells only thymocytes show increased apoptosis. To determine if GM1 gangliosides can increase the occurrence of apoptosis in feline thymocytes directly, we added exogenous GM1 ganglioside (GM1) to feline thymocyte primary cultures and compared the results to apoptotic changes seen in untreated cells or in cells treated with dexamethasone (Dex), a known inducer of thymocyte apoptosis in other species. Incorporation of exogenous GM1 into thymocyte cytoplasmic membranes was confirmed by flow cytometric analyses of cholera toxin B labelling. Apoptosis in feline thymocytes was analyzed by electron microscopy, spectrophotometric evaluation of DNA fragmentation, flow cytometric enumeration of apoptotic nuclei, and gel electrophoretic analysis of degraded DNA. Alterations in percentages of thymocyte immunophenotype following GM1 incorporation were determined by flow cytometric analyses of labelled cell surface markers for feline CD4 and CD8. Because in vitro addition of GM1 gangliosides has been reported in other species to decrease surface expression of CD4 on both thymocytes and peripheral lymphocytes, we evaluated GM1-associated down-regulation of CD4 on the surface of feline thymocytes and peripheral lymph node cells by flow cytometry. Additionally, we compared the apoptotic response of the more mature peripheral lymph node cells to the less mature thymocytes. Our results indicate that incorporation of exogenous GM1 into feline thymocyte cell membranes produces a dose-dependent increase of apoptotic cell death. Although, CD4 expression on both feline thymocyte and lymph node cell membranes was abruptly decreased after introducing exogenous GM1, enhanced apoptotic death was observed only in thymocytes, not in lymph node cells at the same GM1 concentration. Enhancement of thymocyte apoptosis appears to be age-related since cells derived from cats <3 months of age were more vulnerable than those from cats >3 months of age.

Aging↗

PubMed1998

Ganglioside GM1 alters neuronal morphology by modulating the association of MAP2 with microtubules and actin filaments.

In previous studies, we demonstrated that the exogenous ganglioside GM1 increased the complexity of the microtubular network and level of tubulin, selectively changed the distribution of microtubule associated protein-2 (MAP2) immunoreactivity from the perikarya to distal neuritic processes and increased immunogold label of MAP2 in the subplasmalemmal cytoplasm, neuritic filopodia and growth cones of Neuro-2a neuroblastoma cells. Since these areas are rich in actin filaments, our data suggested that MAP2 may be associated with microfilaments in the early stages of ganglioside-induced neuritogenesis. To determine if GM1 alters neuronal morphology by facilitating the interaction of actin and MAP2, we examined the immunolocalization of these two proteins with confocal and electron microscopy. We found that along with the redistribution of MAP2 from perikaryal to neuritic regions, there was parallel redistribution of actin. The uniform subplasmalemmal actin meshwork was disrupted in areas of processes and filopodia with a redistribution of actin to these areas in close association with MAP2. Our present results suggest that gangliosides enhance neuritogenesis by redistributing actin as well as MAP2 to processes and filopodia thereby facilitating their interaction. The association of MAP2 with actin filaments is likely to be an early step in ganglioside-mediated filopodia formation.

Actins↗

PubMed1999

Subclass distribution and the secretory component of serum IgA anti-ganglioside antibodies in Guillain-Barré syndrome after Campylobacter jejuni enteritis.

Previously, we reported that IgA anti-GM1 antibody is more closely associated with preceding Campylobacter jejuni enteritis in Guillain-Barré syndrome (GBS) than are IgG and IgM antibodies. However, the mechanism of the induction of IgA anti-ganglioside antibodies is not clear. In this study, serum IgA antibodies against GM1, GM1b, and GD1a, and GalNAc-GD1a were examined in 152 GBS patients. In GBS, antecedent C. jejuni infection is closely associated with IgA antibodies, other than GM1, against GM1b. The IgA subclass distribution is completely restricted to IgA1, no secretory IgA anti-ganglioside antibody being detected. This result does not support the hypothesis that the serum IgA antibodies present in GBS after C. jejuni enteritis originate at mucosal sites, such as the gut mucosal immune system. Seventeen (85%) of 20 patients with IgA anti-ganglioside antibodies had serological evidence of C. jejuni infection and/or a history of antecedent diarrhea. Moreover, a motor nerve conduction study showed that patients with IgA antibodies frequently had axonal neuropathy, whereas none had demyelinating neuropathy. This may support the previous report that IgA isotype anti-GM1 antibodies are more closely associated with poor outcome than are the IgG or IgM isotypes. The induction mechanism of IgA anti-ganglioside antibodies must be clarified by determining whether concentrations of cytokines, which increase the IgA class switch, are elevated in patients with GBS after C. jejuni enteritis.

Antibodies↗

PubMed1997

Formation of a ternary complex between GM2 activator protein, GM2 ganglioside and hexosaminidase A.

The GM2 activator is a 17 kDa protein required for the hydrolysis of GM2 ganglioside by the lysosomal enzyme hexosaminidase A (HexA). The activator behaves as a substrate binding protein, solubilizing GM2 ganglioside monomers from micelles (in vitro) or membranes (in vivo). However, the activator also shows a high order of specificity for activation of lysosomal hydrolases and has been predicted to form a ternary complex with the heterodimeric enzyme (alphabeta) Hex A and GM2 ganglioside. We demonstrated a transient interaction between HexA and the GM2 activator. A chimeric protein containing the FLAG epitope sequence upstream of the GM2 activator was expressed in Escherichia coli and purified using the M1 immunoaffinity (anti-FLAG) column. Binding of the FLAG-GM2 activator (FLAG-AP) fusion protein to the M1 column led to the specific retardation of Hex A applied to the column. Other proteins were not retarded by the column nor did they compete with Hex A for binding to FLAG-AP. Hex A and GM2 ganglioside could be simultaneously bound to the column, but the binding of each ligand was independent of the other. The homodimeric (beta beta) isozyme Hex B did not bind to the immobilized activator. The alpha alpha homodimer, HexS, bound weakly, confirming that a hexosaminidase alpha subunit is required for interaction of enzyme and activator.

Dimerization↗

PubMed2001

Small cell lung cancer is not associated with the presence of anti-fucosyl-GM1 ganglioside autoantibodies reactive in immunoenzymatic test.

The characteristic feature of small cell lung cancer carcinoma (SCLC) is the aberrant expression and abundant presentation of fucosyl-GM1 ganglioside (FucGM1). In the present study we searched for the presence of anti-FucGM1 ganglioside, as well as anti-GM1, GM2 and GD3 ganglioside autoantibodies in the sera of patients with SCLC and as a control, in sera of patients with renal cell cancer (RC) and healthy blood donors. The autoantibodies against FucGM1 were present at low titer in only three of 36 SCLC patients, and with similar titer in two of 36 RC patients and four of 36 healthy controls. Likewise, the autoantibodies against GM2 and GM3 gangliosides were found only sporadically and with the same titer and frequency in cancer patients as in healthy persons. Anti-GD3 autoantibodies could not be detected in any of the screened sera.

Autoantibodies↗

PubMed1997

Suppression by gangliosides of polymerization of glial cytoskeletons prepared from rat astrocytes: a role of sialic acid moiety.

This study investigated in vitro the effects of gangliosides on polymerization of either the depolymerized microfilament preparation (MF) or depolymerized glia filament preparation (GF) extracted separately from the crude cytoskeletal fraction of rat astrocytes. Gangliosides GM1, GM2 and GM3 markedly suppressed polymerization of both MF and GF. The concentration of GM1, GM2 or GM3 required to induce 50% inhibition of the polymerization of 7.5 micrograms MF protein/200 microliters (IC50 of GM1, GM2, or GM3) was 3.2, 2.8 or 5.6 micrograms/200 microliters, respectively. The IC50 of each ganglioside for the polymerization of 7.5 micrograms/200 microliters of GF, furthermore, was 3.3, 3.5 or 7.4 micrograms/200 microliters, respectively, suggesting that the inhibitory activities of GM1 and GM2 on polymerization of both MF and GF were greater than those of GM3. GM1, GM2 and GM3 also suppressed dose-dependently the polymerization of both actin and vimentin. The inhibitory activities of GM1 and GM2 on the polymerization of actin or vimentin were greater than GM3, as in the case of polymerization of MF or GF. The IC50S of GD1a and GT1b for MF polymerization at the same concentration were 2.2 and 1.2 micrograms/200 microliters, respectively, and those for GF polymerization were 2.7 and 1.7 micrograms/200 microliters, respectively. The IC50 of GD3 for MF polymerization was 3.9 micrograms/200 microliters, and that for GF polymerization 4.0 micrograms/200 microliters, implying that the inhibitory activities of GD3 on polymerization of both MF and GF were greater than those of GM3. The findings suggested that the inhibitory activities of gangliosides on MF or GF polymerization became greater with increasing number of sialic acid residues. AsialoGM1 suppressed neither MF nor GF polymerization, and inhibited dose-dependently the ability of GM1 to suppress MF polymerization.

Actin Cytoskeleton↗

PubMed2000

Inhibition of tetanus toxin fragment C binding to ganglioside G(T1b) by monoclonal antibodies recognizing different epitopes.

Anti-tetanus toxoid monoclonal antibodies would be useful in exploring the relationship of tetanus toxin structure to its function. Tetanus toxin fragment C has been shown to be responsible for binding to neurons via gangliosides. Eleven new and two previously derived monoclonal antibodies specific for tetanus toxin fragment C were shown to recognize five different fragment C epitopes, two of which were overlapping. Three of these epitopes participate in the binding to ganglioside G(T1b). One epitope was defined by a monoclonal antibody that did not inhibit the interaction between fragment C and ganglioside. This antibody however, was blocked from binding to fragment C by antibodies that were able to inhibit the fragment C-ganglioside interaction.

Animals↗

PubMed1999

Gangliosides asymmetrically alter the membrane order in cultured PC-12 cells.

Exogenous gangliosides readily associate with the cell membranes and produce marked effects on cell growth and differentiation. We have studied the effect of bovine brain gangliosides (BBG) on the membrane dynamics of intact cells. The structural and dynamic changes in the cell membrane were monitored by the fluorescence probes DPH, TMA-DPH and laurdan. Incorporation of BBG into the cell membrane decreased the fluorescence intensity, lifetime and the steady state anisotropy of TMA-DPH. Analysis of the time resolved anisotropy decay by wobbling in the cone model revealed that BBG decreased the order parameter, and increased the cone angle without altering the rotational relaxation rate. The fluorescence intensity and lifetime of DPH were unaffected by BBG incorporation, however, a modest increase was observed in the steady state anisotropy. BBG incorporation reduced the total fluorescence intensity of laurdan with pronounced quenching of the 440-nm band. The wavelength sensitivity of generalized polarization of laurdan manifested an ordered liquid crystalline environment of the probe in the cell membrane. BBG incorporation reduced the GP values and augmented the liquid crystalline behavior of the cell membrane. BBG incorporation also influenced the permeability of cell membranes to cations. An influx of Na+ and Ca2+ and an efflux of K+ was observed. The data demonstrate that incorporation of gangliosides into the cell membrane substantially enhances the disorder and hydration of the lipid bilayer region near the exoplasmic surface. The inner core region near the center of the bilayer becomes slightly more ordered and remains highly hydrophobic. Such changes in the structure and dynamics of the membrane could play an important role in modulation of transmembrane signaling events by the gangliosides.

2-Naphthylamine↗

PubMed2003

Screening for anti-ganglioside antibodies in hypocretin-deficient human narcolepsy.

Narcolepsy is a sleep disorder caused by defective hypocretin (orexin) neurotransmission. It is thought to result from an autoimmune destruction of hypocretin producing neurons. Recently, low hypocretin levels were found in patients with Guillain-Barré syndrome, a post-infectious immune-mediated disorder in which a variety of circulating antibodies against neuronal gangliosides are found. We therefore considered gangliosides to be candidate antigens in narcolepsy as well, and screened for the presence of a panel of serum anti-ganglioside antibodies in a group of 28 well-characterized narcoleptic patients. We did not find a correlation between increased titers of anti-ganglioside antibodies and hypocretin-deficient narcolepsy. This study does not support the hypothesis that an autoimmune response is involved in narcolepsy. However, as an autoimmune attack may be selective and/or transient, future studies are needed to ultimately refute or confirm the autoimmune hypothesis.

Adolescent↗

PubMed1996

Role of gangliosides in tumour progression: a molecular target for cancer therapy?

In a number of patients with tumours of either neuroectodermal or epithelial origin, polysialylated gangliosides (e.g. GD3) are over-expressed. The mechanism of ganglioside over-expression may be different for the two classes of tumour and could represent distinct secondary genetic mutations or epigenetic changes affecting the enzymes (transferases and/or hydrolases) controlling the metabolic interconversions of these gangliosides. Tumour cells of neuroectodermal origin (e.g. melanomas and brain tumours) are known to produce and shed polysialylated gangliosides, whereas paracrine signal(s) from tumour cells of epithelial origin (e.g. carcinomas of cervix, lung, prostate, breast, head and neck, colon and ovary) may stimulate over-expression and shedding from tumour infiltrating mesenchymal cells (e.g. macrophages and/or fibroblasts). This cellular membrane over-expression and shedding of acidic glycosphingolipids into the interstitial spaces and blood of cancer patients may play a central role in increased tumour cell growth, lack of immune cell recognition and neovascularization and could represent a molecular target for cancer therapy.

Animals↗

PubMed2003

[Relationship between lipids and cutaneous immunity: example of the gangliosides].

Gangliosides are glycosphingolipids made of hydrophobic ceramides coupled to hydrophilic sialylated oligosaccharides. They belong to lipid rafts located on the outer leaflet of the plasma membrane and their oligosaccharide moieties are exposed on the cell surface. Gangliosides are shed as monomeric molecules from the plasma membrane by a largely unknown mechanism into the extracellular medium and they are synthesized de novo by the cells. The shed gangliosides bind to lipoproteins from which they are taken up by erythrocytes and leukocytes. The ganglioside enrichment of leukocytes results in an alteration in the transduction of activation signals, leading to an impaired cellular immunity.

Cytokines↗

PubMed1982

Rapid separation of gangliosides by high-performance liquid chromatography.

We have developed a high-performance liquid chromatographic (HPLC) procedure for the rapid separation of individual ganglioside components on a 5-micron porous silica gel column using a mixture of isopropanol-hexane-water with increasing water content and decreasing hexane content. Total ganglioside mixtures were first fractionated on DEAE-silica gel according to the number of sialic acid residues. Each fraction was then separated into individual ganglioside components by HPLC. Total elution time was less than 2 h. This procedure has been applied for the separation of major ganglioside components of human erythrocytes and beef brain and is highly reproducible.

Animals↗

PubMed1983

High-performance liquid chromatographic resolution of p-nitrobenzyloxyamine derivatives of brain gangliosides.

A new quantitative procedure for the high-performance liquid chromatographic (HPLC) resolution of human brain gangliosides employing reversed-phase chromatography is described. To provide a derivative which can be determined by UV absorption techniques, p-nitrobenzyloxyamine was coupled to the gangliosides. Derivatization involves ozonation and cleavage of the ceramide double bond followed by oxime formation to the nascent aldehyde. Individual gangliosides, as they were resolved by HPLC, were collected. These fractions were then identified by thin-layer chromatography (TLC) and by gas chromatography of their monosaccharides. Quantitative results were obtained along with a marked increase in sensitivity over conventional resorcinol-hydrochloric acid quantitation of TLC-resolved gangliosides.

Brain Chemistry↗

PubMed1998

Large scale purification of gangliosides GM3(Neu5Ac) and GM3(Neu5Gc) by trimethylaminoethyl-Fractogel high-performance liquid chromatography.

A preparative anion-exchange high-performance liquid chromatographic method for the separation of the closely allied monosialogangliosides GM3(Neu5Ac) and GM3(Neu5Gc) has been developed. Hybridoma cells, readily available material derived from industrial monoclonal antibody production, were used as ganglioside source and led to fractions with pure GM3(Neu5Ac) and GM3(Neu5Gc) in high milligram quantities. The crude ganglioside extract was loaded onto columns filled with the strong anion-exchanger trimethylaminoethyl (TMAE)-Fractogel. Gangliosides were eluted from the stationary phase with a gradient system of ammonium acetate in methanol. The scaled-up approach ranged over more than one order of magnitude from 20 to 500 mg batches of GM3 gangliosides. Thus, the high-resolution power of the strong anion-exchanger TMAE-Fractogel allowed the preparative isolation by one-step column chromatography of two GM3 specimens which only differ in one hydroxyl group at position 5 of the neuraminic acid (N-acetyl-versus N-glycolylneuraminic acid).

Animals↗