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PubMed2001

High beta-galactosidase and ganglioside GM1 levels in the human parotid gland.

BACKGROUND: Ganglioside G(M1) is a membrane glycolipid typical of nerve cell membranes, where it partakes in neurotransmitter release and is catabolized by the lysosomal beta-galactosidase (GM1ase) (EC 3.2.1.23). After demonstrating a novel degenerative disease of the parotid gland in mice deficient in GM1ase, mimicking the human storage disease GM(1) gangliosidosis, we studied GM1ase and ganglioside G(M1) content in the human parotid glands. STUDY DESIGN: Levels of GM1ase and ganglioside G(M1) were determined in samples of parotid tissues and neighboring muscle (as a negative control) for 3 subjects. Tissues were also processed for histochemical demonstration of GM1ase. RESULTS: The mean specific activity of GM1ase was more than 6-fold higher in the healthy human parotid tissues (1.4 +/- 0.5 nmol of 4-methylumbelliferone per minute per milligram of protein) relative to the neighboring muscle tissue (0.23 +/- 0.07 nmol of 4-methylumbelliferone per minute per milligram of protein). Activity of GM1ase was histochemically localized mainly to striated duct and acinar cells of the parotid gland. Ganglioside G(M1) content in the parotid gland was on average 30-fold higher relative to muscle. CONCLUSIONS: Our results are consistent with previous findings reported in the mouse and the rabbit, and probably reflect a general property of the mammalian parotid glands. The novel mechanism we previously proposed for the mouse parotid saliva secretion, mimicking neurotransmitter release in ganglioside G(M1)-containing nerve cells, is probably applicable also to the human parotid gland. Similarly, the human parotid gland is probably also severely affected in GM(1) gangliosidosis.

Adult↗

PubMed1996

Induction of antibodies reactive with GM2 ganglioside after immunization with lipopolysaccharides from Camplyobacter jejuni.

Ganglioside GM2, expressed on the surface of some human cancers, is a promising target for immune therapy, since GM2 antibodies are cytotoxic, can be induced in humans by vaccination, and the presence of GM2 antibodies is associated with a better prognosis in melanoma patients. In our efforts to induce long-lived, cytotoxic GM2 antibodies, we investigated lipopolysaccharides (LPS) containing "GM2-like" oligosaccharides. LPS were prepared from Campylobacter jejuni serotypes O:1, O:23, or O:36 (all sharing the oligosaccharide structure GalNAcbeta1-4Gal(113NeuAc)-Hex with ganglioside GM2), and tested for their ability to induce GM2-reactive antibodies. Immunization of NZW rabbits (2 animals per vaccine) with LPS from C. jejuni serotype O:1 in Freund's adjuvant resulted in production of high-titer IgG antibodies reactive with purified bovine brain GM2 in ELISA, dot-blot immune strains and immune thin-layer chromatography, and with GM2 derived from various human tumors by immune thin-layer chromatography. These rabbit antibodies bound to cancer cell lines expressing GM2 on their cell surface, as determined by mixed hemadsorption assays, mediating strong antibody-dependent cellular cytotoxicity (ADCC) with tumor cells expressing cell-surface GM2. Antibodies induced by vaccination with C. jejuni serotype O:1 were higher-titer (IgG ELISA titer > 1:60,000) than antibodies induced by immunization with purified GM2 (IgG ELISA titer > 1:200). Immunization with LPS from C. jejuni serotype O:36 resulted in production of moderately high-titer IgM and low-titer IgG GM2 antibodies. Immunization with LPS from C. jejuni serotype O:23 did not elicit GM2-reactive antibodies. No clinical symptoms were observed in animals immunized with these LPS preparations, with purified GM2 ganglioside, or with LPS derived from C. jejuni serotype O:19 (containing a GM1-like oligosaccharide). Our results indicate that lipopolysaccharides sharing carbohydrate epitopes with gangliosides may be useful immunogens for inducing antibodies to ganglioside antigens.

Animals↗

PubMed2000

T cell receptor-dependent activation of human lymphocytes through cell surface ganglioside GT1b: implications for innate immunity.

Gangliosides form a component of the glycosphingolipid-rich membrane microdomains recently shown to play an important role in receptor signal transduction. Specific gangliosides also serve as receptors for binding and internalization of bacterial toxins. In the course of characterizing the basis of the native tetanus toxin (TTx) reactivity of a human gamma delta T cell clone, we observed that transfer of the TCR was required to impart TTx reactivity on a TCR-negative recipient T cell. However, the reconstitution of toxin reactivity could be achieved regardless of the antigen specificity of the TCR chains. Further analysis showed that the T cell recognition of native TTx was dependent on the presence of its ganglioside receptor, GT1b, on the T cell surface. Incorporation of exogenous GT1b into plasma membrane conferred TTx reactivity on otherwise non-reactive T cells provided these cells expressed the TCR. Finally, reconstitution of TCR-negative Jurkat T cells with a CD8-CD3zeta chain chimera demonstrated that the cytoplasmic region of the CD3zeta chain was sufficient to couple ganglioside-mediated TTx binding to T cell activation. These data reveal a novel mode of TCR-dependent reactivity to a bacterial toxin that could mobilize a large subset of T cells, thus representing a form of innate immunity. Given the possibility that endogenous ligands may bind to cell surface gangliosides, regulation of their levels and topology on the cell surface may constitute an immunoregulatory mechanism.

Cell Line, Transformed↗

PubMed1995

Neuroprotective effects of gangliosides may involve inhibition of nitric oxide synthase.

Gangliosides are polar, sugar-containing lipids that are major constituents of neuronal membranes. Gangliosides are neuroprotective in animal models of neurotoxicity and may also be useful in patients with clinical conditions such as spinal cord injury. We show that a series of gangliosides inhibit nitric oxide synthase activity by binding calmodulin. The prevention of glutamate neurotoxicity in cortical cultures by gangliosides closely parallels their potencies in binding calmodulin and inhibiting nitric oxide synthase. Neuroprotective effects of gangliosides may arise from blockade of nitric oxide formation.

Amino Acid Oxidoreductases↗

PubMed2001

Dietary gangliosides positively modulate the percentages of Th1 and Th2 lymphocyte subsets in small intestine of mice at weaning.

We studied the influence of dietary gangliosides on the number of spontaneous cytokine-secreting cells from two intestinal lymphocyte populations: lamina propria lymphocytes and Peyer's patches lymphocytes in Balb/c mice for 28 days after weaning. Weanling mice were separated into two groups, designated as Control and BG. The Control group was fed with a semipurified diet without gangliosides and the BG group was fed with the semipurified diet supplemented with 47 mg/kg of a mixture of bovine brain gangliosides. Intestinal lymphocytes were isolated from mice killed at 3, 7, 14 and 28 days after weaning, and the percentages of spontaneous Th1 as well as Th2 cytokine-secreting lymphocytes were determined using the ELISPOT assay. The BG group animals showed an earlier development in the number of cytokine-secreting cells, which appeared one week later in Control animals. In addition, mice fed with the ganglioside-supplemented diet showed a significantly higher number of Th1 and Th2 cytokine-secreting lymphocytes than Control mice in lamina propria and Peyer's patches lymphocytes at the end of the experimental period (28 days). Our results suggest that dietary gangliosides influence the maturation process of the intestinal immune system that take place during weaning.

Animals↗

PubMed1990

Rapid detection of extended ganglio-series gangliosides with terminal GalNAc beta 1-4Gal sequence on high performance thin layer chromatography plates.

The mouse monoclonal antibody 2D4, which recognizes the terminal GalNAc beta 1-4Gal-disaccharide of GgOse3Cer and GgOse5Cer, was used for the detection of ganglio-series gangliosides. The method involves separation of gangliosides on thin layer chromatography plates, followed by silica gel fixation, Arthrobacter ureafaciens neuraminidase treatment and final immunostaining of desialylated gangliosides with the monoclonal antibody 2D4. Both neuraminidase and the hybridoma 2D4 producing the specific monoclonal antibody are commercially available and therefore accessible to all researchers working in this field. Gangliosides from mouse T lymphocytes and the mouse T cell lymphoma YAC-1 have been used as examples. This technique may be used for fast screening of gangliosides with the GgOse5Cer core structure which have been described as T cell markers, antigens in human neuronal disease and receptors for certain pathogenic bacteria.

Animals↗

PubMedDate not supplied

Detection of gangliosides with the fluorochrome NBD dihexadecylamine and its application for preparative high performance thin layer chromatography.

A new method for the detection of gangliosides based on the lipophilic fluorescence agent 4-(N,N-dihexadecyl)amino-7-nitrobenz-2-oxa-1,3-diazole (NBD dihexadecylamine) and its application for preparative high performance thin layer chromatography is described. Brain gangliosides were chromatographed on silica gel coated thin layer plates and located with non-destructive fluorochrome under longwave ultraviolet light. The fluorescent zones were scraped off and the gangliosides were extracted with a mixture of chloroform/methanol/water (30/60/8; v/v/v). The gangliosides were separated from uncharged NBD dihexadecylamine by anion exchange chromatography and impurities were removed by Iatrobeads chromatography. The method described offers a simple and successful preparative thin layer chromatographic strategy to obtain pure gangliosides in microgram and milligram quantities.

4-Chloro-7-nitrobenzofurazan↗

PubMed2003

Cholera toxin activates dendritic cells through dependence on GM1-ganglioside which is mediated by NF-kappaB translocation.

Cholera toxin (CT) is a potent adjuvant; however, the mechanism for its ability to enhance mucosal immunity has not been fully elucidated. We report here that CT exerts its adjuvant properties by signaling through the GM1 ganglioside receptor. When ganglioside-defective mice were given the antigen (Ag) ovalbumin (OVA) with CT by the oral route, CT failed to support either OVA-specific antibody or CD4+ T cell responses. In vitro treatment of murine bone marrow-derived dendritic cells (DC) with CT induced full maturation as evidenced by up-regulation of the costimulatory molecules, as well as by an enhanced ability to effectively present OVA for Ag-specific T cell responses. On the other hand, ganglioside-defective DC failed to differentiate to full function as Ag-presenting cells in response to CT. Since ganglioside-defective DC showed a mature phenotype after stimulation with lipopolysaccharide (LPS), the effects of CT on DC was independent of signal transduction through adjuvant receptor for LPS, the Toll-like receptor 4. Furthermore, CT also induced nuclear translocation of nuclear factor (NF)-kappaB in DC in a GM1-dependent fashion. These results highlight gangliosides expressed by DC for recognition of the non-self protein bacterial enterotoxin, which employ a unique signaling pathway to induce both innate and adaptive immunity.

Animals↗

PubMed1988

Changes in plasma gangliosides in relation to tumor growth and their tumor-enhancing effect.

Gangliosides in the plasma of Ehrlich ascites tumor-bearing mice showed changes, both quantitative and qualitative, with progress of tumor. Quantitative changes assessed by chemical estimation indicated a gradual increase of gangliosides up to day 6 of tumor growth followed by a decline leading to a level below the normal by day 12. Qualitative changes studied by thin-layer chromatography indicated appearance of new gangliosides in the plasma of tumor-bearing mice, which were absent from normal plasma. One of these gangliosides appears to be of tumor-cell origin. Gangliosides obtained from tumor-bearing mouse plasma enhanced tumor growth when adoptively transferred with tumor cells into normal mice.

Animals↗

PubMed1993

Ganglioside expression on human malignant melanoma assessed by quantitative immune thin-layer chromatography.

The ganglioside composition of 20 human malignant melanomas and 5 normal tissues (muscle, spleen, kidney, liver and brain) was analyzed by high-performance thin-layer chromatography (HPTLC) and immune HPTLC using a panel of antiganglioside monoclonal antibodies, and quantified by photodensitometry. The most prominent gangliosides were GM3 and GD3, present in all 20 melanomas; however these were expressed in the 5 normal tissues as well. GD2, GM2, GT3 and 9-O-Ac-GD3 were each expressed in at least 17 of 20 melanomas, but distribution on the normal tissues examined was largely restricted to brain. The detection of several additional glycolipids was studied. GMI was highly expressed in normal brain tissue, but was not detected in any melanoma biopsies, and SGPG was detected in neither. Fuc-GMI was identified in 3 melanoma specimens and a base-sensitive ganglioside, not previously identified in melanoma, was detected in 4 of 20 melanomas with the anti-GD2 MAb 3F8. This compound is most likely O-acetylated GD2. GD3 lactones were identified in 16 of 20 melanoma biopsies, however the proportion that are naturally occurring rather than artifacts of extraction is unclear. The total expression of the more restricted gangliosides (GM2, GD2, GT3 and 9-O-Ac-GD3) in these 20 melanomas ranged between 2.4 and 102.5 micrograms/g, representing 8 x 10(6) to 3 x 10(8) ganglioside molecules per cell. This number of tumor-surface antigens provides the rationale for a polyvalent anti-melanoma vaccine containing GM2, GD2, GT3 and 9-O-Ac-GD3.

Antibodies, Monoclonal↗

PubMed1990

Cautionary note on the use of the B subunit of cholera toxin as a ganglioside GM1 probe: detection of cholera toxin A subunit in B subunit preparations by a sensitive adenylate cyclase assay.

The use of the B subunit of cholera toxin, a protein that binds specifically to ganglioside GM1, has provided a new paradigm for studying physiological functions of ganglioside GM1. The B subunit inhibited the growth of rat glioma C6 cells that had been pretreated with ganglioside GM1. In some preparations of the B subunit, the inhibition was independent of adenylate cyclase activation and was due to the binding of the B subunit to ganglioside GM1 inserted onto the cell surface. However, in other preparations of the B subunit, there was an additional inhibitory effect due to small contaminations with the A subunit, which caused increases in intracellular cyclic adenosine monophosphate (cAMP) levels and concomitant growth inhibition. This vanishingly small contamination with the A subunit could not be detected by conventional protein sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis but could be measured utilizing a sensitive adenylate cyclase activation assay. Thus caution must be used to ensure that any biological effects of the B subunit are not due to contaminating A subunit and are due solely to the binding of the B subunit to ganglioside GM1 exposed on the cell surface. This is especially important in cyclic nucleotide-sensitive systems.

Adenylyl Cyclases↗

PubMed1989

Diagnostic value of ganglioside patterns in plasma of human diseases.

A method that could be facilitated for the quantitation and qualitation of gangliosides in human plasma was developed and applied in the present study for characterization of ganglioside patterns in plasmas of patients with neoplastic diseases including gastric cancer, adult T-cell leukemia (ATL), and acute lymphocytic leukemia (ALL). As a retrovirus-infected disease with different clinical entity, human T-cell lymphotropic virus type I-associated myelopathy (HAM) was also subjected to this study. The results were compared with the patterns obtained from normal control plasmas. The analytical data revealed that GM3 increased in gastric cancer, GT1b decreased in HAM and ATL, and GD3, GM1 and GM3 decreased in ALL. There were close correlations between various human diseases and the presence of gangliosides with their specific patterns. Furthermore, gangliosides purified from plasma of patients with HAM significantly inhibited the expression of CD4 antigen on human T lymphocyte membrane. Therefore, analytical studies of plasma gangliosides could provide diagnostic and therapeutic values in retroviral infections.

Adult↗

PubMed1992

Growth and motility of microvascular endothelium are modulated by the relative concentration of gangliosides in the medium.

The data reported were obtained as an attempt to understand whether the change in total concentration and relative ratios of the 3 major corneal gangliosides (GM3, GM2, GD3) previously observed in corneas stimulated by an angiogenic molecule (Ziche et al., 1989) was a relevant event in the angiogenic response of the tissue. The effect on endothelial cell growth was tested for the 3 corneal gangliosides added singly to the culture medium, and GM3 was found to possess a substantial growth inhibitory effect as compared to GM2 and GD3. The growth-limiting effect of GM3 was counteracted to a different degree by the addition of a second ganglioside to the culture medium. A mixture of GM3 + GM2 + GD3 in the proportion similar to that found in the cornea stimulated by an angiogenic molecule was able to sustain a sharp increment in cell growth and motility when added to cultures of capillary endothelium. On the contrary, when the 3 components of the mixture were in the proportion present in the normal cornea, the increment in growth or motility did not occur. A simple change in the relative proportions of the 3 gangliosides was sufficient to trigger or prevent an increment in growth and motility of the endothelial cells. These data in vitro suggest that the changes in concentration and relative ratios of the 3 major corneal gangliosides observed in vivo when the cornea was stimulated by an angiogenic molecule were an event targeted to favour growth and mobilization of the capillary endothelium located within the limbal vessels at the periphery of the cornea.

Animals↗

PubMed2003

Expression of gangliosides in an immortalized neural progenitor/stem cell line.

Glycosphingolipids (GSLs) are known to play important roles in cellular growth and differentiation in the nervous system. The change in expression of gangliosides is correlated with crucial developmental events and is evolutionarily conserved among many vertebrate species. The emergence of neural progenitors represents a crucial step in neural development, but little is known about the exact composition and subcellular localization of gangliosides in neural progenitor cells. The C17.2 cell line was derived after v-myc transformation of neural progenitor cells isolated from neonatal mouse cerebellar cortex. The developmental potential of C17.2 cells is similar to that of endogenous neural progenitor/stem cells in that they are multipotential and capable of differentiating into all neural cell types. We characterized the GSL composition of C17.2 cells and found the presence of only a-series gangliosides. Subcellular localization studies revealed that GM1 and GD1a are localized mainly on the plasma membrane and partly in the cytoplasm, both as punctate clusters. Reverse transcription-polymerase chain reaction revealed the absence of ST-II transcripts in C17 cells, which most likely accounts for the lack of expression of b- and c-series complex gangliosides in this cell line. These data suggest that the divergence in ganglioside expression in C17.2 cells is regulated at the transcriptional level.

Animals↗

PubMed1984

Biosynthesis of gangliosides in the developing chick embryo retina.

Chick embryo retinas were cultured with [3H]glucosamine on each day between days 6 and 12 of development. The total labeling of gangliosides decreased from day 6 to day 12. The decrease was mostly due to the decrease in the labeling of disialosyllactosylceramide (GD3), which diminished to less than 2%, while the labeling of the disialoganglioside GD1a decreased to about 30%. Labeling of endogenous gangliosides by incubating retina homogenates with CMP-[3H]N-acetylneuraminic acid, in addition to showing a decrease in the labeling of GD3, showed a twofold increase in the labeling of GD1a. The changes in the pattern of labeling correlated with the decrease of both the incorporation of [3H]thymidine into DNA and the activity of CMP-NeuAc:GM3 sialosyltransferase and with the increase of both the activities of UDP-Ga1NAc:GM3 N-acetylgalactosaminyltransferase and choline acetyltransferase. The results suggest that the shift in the pattern of labeling of gangliosides occurs in association with the transition from the proliferative to the nonproliferative state of neuronal cells. Retinas at each age cultured with [3H]glucosamine for 22 hr maintain the radioactivity in gangliosides for at least 4 additional days in culture. This indicates that within this developmental interval there is not a period characterized by having a high turnover rate of gangliosides.

Age Factors↗

PubMed1987

Effect of Purkinje cell loss on cerebellar gangliosides in nervous mutant mice.

The distribution of cerebellar gangliosides was studied in adult (73 +/- 2 days) nervous (nr/nr) mutant mice which lose 50-90% of their Purkinje cells. This neuronal loss is associated with significant reductions in cerebellar weight and ganglioside concentration. The cerebellar dry weights (mg) and the ganglioside concentrations (microgram N-acetylneuraminic acid per 100 mg dry weight) in nr/nr mice and age-matched normal littermates (+/?) are 7.4 +/- 0.3 mg and 13.2 +/- 0.4 mg; and 411.7 +/- 4.8 micrograms and 438.5 +/- 2.1 micrograms, respectively. Abnormalities were also observed for the concentration of certain ganglioside species. Most notably, GT1a is significantly reduced by 42%, and GD3 is significantly increased by 29% in the nr/nr mice compared to the +/? mice. The nr/nr mice also express a slight but significant reduction in GT1b. No ganglioside abnormalities were observed between the nr/nr and +/? mice in cerebral cortex. We previously found reduced cerebellar GT1a content in other mutants that also lose Purkinje cells, i.e., sg/sg, pcd/pcd, and Lc/+. GT1a is not reduced, however, in wv/wv mice that lose mostly granule cells. The findings in nr/nr mice are therefore consistent with our hypothesis that GT1a is enriched in Purkinje cells. GD1a, which is enriched in mature granule cells, is not reduced in the nr/nr mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Glycolipid sialosyltransferase activity in synaptosomes exhibits a product specificity for (2-8)disialosyl lactosyl ceramide (ganglioside GD3).

Intact synaptosomes prepared from 28-day-old rat brains were incubated with CMP-N-acetyl-(14C) neuraminic acid in Krebs-Henseleit buffer in an atmosphere of 95% O2: 5% CO2, at 37 degrees C. The activity of CMP-NANA:ganglioside sialosyltransferase using endogenous acceptors was 0.84 pmoles NANA transferred/mg synaptosomal protein/hr. Analysis of the distribution of labeled sialic acid revealed that GD3 ganglioside (alpha 2----8 disialosyl, alpha 2----3 galactosyl, beta 1----4 glucosyl, beta 1----1-ceramide) was the major product in the membrane carrying 32% of the total lipid bound label. Treatment of the reaction products with Clostridium neuraminidase liberated labeled sialic acid from GD3 and yielded labeled GM3, then unlabeled lactosyl ceramide. Lac-cer and GM3 are present in small amounts in synaptosomes, and GD3 represents less than 2% of the total ganglioside. Our findings indicate that the sialosyltransferase activity of synaptosomes exhibits a preferential product specificity for the small pool of synaptosomal membrane GD3 ganglioside that may be formed in situ, via sialosylation of its precursor (GM3 or lactosyl ceramide) which pre-exists in the synaptosomal plasma membrane. The second major labeled product quantitatively was GD1a whose precursor substrate, GM1, is quite abundant in the membrane, so that the conversion rate of GM1 to GD1a was low in comparison with GD3 formation. Sialosylation of other synaptosomal membrane gangliosides was negligible.

Animals↗

PubMed1989

Ganglioside and lipid composition of bulk-isolated rat and bovine oligodendroglia.

We have examined the ganglioside composition of 30-day and 60-day postnatal rat oligodendroglia, adult bovine oligodendroglia, gray matter, white matter, and myelin and also the total lipid composition of the oligodendroglial preparations. The ganglioside patterns of rat and bovine oligodendroglia, as previously found for human oligodendroglia, were more complex than those of myelin. These data indicate that oligodendroglial perikarya can synthesize many brain type gangliosides, not all of which are incorporated into the compact myelin. Alternatively, the ganglioside composition of myelin may be altered in situ by the myelin-associated neuraminidase. In these two species, as in human, GM4 appears specific to oligodendroglia and myelin, while GD3 and GM3 are enriched in oligodendroglia but not myelin. In bovine oligodendrocytes GD3 is the major ganglioside. The total lipid concentration, as well as the percentage of cholesterol, sphingomyelin, phosphatidylinositol, and phosphatidylserine, differ for 30- and 60-day-old rat oligodendroglia and may be developmentally correlated with changes in myelin composition during myelinogenesis. There are also marked differences in the lipid composition of bovine oligodendroglia compared to rat oligodendroglia, with the former having more galactolipid and less ethanolamine phosphoglycerides.

Animals↗