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PubMed2001

The plasma membrane ganglioside sialidase cofractionates with markers of lipid rafts.

Gangliosides of the plasma membrane are important modulators of cellular functions. Recent reports have shown their enrichment in glycosphingolipid-containing membrane microdomains, called glycosphingolipid-signaling domain or rafts, which can be isolated due to their insolubility in Triton X-100 and flotation through a sucrose gradient. In previous work on neuroblastoma cells we had found that a ganglioside-specific sialidase activity of the plasma membrane controlled proliferation and differentiation through selective ganglioside desialylation. Assuming the ganglioside sialidase to be close to its substrates in the membrane, we investigated its association with detergent-insoluble microdomains in the neuroblastoma cell line SK-N-MC. The results show that the ganglioside sialidase codistributes with the raft markers ganglioside GM1, flotillin, src family kinases, and glycosylphosphatidylinositol-anchored proteins in a fraction containing about 2% of cellular protein. The association of the ganglioside sialidase with glycosphingolipid-enriched membrane fractions therefore is in support of a role of this glycosidase in ganglioside-dependent signaling processes.

Biomarkers↗
PubMed1989

Ganglioside GD3 shedding by human malignant melanoma cells.

Gangliosides appear to be important target molecules for immunological effector mechanisms on neuro-ectodermal tumors. Therefore in vitro studies were performed to examine whether ganglioside GD3, which is highly expressed on the cell surface of cultured human melanoma cells, is being shed into the culture medium. Measurable quantities of gangliosides GM3 and in particular GD3 were shed by the melanoma cells we have tested as detected on thin-layer chromatograms (TLC) stained with orcinol. Ganglioside GD3 was also evidenced by immunostaining with anti-GD3 MAb and by ELISA. The concentration of GD3 in the supernatant of human melanoma cells depended on the ganglioside pattern of the cell line. Cells containing high levels of GD3 shed large amounts, cells with low levels shed no detectable GD3. Ganglioside GD3 was detectable in sera, but no major quantitative differences were observed in sera of patients with GD3-positive tumors and normal controls. This points to a local accumulation of ganglioside GD3 at the tumor site.

G(M3) Ganglioside↗
PubMed1990

Reversibility of ganglioside effects on astrocyte morphology.

The B-subunit of cholera toxin (BCT) induces a morphological change in cultured rat cerebral astrocytes from flat (epithelioid) to stellate (process-bearing). This stellation is reversed by the gangliosides GM1 and GD1a at concentrations of 10 microM or higher. Upon changing to a ganglioside-free medium, the flat astrocytes reacquire the stellate morphology within 3 hr, indicating that the antistellation effect of gangliosides is reversible. The possibility that this reversibility was due to a loss of exogenously acquired gangliosides from the cell membrane can be ruled out since pretreatment with GM1, but not GD1a, which does not bind BCT, results in an increased responsiveness to BCT, which was identical whether measured immediately after withdrawal of the ganglioside or 3 hr later. Asialo-GM1, which neither binds BCT nor reverses BCT-induced stellation by itself, prevents the return to stellation after withdrawal of the gangliosides. These data suggest that while gangliosides remain associated with the cell, their effect on astrocytes can change from opposing to permitting the stellate morphology.

Animals↗
PubMed2000

Determination of N-acetyl- and N-glycolylneuraminic acids in gangliosides by combination of neuraminidase hydrolysis and fluorometric high-performance liquid chromatography using a GM3 derivative as an internal standard.

A highly sensitive method for quantification of sialic acids in gangliosides was developed. The sialic acids, released by hydrolysis of gangliosides, were converted to fluorescent derivatives with 1,2-diamino-4,5-(methylenedioxy)benzene (DMB) and separated on a reversed-phase C18 column with an isocratic elution. As little as 0.1-1.0 nmol of sialic acid in ganglioside was quantified. The use of acetate buffer instead of water in the mobile phase could prevent damage on the column and reduce background peaks derived from the reagents. When gangliosides were subjected to acid hydrolysis, the velocity of hydrolysis varied depending on their structures and a part of the sialic acid liberated decomposed with prolonged heating time. Therefore gangliosides were hydrolyzed by Arthrobacter ureafaciens neuraminidase in the presence of sodium cholate after addition of an internal standard. For the internal standard, GM3 with N-propionylneuraminic acid (GM3(NeuPr)) was synthesized from GM3(NeuAc) by N-deacylation followed by N-propionylation. Folch partition was used to decrease lipophilic materials included in the sample, and the sialic acids released were recovered from the upper phase. The present method has a satisfactory sensitivity in the simultaneous quantification of NeuAc and NeuGc in purified gangliosides as well as in crude lipid fractions containing a variety of gangliosides.

Carbohydrate Sequence↗
PubMed2000

A functional role for complex gangliosides: motor deficits in GM2/GD2 synthase knockout mice.

Although gangliosides are abundant molecular determinants on all vertebrate nerve cells (comprising approximately 1.5% of brain dry weight) their functions have remained obscure. We report that mice engineered to lack a key enzyme in complex ganglioside biosynthesis (GM2/GD2 synthase), and which express only the simple ganglioside molecular species GM3 and GD3, develop significant and progressive behavioral neuropathies, including deficits in reflexes, strength, coordination, and balance. Quantitative indices of motor abilities, applied at 8 and 12 months of age, also revealed progressive gait disorders in complex ganglioside knockout mice compared to controls, including reduced stride length, stride width, and increased hindpaw print length as well as a marked reduction in rearing. Compared to controls, null mutant mice tended to walk in small labored movements. Twelve-month-old complex ganglioside knockout mice also displayed significant incidence of tremor and catalepsy. These comprehensive neurobehavioral studies establish an essential role for complex gangliosides in the maintenance of normal neural physiology in mice, consistent with a role in maintaining axons and myelin (Sheikh, K. A. , J. Sun, Y. Liu, H. Kawai, T. O. Crawford, R. L. Proia, J. W. Griffin, and R. L. Schnaar. 1999. Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects. Proc. Natl. Acad. Sci. USA 96: 7532-7537), and may provide insights into the mechanisms underlying certain neural degenerative diseases.

Animals↗
PubMed1994

Functional relationship between ammonia and gangliosides in brain.

The functional significance of ammonia production in brain under physiological or pathological conditions is not clearly known. NH4+ stimulates Na+, K+ activated ATPase causing stabilization of neuronal membranes of which gangliosides are major structural components. Moreover ammonia is known to inhibit lysosomal enzymes which include enzymes degrading gangliosides. Gangliosides have been shown to stimulate neuritogenesis in neuronal cultures and prevent the damage of the neurons from glutamate toxicity particularly in areas of brain ischemia. Hyperammonemia without any behavioural changes was induced in experimental rats by intraperitoneal administration of either a single dose (0.8 mmol/100 g wt.) or by six 'hourly' doses (0.6 mmol/100 g wt.) of ammonium acetate. An increase in the content of gangliosides along with a rise in the content of GD1A and GD1B without any change in beta-galactosidase and N-acetylhexosaminidase was observed in cerebral cortex, cerebellum, and brain stem, following the administration of single dose of ammonium acetate. Gangliosides, after extraction from the different brain regions, were estimated by the thiobarbituric acid method and expressed in terms of sialic acid. Individual gangliosides were separated and estimated by thin layer chromatography using resorcinol as the staining agent. These results suggest that ammonia production in the neuronal pathways in brain either as a result of repeated stimulation under physiological conditions or as a result of focal ischemia or injury, may likewise cause an increase in the content of gangliosides which may help in neuritic growth (physiological conditions facilitating synaptic plasticity) and may exert a protective effect on the neurons in the ischemic area against glutamate toxicity.

Acetates↗
PubMed1988

Genetic control of ganglioside biosynthesis in mice.

The enzymatic basis for the differences in hepatic ganglioside patterns in the mouse strains C57Bl/6 and Swiss White (SW) was investigated. SW has a "Swiss-type" ganglioside profile, expressing GM1- and GD1a- in addition to GM2- as major hepatic gangliosides, whereas C57Bl/6 shows a "GM2-type" profile, expressing only GM2- as the major hepatic ganglioside. The enzyme UDP-galactose:GM2 ganglioside galactosyltransferase (GM2-GalT), which catalyzes the synthesis of GM1 ganglioside, showed a four- to fivefold elevation in intact and solubilized liver Golgi membrane fractions of the SW strain compared to C57Bl/6. Crosses between C57Bl/6 and SW produced an F1 generation with a hepatic ganglioside and enzymatic phenotype intermediate between those of the two parental strains. All three genotypic groups show two forms of the Golgi apparatus enzyme with isoelectric points of 6.5-6.8 and 8.3-9.0. The simplest mode of action of genes which control the enzymatic phenotype that would be consistent with these findings are one or two structural genes or one or two cis-regulatory genes affecting the rate of enzyme synthesis.

Animals↗
PubMed2003

Enterotoxigenic Escherichia coli strains bind bovine milk gangliosides in a ceramide-dependent process.

Diarrhea caused by enterotoxigenic Escherichia coli (ETEC) is the main infectious disease of newborn calves. The first step of infection involves bacterial attachment to the intestinal mucosa. This adhesion is mediated by fimbriae that recognize some glycoconjugates on the host cell surface, in particular, several gangliosides. Because milk also contains gangliosides, these have been suggested to serve as ligands for bacterial fimbriae and thus prevent the bacterial attachment to mucosa. The most relevant ETEC strains in calves, including those with K99 and F41 fimbriae, were assayed to determine whether they are able to bind gangliosides isolated from several stages of bovine lactation. Both GM3 and GD3, the main gangliosides of milk, were recognized by ETEC strains, although the different fimbriae showed diverse levels of affinity. Unexpectedly, the adhesion to colostral gangliosides was considerably weaker than that to gangliosides from the other stages of lactation. Because the carbohydrate moiety did not change and because differences in the percentages of unsaturated FA and sphingosine between colostrum and other stages were observed, we conclude that the differences in adhesion could be due to a different composition of the ganglioside ceramide.

Animals↗
PubMed1992

Characteristics and regulation of ganglioside-induced elevation of free cytoplasmic Ca2+ in human blood platelets.

We have found that gangliosides GD3 and GM3 induced rapid, reversible elevation of free cytoplasmic Ca2+ in fura-2-loaded human blood platelets. The effect persisted in Ca(2+)-free medium, indicating that gangliosides stimulated mobilization of intracellular stores. The action of gangliosides was concentration-dependent with EC50 of about 1 microM. The Ca(2+)-mobilizing effects of gangliosides were potentiated by epinephrine and inhibited by substances inducing activation of protein kinase C and cAMP-dependent protein kinases. Acidic phospholipids partially mimicked the Ca(2+)-mobilizing effects of gangliosides indicating that lipid head charge is essential for this activity. While the elevation of [Ca2+]i produced by arachidonic acid was almost completely blocked by aspirin pretreatment, the effects of gangliosides were diminished only 2-fold, indicating that gangliosides activate both aspirin-sensitive and aspirin-insensitive mechanisms of [Ca2+]i elevation.

Arachidonic Acid↗
PubMed1982

Uniform distribution and similar turnover rates of individual gangliosides along axons of retinal ganglion cells in the chicken.

In 5-month-old chickens, an intracranial injection of N-[3H]acetylmannosamine led to a labeling of all optic lobe ganglioside species in a fashion paralleling the relative ganglioside distribution. In contrast, after an intraocular injection of the same precursor, the optic nerve and the optic lobe connected to the injected eye, possessed an exceptionally high labelling of GD1a (in comparison with GD1a-sialic acid), and only negligible incorporation of radioactivity into the myelin-specific GM4 and into a fraction migrating close to GM1. Subtracting both these very low labelling fractions from the total gave a percentage distribution of ganglioside sialic acid which now corresponded well to the distribution of radioactivity along the whole optic nerve, including the region of nerve terminals in the optic lobe. This pattern of ganglioside labelling, which indicates that GD1a carries about 60% of total ganglioside sialic acid of retinal ganglion cell axons, did not change remarkably during post-hatching development up to 5 months. Long-time incorporation studies revealed similar turnover rates of the main retinal ganglion cell gangliosides. The average half-lives were 34 (GD1a), 35 (GQ1b), 36.3 (GT1b) and 38.5 days (GD3). The findings suggest that the retinal ganglion cell axons and their presynaptic terminals possess a similar ganglioside pattern, characterized by a high content of GD1a.

Aging↗
PubMed1993

Dot-blot immunodetection of antibodies against GM1 and other gangliosides on PVDF-P membranes.

A simple and rapid assay for detection of antibodies against GM1 and other gangliosides (GM3, GM2, GD1a, GD1b, GT1b, GD3) is described. Purified gangliosides were applied individually in 1 microliter of methanol to polyvinylidene difluoride (PVDF) membranes. Anti-ganglioside antibodies in human sera were allowed to bind and were revealed with a second antibody coupled to peroxidase. The specificity of antibodies binding to gangliosides was confirmed using established techniques to detect anti-ganglioside antibodies such as immunostaining of gangliosides after high performance thin layer chromatography according to Derrington et al. (1989) and ELISA procedure according to Adams et al. (1991) or using the ability of cholera toxin beta subunit to remove GM1 bound antibodies. The dot-blot assay is the simplest and quickest method to run and it appears to be suitable for large routine screening detection of anti-ganglioside antibodies in sera of patients with neurological diseases.

Animals↗
PubMedDate not supplied

Normal developmental profiles of CSF gangliotetraose-series gangliosides from neonatal period to adolescence.

The normal developmental profiles of cerebrospinal fluid (CSF) gangliosides were examined from the neonatal period to adolescence, using 1 ml of clinically available CSF, by the thin-layer chromatography/enzyme-immunostaining method. The level of total gangliotetraose-series gangliosides, including GM1, GD1a, GT1a, GD1b, GT1b, and GQ1b, increased 3.8-fold from the neonatal period to age 5 years, followed by a plateau, and then a mild decrease. The developmental profiles of individual gangliosides differed from each other. CSF gangliosides change with age, reflecting the maturational changes of the central nervous system gangliosides in situ. CSF ganglioside analysis and this developmental profile might be useful for examining ganglioside aberrations and basic neurochemical mechanisms underlying neurologic disorders, especially age-dependent diseases.

Adolescent↗
PubMed2005

Generation of anti-Neu-glycolyl-ganglioside antibodies by immunization with an anti-idiotype monoclonal antibody: A self versus non-self-matter.

We have previously generated a murine anti-idiotype (Ab2) monoclonal antibody (mAb) to a murine Ab1 mAb, named P3, which selectively binds Neu-glycolyl (NeuGc)-sialic acid on several monosialo- and disialogangliosides, and also reacts with sulfatides and antigens expressed in human melanoma and breast tumors. This Ab2 mAb, designated as 1E10, induced anti-anti-idiotype antibodies (Ab3) in mice and cancer patients. These Ab3 generated by 1E10 mAb were characterized by bearing P3 mAb idiotopes (Ab3, Id +). But when the specificity of these Ab3 antibodies was tested, no specific humoral response against NeuGc-containing gangliosides was detected in sera from immunized mice. However, hyperimmune sera from melanoma and breast cancer patients vaccinated with this Ab2 mAb were able to react specifically with these gangliosides. The different expression of NeuGc-containing gangliosides in the normal tissues of mice and humans could explain these results. In order to demonstrate these findings in other animal species with a different NeuGc-sialic acid expression, we performed similar studies in monkeys and chickens. In monkeys, as in most mammals, NeuGc-containing gangliosides are self-antigens. In contrast, chickens, like humans, lack the expression of these antigens in normal tissues. Here we report that the antibody response against NeuGc-containing gangliosides induced by immunization with 1E10 mAb was completely different in both species. No specific antibody response against these gangliosides was detected in hyperimmune monkey sera. In contrast, a strong and specific Ab3 response against GM3(NeuGc) and GM2(NeuGc) gangliosides (Ab3, Ag+) was generated in chickens due to the administration of 1E10 mAb.

Animals↗
PubMed1998

Interaction of gangliosides with proteins depending on oligosaccharide chain and protein surface modification.

By using neutron and synchrotron x-ray small-angle scattering techniques, we investigated the process of the complexation of gangliosides with proteins. We treated monosialoganglioside (G(M1)), disialoganglioside (G(D1a)), and a mixture of G(M1)/G(D1a). Proteins used were bovine serum albumins whose surfaces were modified with different sugars (deoxy-D-galactose, deoxy-L-fucose, deoxymaltitol, and deoxycellobiitol), which were used as model glycoproteins in a membrane. We found that the complexation of gangliosides with albumins greatly depends on the combination of ganglioside species and protein surface modification. With a varying protein/ganglioside ratio in a buffer solution at pH 7, the complexation of G(M1) or G(D1a) with albumins modified by monosaccharides appears to be less destructive for ganglioside aggregate structures in forming large complexes; the complexation of G(D1a) with the albumins modified by disaccharides induces the formation of complexes with a dimeric structure; and the complexation of G(M1) with albumins modified by disaccharides, to form small complexes, is very destructive. The present results show a strong dependence of the interaction between ganglioside and protein on the characteristics of the ganglioside and protein surface, which would relate to a physiological function of gangliosides, such as a function regulating the receptor activity of glycoproteins in a cell membrane.

Animals↗
PubMed1997

Gangliosides of dogfish (Squalus acanthias) brain.

Eighteen gangliosides were isolated from dogfish (Squalus acanthias) brain, and their structures and compositions were determined by methylation analysis, enzymatic hydrolysis and partial hydrolysis with mild acid. Tetra- and pentasialogangliosides were also analysed by liquid secondary ion mass spectrometry. The dogfish brain gangliosides were characterized by a variety of molecular species. The most abundant ganglioside was GM2 (22.8% of the total sialic acid content), followed by GQ1c (16.0%), GP1c (13.4%), and GD2 (12.5%). The abundance of gangliosides containing a gangliotriaose core (GM2 and GD2), and c-series polysialogangliosides (GQ1c and GP1c) was a prominent feature of dogfish brain, differing from the brain gangliosides of teleosts and other vertebrates. A battery of trisialogangliosides was also found. A ganglioside which had an a- and alpha-series hybrid-structure (IV3NeuAc,III6NeuAc,II3NeuAc-Gg4Cer) comprised 1.4% of the total. The major fatty acids comprised 16:0, 18:0, 18:1, 22:1 and 24:1. The gangliosides with a gangliotriaose core predominantly contained 22:1. Sphinganine and 4-sphingenine comprised the long-chain bases.

Animals↗
PubMed1980

Interaction of activating protein and surfactants with human liver hexosaminidase A and GM2 ganglioside.

The effects of surfactants on the human liver hexosaminidase A-catalysed hydrolysis of G(m2) ganglioside were assessed. Some non-ionic surfactants, including Triton X-100 and Cutscum, and some anionic surfactants, including sodium taurocholate, sodium dodecyl sulphate, phosphatidylinositol and N-dodecylsarcosinate, were able to replace the hexosaminidase A-activator protein [Hechtman (1977) Can. J. Biochem.55, 315-324; Hechtman & Leblanc (1977) Biochem. J.167, 693-701) and also stimulated the enzymic hydrolysis of substrate in the presence of saturating concentrations of activator. Other non-ionic surfactants, such as Tween 80, Brij 35 and Nonidet P40, and anionic surfactants, such as phosphatidylethanolamine, did not enhance enzymic hydrolysis of G(m2) ganglioside and inhibited hydrolysis in the presence of activator. The concentration of surfactants at which micelles form was determined by measurements of the minimum surface-tension values of reaction mixtures containing a series of concentrations of surfactant. In the case of Triton X-100, Cutscum, sodium taurocholate, N-dodecylsarcosinate and other surfactants the concentration range at which stimulation of enzymic activity occurs correlates well with the critical micellar concentration. None of the surfactants tested affected the rate of hexosaminidase A-catalysed hydrolysis of 4-methylumbelliferyl N-acetyl-beta-d-glucopyranoside. Both activator and surfactants that stimulate hydrolysis of G(m2) ganglioside decrease the K(m) for G(m2) ganglioside. Inhibitory surfactants are competitive with the activator protein. Evidence for a direct interaction between surfactants and G(m2) ganglioside was obtained by comparing gel-filtration profiles of (3)H-labelled G(M2) ganglioside in the presence and absence of surfactants. The results are discussed in terms of a model wherein a mixed micelle of surfactant or activator and G(M2) ganglioside is the preferred substrate for enzymic hydrolysis.

Acetylglucosamine↗
PubMed1983

Occurrence of glycosylation and deglycosylation of exogenously administered ganglioside GM1 in mouse liver.

Ganglioside GM1, 3H-labelled at the level of terminal galactose or of sphingosine, was intravenously injected into Swiss albino mice and some steps in its metabolic fate in the liver were investigated. After administration of [3H]sphingosine-labelled GM1 all major liver gangliosides [GM3, GM2, GM1, GD1a-(NeuAc,NeuGl)] became radioactive, the radioactivity residing in all cases on the sphingosine moiety. The specific radioactivity was highest in GM1, which carried about 53% of the radioactivity incorporated into gangliosides, followed by GM2, with 34.5% of incorporated radioactivity, GM3 and GD1a-(NeuAc,NeuGl), both with about 5% of incorporated radioactivity. After administration of [3H]galactose-labelled GM1 the only radioactive gangliosides present in the liver were GM1 and GD1a-(NeuAc,NeuGl), the former carrying about 95% of the total ganglioside-incorporated radioactivity, the latter about 3%. Both gangliosides were radioactive exclusively in the terminal galactose residue. According to these results exogenously administered GM1, after being taken up by the liver, is mainly degraded to GM2 and GM3, a part being, however, sialylated to GD1a-(NeuAc,NeuGl). All this suggests that exogenous GM1 may be involved in the metabolic routes of endogenous liver gangliosides.

Animals↗
PubMed1995

Ganglioside profiles of experimental melanomas and of their melanosomal fractions.

We compared ganglioside profiles of animal tumours (B16 and Cloudman S91 murine melanomas, Bomirski Syrian hamster melanoma), which are widely used as models of human melanoma, and of their melanosomal fractions. A ganglioside fraction was extracted and purified and the amount of each component ganglioside was assessed by thin-layer chromatography. GM3 was the dominant ganglioside species in the murine melanomas studied. Unlike human melanomas, the GD3 expression in mouse melanomas was low. GD3 and GM3 were major gangliosides in Bomirski hamster melanoma. Alkali-labile O-acetyl-GD3, a melanoma-specific ganglioside, was detected only in Bomirski melanoma. GD2, which in human melanoma is seen as a distinct signal of tumour progression, was not found in the animal melanomas studied. Melanosomes isolated from B16 and Bomirski melanomas contained GM3 and GD3 as their major ganglioside components. These data extend the group of common antigenic determinants shared by melanosomes and cell surface of pigment cells.

Animals↗