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PubMed1989

The identification of lysosomal ganglioside sialidase in human cells.

In this report we present evidence for the existence of a lysosomal ganglioside sialidase. The sialidase activity was solubilized by sonication and stimulated by cholate. The absence of ganglioside sialidase activity in sialidosis patients indicates that lysosomal sialidase is active towards gangliosides and glycoproteins. The plasma membranes were associated with two types of ganglioside sialidase activities, one was enhanced by cholate while the other was partially inhibited by this detergent.

Cell Fractionation↗
PubMed1981

Activation of (Na+, K+)-ATPase by nanomolar concentrations of GM1 ganglioside.

GM1 ganglioside binding to the crude mitochondrial fraction of rat brain and its effect on (Na+, K+)-ATPase were studied, the following results being obtained: (a) the binding process followed a biphasic kinetics with a break at 50 nM-GM1; GM1 at concentrations below the break was stably associated, while over the break it was loosely associated; (b) stably bound GM1 activated (Na+, K+)-ATPase up to a maximum of 43%; (c) the activation was dependent upon the amount of bound GM1 and was highest at the critical concentration of 20 pmol bound GM1 X mg protein-1; (d) loosely bound GM1 suppressed the activating effect on (Na+, K+)-ATPase elicited by firmly bound GM1; (e) GM1-activated (Na+, K+)-ATPase had the same pH optimum and apparent Km (for ATP) as normal (Na+, K+)-ATPase but a greater apparent Vmax; (f) under identical binding conditions (2 h, 37 degrees C, with 40 nM substance) all tested gangliosides (GM1, GD1a, GD1b, GT1b) activated (Na+, K+)-ATPase (from 26-43%); NeuNAc, sodium dodecylsulphate, sulphatide and cerebroside had only a very slight effect. It is suggested that the ganglioside activation of (Na+-K+)-ATPase is a specific phenomenon not related to the amphiphilic and ionic properties of gangliosides, but due to modifications of the membrane lipid environment surrounding the enzyme.

Animals↗
PubMed1987

Ganglioside GM1 causes expression of type B monoamine oxidase in a rat clonal pheochromocytoma cell line, PC12h.

The effects of ganglioside supplementation of culture medium on monoamine oxidase (MAO) type A and B activities in a rat clonal pheochromocytoma cell line, PC12h, were examined. The MAO activity in PC12h cells proved to be mainly due to type A MAO, and type B MAO activity was negligible. After supplementation of the culture medium with ganglioside GM1, the PC12 cells were found to express type B MAO activity after 4 days of culture, and the amount of type B activity increased with the number of days of culture. After 3 weeks of culture in the presence of GM1, type B activity was about 10% of the total, whereas in control cells type B MAO activity was only about 0.6% of the total. By kinetic analyses of type A and B MAO in PC12h cells after 3 weeks of culture, the increase of type B MAO activity was found to be due to the increase in amount of type B MAO; the Km values were almost the same and only the Vmax values were increased in the cells supplemented with GM1. Among gangliosides tested GM1 was the most effective in causing expression of type B MAO activity, whereas nerve growth factor was not effective. These results suggest that GM1 and other gangliosides may be involved in the expression of type B MAO in nerve cells and in the regulation of levels of the biogenic amines in the brain.

Adrenal Gland Neoplasms↗
PubMed1990

Expression of the ganglioside GD3 in human meningiomas is associated with monosomy of chromosome 22.

The ganglioside composition of 59 meningiomas has been compared with a molecular genetic analysis of chromosome 22 in the same specimens. Major gangliosides were GM3 (II3NeuAc-LacCer) and/or GD3 [II3(NeuAc)2-LacCer]. In specimens with no or partial deletions of chromosome 22, the GM3 ganglioside predominated, and the mean value for GM3, 61% of total sialic acid, was around four times higher than that for GD3. A loss of chromosome 22, found in 56% of the specimens, was shown to be associated with an increase in the proportion of ganglioside GD3, with the ratio between mean values of GM3 and GD3 being approximately 1:1. Logistic regression revealed that the probability of predicting monosomy of chromosome 22 by the GD3 proportion was 66%.

Aged↗
PubMed1990

Nerve growth factor enhances the expression of the cholinergic-specific ganglioside Chol-1 in cocultures of rat septum and hippocampus.

Cocultures of septal and hippocampal tissues taken from 6- to 7-day-old rats were maintained in culture for up to 30 days in the presence and absence of nerve growth factor (NGF), and their Chol-1 contents determined at varying time intervals by a modified enzyme-linked immunosorption assay (ELISA). The major brain gangliosides were determined densitometrically after spraying chromatograms with resorcinol reagent. There was little change in the contribution of the major gangliosides to the total ganglioside content of the explants either with time or the presence or absence of NGF, the only exception being an NGF-insensitive fall in the contribution of GM1 to about 60% of its initial value at 20 and 30 days. By contrast, the concentration of Chol-1 expressed either per unit weight of ganglioside sialic acid or protein increased considerably in culture and this increase was enhanced by NGF. The effect of NGF resembles that on other cholinergic markers, choline acetyltransferase and acetylcholinesterase, and may be attributed to an NGF-stimulated hippocampal ingrowth of cholinergic fibres and enhanced survival of cholinergic septal neurons. The Chol-1 concentration finally attained in the presence of NGF and the time course of its increase parallel those previously found in vivo and indicate the potential usefulness of septal-hippocampal cocultures for investigating the function of Chol-1.

Animals↗
PubMed1981

An immunological model of epilepsy: seizures induced by antibodies to GM1 ganglioside.

Following observations that the intracerebral injection into rats of antiserum to brain gangliosides resulted in recurrent epileptiform activity and that seizure activity was not seen if antibodies were removed by absorption of the antiserum with pure GM1 ganglioside, a study was undertaken to establish characteristics of the immunological agents used to produce this model of epilepsy. It was determined that the potencies (antibody titers with GM1 ganglioside) of antiganglioside sera can be correlated with the intensities of epileptiform activity they induce; that immunoglobulin fractions from antiganglioside sera are even more effective biologically than the antisera; and that antibodies to GM1 ganglioside purified by affinity chromatography can also induce recurrent epileptiform discharges but are not as effective as either native antiserum or immunoglobulin fractions.

Animals↗
PubMed1983

Cellular localization of GM1-ganglioside with biotinylated choleragen and avidin peroxidase in primary cultured cells from rat brain.

A new technique capable of demonstrating the presence and cellular localization of the ganglioside GM1 in primary cultured cells from the brains of newborn rats is described. The method is based on the highly specific binding of biotinylated choleragen to ganglioside GM1, and takes advantage of the high affinity of avidin for biotin. Thus, the biotinylated choleragen-ganglioside GM1 complex can be visualized by the use of avidin peroxidase. The results of this nonimmunologic method indicate that the concentration of ganglioside GM1 is much lower in culture astroglial cells than in neurons and oligodendroglial cells.

Animals↗
PubMed1976

Lipolytic action of cholera toxin on fat cells. Re-examination of the concept implicating GM1 ganglioside as the native membrane receptor.

The possible role of galactosyl-N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosylceramide (GM1) ganglioside in the lipolytic activity of cholera toxin on isolated fat cells has been examined. Analyses of the ganglioside content and composition of intact fat cells, their membranous ghosts, and the total particulate fraction of these cells indicate that N-acetylneuraminylgalactosylglucosylceramide (GM3) represents the major ganglioside, with substantial amounts of N-acetylgalactosaminyl-[N-acetylneuraminyl]-galactosylglucosylceramide (GM2) and smaller amounts of other higher homologues also present. Native GM1 was not detected in any of these preparations. Examination of the relative capacities of various exogenously added radiolabeled sphingolipids to bind to the cells indicated that GM2 and glucosylsphingosine were accumulated by the cells to extents comparable to GM1. Galactosylsphingosine and sulfatide also exhibited significant, although lesser, binding affinities for the cells. The adipocytes appeared to nonspecifically bind exogenously added GM1; saturation of binding sites for GM1 could not be observed up to the highest concentration tested (2 X 10(-4) M), wherein about 7 X 10(9) molecules were associated with the cells. Essentially all of this exogenously added GM1 was found bound to the plasma membrane "ghost" fraction. Investigation of the biological responses of the cells confirmed their sensitivities to both cholera toxin and epinephrine-stimulated lipolysis, as well as the lag period displayed during the toxin's action. While we could confirm that the toxin's lipolytic activity can be enhanced by prior treatment of the fat cells with GM1, several of the observed characteristics of this phenomenon differ from earlier reported findings. Accordingly, added GM1 was able to enhance only the subsequent rate, but not the extent, of toxin-stimulated glycerol release (lipolysis) from the cells. We also were unable to confirm the ability of GM1 to enhance the toxin's activity at either saturating or at low toxin concentrations. The limited ability of added GM1 to enhance the toxin's activity appeared in a unique bell-shaped dose-response manner. The inability of high levels of GM1 to stimulate a dose of toxin that was ineffective on native cells suggests that the earlier reported ability of crude brain gangliosides to accomplish this was due to some component other than GM1 in the crude extract. While several glycosphingolipids and some other carbohydrate-containing substances that were tested lacked the ability to mimic the enhancing effect of GM1, 4-methylumbelliferyl-beta-D-galactoside exhibited an effect similar to, although less pronounced than, that of GM1. The findings in these studies are unable to lend support to the earlier hypothesis that (a) GM1 is cholera toxin's naturally occurring membrane receptor on native fat cells, and (b) the ability of exogenously added GM1 to enhance the toxin's lipolytic activity represents the specific creation of additional natural receptors on adipocytes...

Adipose Tissue↗
PubMed2001

Immunoglobulin G subclass distribution of autoantibodies to gangliosides in patients with Guillain-Barre syndrome.

IgG anti-ganglioside antibodies are present in a proportion of patients with the Guillain-Barré syndrome (GBS). To determine if antibodies to gangliosides are restricted in IgG subclass distribution, we evaluated IgG subclass antibody responses to gangliosides in sera of patients with GBS. Sera from GBS patients with IgG activity against gangliosides were analyzed for IgG subclass distribution using an enzyme-linked immunosorbent assay. The anti-LM1 antibodies in sera from GBS patients were predominantly of the IgG3 subclass while anti-GM1 and anti-GT1a antibodies were predominantly of the IgG1 and IgG3 subclasses. The results indicate a Th2-dependent antibody response.

Autoantibodies↗
PubMed1992

Angiogenesis can be stimulated or repressed in vivo by a change in GM3:GD3 ganglioside ratio.

BACKGROUND: We had previously observed that rabbit cornea stimulated by an angiogenic factor 1) became richer in total gangliosides and 2) reduced the GM3:GD3 ganglioside ratio. Moreover, experimentally induced global enrichment of corneal gangliosides favors angiogenesis. EXPERIMENTAL DESIGN: The objective of this work was to explain the possible relationship between angiogenic response and changes in the GM3:GD3 ratios observed in vivo. Cornea was utilized because it is avascular and transparent; i.e., the onset of opacity permitted exclusion of angiogenesis produced by a generic inflammatory response. Prostaglandin E1 or basic fibroblast growth factor were applied as angiogenesis triggers. Angiogenesis in vivo and mobilization and growth of microvascular endothelium in vitro were taken as parameters to indicate whether differences in GM3:GD3 ratios could modify the extent of the angiogenic response. RESULTS: In vivo angiogenesis, whether prostaglandin E1 or basic fibroblast growth factor induced, was repressed by GM3 and enhanced by GD3 or GM1 enrichment of the cornea. In vitro growth and motility of microvascular endothelium were reduced by GM3 addition to the medium and returned to normal levels by addition of GD3. CONCLUSIONS: Formation of new vessels induced by two different angiogenic factors could be stimulated or repressed in the cornea by reduction or enhancement of the GM3:GD3 ratio of tissue gangliosides. Changes in the relative proportion of molecules normally present in adult tissues, like prostaglandin E1, basic fibroblast growth factor, GM3, GD3, were sufficient to modulate or even block angiogenesis.

Alprostadil↗
PubMed1992

Differences in cerebrospinal fluid gangliosides between "probable Alzheimer's disease" and normal aging.

The four major brain gangliosides, GM1, GD1a, GD1b, and GT1b, were determined in cerebrospinal fluid (CSF) of 43 patients with "probable Alzheimer's disease (AD)" and 40 healthy controls without psychiatric or neurological disorders. The total concentration of the four gangliosides did not differ significantly between "probable AD" group (116 +/- 58 nmol/L) and controls (92 +/- 31 nmol/L), but the proportion between the gangliosides was changed. In the "probable AD" group compared with the age-matched control group, there was an increase in both the GM1 (22.6 +/- 9.3% vs 12.6 +/- 4.1%; p < 0.0001) and GD1a (32.1 +/- 9.8% vs 23.3 +/- 5.7%; p < 0.0005) proportion, and a decrease in the GD1b (20.0 +/- 6.6% vs 23.8 +/- 6.0%; p < 0.05) and GT1b (25.3 +/- 7.9 vs 40.3 +/- 9.3%; p < 0.0001) proportion. The proportion of GM1 showed a positive correlation with age in the control group (r = 0.45; p < 0.01), but a negative correlation with age in the "probable AD" group (r = -0.37; p < 0.05). Thus, although the increase in proportion GM1 in the "probable AD" group was preferentially found in younger "probable AD" patients, it was not caused by age differences. While the pathogenetic mechanism for these changes in CSF-gangliosides in "probable AD" remains to be established, it may reflect the degeneration of nerve cells and synapses.

Adolescent↗
PubMed1985

Syngeneic monoclonal antibody against melanoma antigen with interspecies cross-reactivity recognizes GM3, a prominent ganglioside of B16 melanoma.

It has previously been reported that a mouse (C57BL/6) monoclonal antibody, M2590, was established against syngeneic melanoma B16 cells, which was shown to react only with melanoma cells from various species but not with other tumor cells or normal tissues (Taniguchi, M., and Wakabayashi, S. (1984) Gann 75, 418-426). In the present study, the specificity of M2590 antibody was shown to be directed to a saccharide arrangement (NeuAc alpha 2-3Gal beta 1-4Glc (or -GlcNAc)) of gangliosides by three different assay systems including enzyme immunostaining on thin layer plates, sandwich radioimmunoassay, and enzyme-linked immunoadsorbent assays using a variety of glycolipids with known structures. Neither gangliosides having NeuGc terminus, including NeuGc alpha 2-3Gal beta 1-4Glc-ceramide and NeuGc alpha 2-3Gal beta 1-4GlcNAc beta 1-3Gal beta 1-4Glc-ceramide, nor ganglio series gangliosides carrying NeuAc reacted with the antibody. An M2590 antibody-reactive antigen was isolated from B16 melanoma cells, and its structure was determined to be NeuAc alpha 2-3Gal beta 1-4Glc-ceramide by fast atom bombardment mass spectrometry, methylation analysis, and exoglycosidase treatment. The ceramide was composed of d18:1 as its long-chain base and C16:0, C24:1, and C24:0 as major fatty acids. The same ganglioside was also detected in the culture supernatant of the melanoma cells as shedding antigen.

Animals↗
PubMed1989

Tumor size-dependent elevations of serum gangliosides in patients with head and neck carcinomas.

Serum gangliosides were studied in 100 patients with benign or tumoral head and neck lesions. Whereas very few changes over the normal level were noticed in benign cases, 78% of patients with head and neck carcinomas had a significant elevation of serum gangliosides, mostly accounted for by GM3 and GD3. Such an increase was correlated with the observed tumor size, and the level of serum gangliosides returned to normal within one month after surgery. Follow-up of patients showed that further elevations of serum gangliosides were associated with relapses.

Biomarkers, Tumor↗
PubMed1985

GM2-ganglioside metabolism in hexosaminidase A deficiency states: determination in situ using labeled GM2 added to fibroblast cultures.

To clarify the relationship between hexosaminidase A (HEX A) activity and GM2-ganglioside hydrolysis in atypical clinical situations of HEX A deficiency, we have developed a simple method to assess GM2-ganglioside metabolism in cultured fibroblasts utilizing GM2 labeled with tritium in the sphingosine portion of the molecule. The radioactive lipid is added to the media of cultured skin fibroblasts, and after 10 days the cells are thoroughly washed, then harvested, and their lipid composition analyzed by HPLC. The degree of hydrolysis of the ingested GM2 is determined by comparing the amount of radioactive counts recovered in undegraded substrate with total cellular radioactivity. A deficiency in GM2-ganglioside hydrolysis was demonstrated in seven HEX A-deficient adults with neurological signs and in two healthy-appearing adolescents with older affected siblings. In each case, an analysis of endogenous monosialoganglioside composition revealed an increase in GM2-ganglioside, confirming the presence of a block in the metabolism of GM2. No defect in GM2-catabolism was found in four other healthy individuals with HEX A deficiency. This method of assay is especially helpful in the evaluation of atypical cases of HEX A deficiency for the definitive diagnosis of GM2-gangliosidosis.

Adult↗
PubMed1986

Ganglioside patterns in normal and lepromatous armadillo tissues.

Gangliosides derived from tissues of normal and lepromatous armadillos were examined by thin-layer chromatography. The ganglioside patterns produced by the Mycobacterium leprae-infected tissues varied from that of the normal tissue. Although increased levels of several gangliosides were observed in the infected tissues, there was an apparent preferential increase in GM3 gangliosides as determined by column chromatography and enzymatic hydrolysis.

Animals↗
PubMed1986

Gangliosides and synaptosomal calcium homeostasis.

In this study, depolarization-dependent (net) calcium transport and binding capacity to rat brain synaptosomes was investigated under conditions affecting the ganglioside composition of the synaptoplasmatic membranes. Specific interaction of the monosialoganglioside GM1 with the membrane, as observed in low (40 nM) concentration of ganglioside, resulted in significant inhibition of the maximal depolarization-induced calcium uptake. The changes in ganglioside composition of synaptosomes produced by N-ase treatment did not affect the maximal net Ca++ uptake. However both procedures resulted in the decrease of calculated half-time of the depolarization-induced calcium influx. Exposure of synaptosomes either to GM1 in 40 nM concentration or to N-ase led to a significant drop in 45Ca++ binding to the membrane and increase in the CTC-Ca++ fluorescence. The results suggest that gangliosides are potent modulators of synaptosomal calcium fluxes and equilibration in the membrane.

Animals↗
PubMed1983

Purification and properties of two enzymes catalyzing galactose transfer to GM2 ganglioside from rat liver Golgi.

An enzyme activity which catalyzed the transfer of galactose from UDP-galactose to GM2 ganglioside was demonstrated in rat liver homogenate and enriched 38-fold in specific activity by preparation of Golgi membranes. This activity could be solubilized from Golgi membranes by sonication and extraction with 1% Triton X-100. The solubilized activity catalyzed the formation of GM1 ganglioside and was completely dependent upon the addition of acceptor. The rate of galactose incorporation was constant for up to 5 h at 30 degrees C. This enzyme activity was further purified by gel filtration on Sepharose CL-6B and ion exchange chromatography on DEAE-Sepharose. The elution position on gel filtration corresponded to a molecular weight for the enzyme of 38,000 which was in good agreement with that obtained by sedimentation velocity studies. Ion exchange chromatography resolved GM2 ganglioside galactosyltransferase into two species. The more basic enzyme (I) comprising 28% of the recovered activity was not retarded by the column, whereas enzyme II was eluted from the resin following the application of a salt gradient. Net purification was 120- to 140-fold for each enzyme with a total recovery of 42%. Unlike the activity in the Golgi extract, the purified enzymes I and II were labile to freezing and could be stored at -20 degrees C only in the presence of 50% glycerol. Both enzymes I and II had similar molecular weights and Michaelis constants and both had a strict requirement for Mn2+. Properties which distinguish the two enzymes included pH optima (enzyme I 7.0, enzyme II 6.0) and surfactant requirements. Neither enzyme was active following removal of Triton X-100 from the preparation. Among a series of glycolipids tested for ability to serve as substrates for galactose transfer only GM2 and asialo-GM2 ganglioside served as acceptors.

Animals↗
PubMed1981

Further characterization of the structure of GM1b ganglioside from rat ascites hepatoma.

A ganglioside named GM1b (Hirabayashi, Y., Taki, T., and Matsumoto, M. (1979) FEBS Let. 100, 253-257) with a sugar composition identical with that of GM1, II3 alpha NeuAc-GgOse4Cer (Gal beta 1 leads to 3GalNAc beta 1 leads to 4Gal(3 leads from 2 alpha NeuAc) beta 1 leads to 4G1c beta 1 leads to 1'ceramide), isolated from rat ascites hepatoma was further characterized. In contrast to GM1, the sialic acid in this ganglioside was susceptible to clostridial sialidase in the absence of bile salts. Based on the sequential enzymic hydrolysis, permethylation analysis and direct probe mass spectrometric analysis, the structure of this ganglioside is determined to be: NeuAc alpha 2 leads to 3Gal beta 1 leads to 3GalNAc beta 1 leads to 4Gal beta 1 leads to 4Glc leads to ceramide. The structure of this ganglioside is identical with that biosynthesized in vitro (Stoffyn, A., Stoffyn, P., and Yip, M. C. M. (1975) Biochim. Biophys. Acta 409, 97-103).

Animals↗