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PubMed1989

Characterization and regional distribution of individual gangliosides in goldfish central nervous system.

Gangliosides were partially purified from goldfish brain and fractionated by DEAE Fractogel column chromatography. Each fraction was then analyzed by HPTLC and also by HPLC after conversion of the gangliosides to 2,4-dinitrophenylhydrazides. The tetrasialoganglioside GQ1c was found to constitute more than 50% of the total gangliosides. Gangliosides in smaller quantities were also tentatively identified. These included GT1b, GT1c, GT2, GT3, GD1a, and several others. By using this information, the amounts of individual gangliosides in various regions of goldfish central nervous system were compared. Although all areas of brain examined contained similar concentrations of gangliosides, with GQ1c as the predominant component, retina and optic nerve contained significantly lower concentrations of GQ1c, and GM3 was the major component.

Animals↗
PubMed1989

Confirmation of the cholinergic specificity of the Chol-1 gangliosides in mammalian brain using affinity-purified antisera and lesions affecting the cholinergic input to the hippocampus.

An antiserum raised to Torpedo electromotor synaptosomal membranes (anti-TSM antiserum) induces a cholinergic-specific immune lysis of mammalian brain synaptosomes and recognizes a group of minor gangliosides appeared, therefore, to be specific to the cholinergic neuron and were designated Chol-1. To confirm the cholinergic specificity of the Chol-1 gangliosidic antigens, we have shown that not only does a mammalian ganglioside fraction that is enriched with respect to the Chol-1 gangliosides inhibit the cholinergic-specific immune lysis induced by the anti-TSM antiserum, but also it can be used to affinity-purify a subpopulation of immunoglobulins from the anti-TSM antiserum that also induce a cholinergic-specific lysis. Furthermore, we have demonstrated that fimbrial lesions, which cause a massive degeneration of cholinergic terminals in the ipsilateral hippocampus, lead to a loss of the Chol-1 gangliosides concomitant with that shown by choline acetyltransferase activity and that lesions to the entorhinal cortex, which cause a loss of mainly glutamergic synapses in the ipsilateral dentate gyrus leading to cholinergic sprouting from adjacent hippocampal areas and an increase in cholinergic markers in the dentate gyrus, produce concomitant increases in choline acetyltransferase activity and Chol-1 content. These results provide strong evidence in favour of the cholinergic specificity of the Chol-1 gangliosides.

Animals↗
PubMed1990

Ganglioside-modulated proteolysis by Ca2(+)-activated neutral proteinase (CANP): a role of glycoconjugates in CANP regulation.

We examined ganglioside modulation of the activity of the millimolar Ca2(+)-sensitive form (mCANP) of calcium-activated neutral proteinase (CANP), which is enriched in myelin, from brain. GM1, GD1a, GT1a, GM2, and GM4 produced a concentration-dependent increase of mCANP activity. GD1a stimulated the greatest increase of enzyme activity (107%), followed by GT1a, whereas GD1b was inhibitory (56%). GM1, GM2, and GM4 stimulated but less so than GD1a and GT1a. Free N-acetylneuraminic acid, asialo-GM1, GM3, and a ganglioside mixture containing GM1, GD3, GD1a, and GD1b had no effect. The ganglioside-mediated modulation was not affected by trifluoperazine and chlorpromazine (phospholipid-binding antagonists). The mCANP Ca2+ requirement was significantly reduced in the presence of stimulatory gangliosides, and this increased sensitivity varied (10-50-fold) with ganglioside structure. Gangliosides may interact with membrane mCANP and modulate its proteolytic action.

Animals↗
PubMed1990

Determination of gangliosides in six human primary medulloblastomas.

The ganglioside composition of six human medulloblastomas was analyzed. The characterization was performed by thin-layer chromatography, sialidase hydrolysis, and immunological staining with a panel of characterized antiganglioside monoclonal antibodies. The total ganglioside content ranged from 60 to 1,130 nmol of ganglioside sialic acid/g wet weight. Neuronal gangliosides (gangliotetraose series) were found in varying amounts in all medulloblastomas. Gangliosides of the neolactotetraose series (3'-LM1 and LD1) were present in all specimens, and the lactotetraose series ganglioside 3'-isoLM1 was found in all cases showing astrocytic differentiation. This supports our previous findings that 3'-isoLM1 is a marker for proliferating astroglial cells.

Adolescent↗
PubMed1990

Different ceramide compositions of gangliosides between human motor and sensory nerves.

Ganglioside analysis of human motor and sensory nerves revealed that ceramide compositions of sensory nerve GD1a, GD1b, and GM1 differed apparently from those in the motor nerve. These gangliosides from sensory nerve contained a large amount of long-chain fatty acids and d18:1 as a major long chain base. On the contrary, the motor nerve gangliosides contained C16-18 fatty acids and a large amount of d20:1 besides d18:1. Furthermore, these gangliosides were enriched more in the axon fraction than in the myelin fraction. LM1, which was a major ganglioside in myelin from human peripheral nerve, was composed of similar ceramide compositions in the two nerves. The present findings suggest that the characteristic ceramide species of nerve gangliosides may reflect in part properties of their own neurons.

Axons↗
PubMed1990

Regulation of Ca2+/calmodulin-dependent protein kinase II by brain gangliosides.

Purified rat brain Ca2+/calmodulin-dependent protein kinase II (CaM-kinase II) is stimulated by brain gangliosides to a level of about 30% the activity obtained in the presence of Ca2+/calmodulin (CaM). Of the various gangliosides tested, GT1b was the most potent, giving half-maximal activation at 25 microM. Gangliosides GD1a and GM1 also gave activation, but asialo-GM1 was without effect. Activation was rapid and did not require calcium. The same gangliosides also stimulated the autophosphorylation of CaM-kinase II on serine residues, but did not produce the Ca2+-independent form of the kinase. Ganglioside stimulation of CaM-kinase II was also present in rat brain synaptic membrane fractions. Higher concentrations (125-250 microM) of GT1b, GD1a, and GM1 also inhibited CaM-kinase II activity. This inhibition appears to be substrate-directed, as the extent of inhibition is very dependent on the substrate used. The molecular mechanism of the stimulatory effect of gangliosides was further investigated using a synthetic peptide (CaMK 281-309), which contains the CaM-binding, inhibitory, and autophosphorylation domains of CaM-kinase II. Using purified brain CaM-kinase II in which these regulatory domains were removed by limited proteolysis. CaMK 281-309 strongly inhibited kinase activity (IC50 = 0.2 microM). GT1b completely reversed this inhibition, but did not stimulate phosphorylation of the peptide on threonine-286. These results demonstrate that GT1b can partially mimic the effects of Ca2+/CaM on native CaM-kinase II and on peptide CaMK 281-309.

Animals↗
PubMed1990

Changes in the ceramide composition of rat forebrain gangliosides with age.

Five major gangliosides (GM1, GD1a, GD1b, GT1b, and GQ1b) were extracted and isolated by normal-phase HPLC from the forebrain of Sprague-Dawley rats of ages ranging from 3 days to 24 months. Each ganglioside was fractionated by reverse-phase HPLC into the molecular species carrying a single long-chain base moiety. At all ages, the C18:1 and C20:1 long-chain base species predominated, whereas the C18:0 and C20:0 ones represented 1-3% of the total. The C18:1 long-chain base species, predominant at 3 days (91-96%), diminished with age and reached, at 2 years, 73%, 65%, 61%, 59%, and 45% of the total for GD1a, GM1, GT1b, GD1b, and GQ1b, respectively. The content of the C20:1 long-chain base species, low at birth (4-9%), increased with age in all gangliosides and reached, at 2 years, 27-55% of the total. The developmental behavior of the ganglioside species containing the C18:1 long-chain base was characterized by the following: (a) a biphasic profile with a maximum around 15 days for GD1a, the most abundant ganglioside at all ages; (b) an increase until 6 months for GM1; (c) a sharp decrease until 30 days, followed by leveling for GT1b; and (d) a low, constant level for GD1b and GQ1b. All the ganglioside species containing the C20:1 long-chain base showed a constant increase during development, the increase being more marked in the first 30 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

Alteration of neuroblastoma ganglioside metabolism by retinoic acid.

Cellular differentiation is often associated with striking changes in ganglioside metabolism. Because retinoic acid causes cellular differentiation in vitro, we have characterized its effect on ganglioside synthesis and shedding by LAN-5 human neuroblastoma cells. Three major observations were made: (a) 20 microM retinoic acid caused a marked (twofold) increase in cellular ganglioside content, with a slight relative enhancement in GD1a and GT1b synthesis, (b) ganglioside shedding increased in parallel with increased cellular ganglioside content, and also, unexpectedly, (c) retinoic acid caused a quantitatively similar increase in content of cell membrane phospholipids, which are also shed. We conclude that enhanced ganglioside synthesis and shedding by retinoic acid are part of a previously undescribed generalized stimulatory effect on membrane lipid metabolism.

Chromatography, Thin Layer↗
PubMed1993

Expression of gangliosides GD3 and 3'-isoLM1 in autopsy brains from patients with malignant tumors.

Three autopsy brains from patients who succumbed to malignant gliomas have been analyzed in various regions with regard to their ganglioside content. The study focused on the gangliosides GD3 and 3'-isoLM1, which in a previous study of biopsies were found to be associated with these tumors. In particular, 3'-isoLM1, was suggested to be a marker for malignant gliomas. The highest concentrations (200-1,000 nmol of sialic acid/g wet weight) of GD3 was found in specimens of macroscopically pure tumor, where the proportion of GD3 was, at the most, 78% (range, 11-78%) of the total ganglioside sialic acid compared with < 10% in normal brain tissue. The proportion of the total ganglioside sialic acid made up by GD3 was also elevated in the periphery of the tumor and in the same region in the opposite hemisphere, where no tumor cells were detected. In four of eight brain metastases of various carcinomas, GD3 was > 10% of the total ganglioside sialic acid (range, 3-37%). The ganglioside 3'-isoLM1, as determined by TLC-enzyme-linked immunosorbent assay using a specific monoclonal antibody (SL-50), was not present at detectable levels in any of the macroscopically homogenous tumor areas. It was, however, found in the periphery of the tumor, in the corpus callosum, and at highest concentrations in the region of the opposite hemisphere corresponding to the tumor. The concentration varied between 0.1 and 6.0 nmol/g wet weight of tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1985

Gangliosides in axolemmal and synaptic membrane fractions from developing rats: effects of maternal ethanol consumption on offspring.

Previous work from this laboratory has shown that in utero exposure to ethanol significantly alters the synthesis of glycoproteins in synaptic, axolemmal, and myelin membranes from developing rats. In an attempt to determine whether in utero exposure to ethanol similarly alters the synthesis of other glycoconjugates involved with cell-cell interactions, the present study examined the influence of chronic maternal ethanol consumption prior to parturition on the content and synthesis of gangliosides in axolemmal and synaptic plasma membranes from developing rats. The results demonstrate that, in contrast to central nervous system glycoproteins, synaptic and axolemmal glycolipids are minimally affected by in utero exposure to ethanol. At all ages examined (17 to 34 days of age), the offspring of control and ethanol-treated rats had a comparable distribution of radiolabel among synaptic and axolemmal gangliosides, a normal concentration of ganglioside sialic acid in synaptic plasma membranes, and a near-normal distribution of sialic acid among synaptic gangliosides. The present study provides evidence which indicates that the radiolabeling patterns of axolemmal and synaptic membrane gangliosides are similar. Specifically, the most heavily labeled synaptic and axolemmal gangliosides were GT1b (20-37% of the total radioactivity) and GD1a (20-32%). A smaller proportion of radioactivity was associated with GD1b (approximately 11-16%), GM1 (5-10%), and GQ1b (4-11%), as well as with GD3 and the other monosialogangliosides (less than 5%). During the age period examined the proportion of radioactive GT1b increased in both membrane fractions.

Animals↗
PubMed1993

Role of gangliosides in behavioral and biochemical actions of alcohol: cell membrane structure and function.

Alcohol exerts its pharmacological effects in adult brain by altering the physicochemical properties of cellular plasma membranes. Although alcohol does induce changes in membrane lipid composition, studies to relate these alterations to the development of behavioral tolerance to alcohol and the withdrawal effects have been unsuccessful. Actions of alcohol on developing brain are even more complex. Some of the reported effects include inhibition of embryogenesis, cell migration, and differentiation, including synaptogenesis. Gangliosides have neuroprotective action against a variety of neural insults (e.g., mechanical injury, drug toxicity, or hypoxic insult). This review addresses the role and significance of gangliosides in the CNS pathophysiology of alcohol exposure, as well as the effect of changes in endogenous gangliosides on membrane structure and function. We also describe the role of exogenous gangliosides in prevention of alcohol (acute and/or chronic)-induced CNS (prenatal and postnatal) neurotoxicity through their action on cellular plasma membranes. We propose that ganglioside's neuroprotective effects against alcohol neurotoxicity involve protection and restoration of plasma membrane structure (proteins and lipids) and thereby its function (ionic homeostasis, neurotransmitter receptor-mediated signal transduction). Thus gangliosides may have potential therapeutic use in treatment of alcohol-related problems.

Alcoholism↗
PubMed1976

Inactivation of the biological activities of the thermostable direct hemolysin of Vibrio parahaemolyticus by ganglioside Gt1.

Biological activities of the thermostable direct hemolysin produced by Vibrio parahaemolyticus, such as its hemolytic activity and lethal activity, were inhibited by neuraminidase-sensitive gangliosides, of which GT1 ganglioside was the most inhibitory. Neuraminidase-resistant gangliosides did not affect the activities of the hemolysin. Results showed that horse erythrocytes, which are resistant to the hemolysin, do not contain the neuraminidase-sensitive gangliosides GT1 and GD1a. Therefore, we propose that neuraminidase-sensitive gangliosides, and especially GT1 ganglioside, may be the receptor sites on the membranes for the thermostable direct hemolysin of V. parahaemolyticus.

Binding Sites, Antibody↗
PubMedDate not supplied

Brain gangliosides during the life span (embryogenesis to senescence) of the rat.

The concentration of gangliosides, sialoglycoproteins and proteins was studied in the whole brains and single brain structures (cortex, olfactory bulb, corpora quadrigemina region equals midbrain, cerebellum, thalamic region and oblongated medulla) of female rats from 14 developmental stages ranging from day 8 of gestation to more than 3 years of age. The content of protein- and ganglioside-bound neuraminic acid showed a peak at 3 weeks of age and then decreased with aging, whereas that of proteins increased until senescence. All over the life span the developmental profiles of 12 individual gangliosides in the different brain structures (cortex, corpora quadrigemina region approximately midbrain, cerebellum, thalamic region, medulla) and in whole brain samples were followed. There are distinct differences between the brain structures. Additionally each brain region is characterized by specific developmental ganglioside profiles. However, some ganglioside changes are common to all regions: GD3 in general is a marker for cell division and migration, whereas the polar ganglioside fractions GQ1b and GP1 are characteristic for nerve cell sprouting and arborization. Especially in the cortex GD1a seems to be the marker for synaptogenesis and GM1 and GM4 for myelination. The results were discussed in view of the main morphological patterns of differentiation.

Age Factors↗
PubMed1996

Comparison of content and distribution of human milk gangliosides from Spanish and Panamanian mothers.

The lactational changes in content and distribution of gangliosides in human milk from Spanish and Panamanian mothers delivering term newborns were studied. There were no statistically significant differences in the concentration of gangliosides between Spanish and Panamanian milk. The ganglioside content expressed as a function of total milk lipids tended to decrease as lactation progressed in both types of milk. There was a significant correlation (r = 0.5896; p = 0.0062) between ganglioside and total lipid contents in Panamanian milk. However, in Spanish milk, the correlation was not significant (r = 0.1516; p = 0.3439). We did not detect important differences in the relative concentrations of individual gangliosides during lactation among milk samples from Spanish and Panamanian mothers. For both of them, GD3 was the most abundant ganglioside in colostrum, whilst in mature milk it was GM3.

Adult↗
PubMed1983

Changes in the concentration and composition of human brain gangliosides with aging.

Ganglioside content and composition were studied in whole brains from 9 neurologically normal male individuals ranging from 25 to 85 years in age. The content of ganglioside-bound sialic acid decreased from 1,070 to 380 micrograms/g fresh tissue at 85 years. Ten individual ganglioside fractions were identified on high-performance thin-layer chromatography, seven of which were quantified. With age, ganglioside composition shifted to a more polar pattern due to an increase in the relative concentration of the more polar fractions GQ1b, GT1b and GD1b and a decrease in GD1a and GM1. Except for GQ1b, the absolute concentration of all gangliosides decreased with age. All changes were more pronounced in younger ages. Results are discussed in relation to structural changes occurring in the aging brain, and the involvement of gangliosides is suggested.

Adult↗
PubMed2004

The crucial role of Campylobacter jejuni genes in anti-ganglioside antibody induction in Guillain-Barre syndrome.

Molecular mimicry of Campylobacter jejuni lipo-oligosaccharides (LOS) with gangliosides in nervous tissue is considered to induce cross-reactive antibodies that lead to Guillain-Barre syndrome (GBS), an acute polyneuropathy. To determine whether specific bacterial genes are crucial for the biosynthesis of ganglioside-like structures and the induction of anti-ganglioside antibodies, we characterized the C. jejuni LOS biosynthesis gene locus in GBS-associated and control strains. We demonstrated that specific types of the LOS biosynthesis gene locus are associated with GBS and with the expression of ganglioside-mimicking structures. Campylobacter knockout mutants of 2 potential GBS marker genes, both involved in LOS sialylation, expressed truncated LOS structures without sialic acid, showed reduced reactivity with GBS patient serum, and failed to induce an anti-ganglioside antibody response in mice. We demonstrate, for the first time, to our knowledge, that specific bacterial genes are crucial for the induction of anti-ganglioside antibodies.

Animals↗
PubMed1999

Monoclonal antibodies raised against Guillain-Barré syndrome-associated Campylobacter jejuni lipopolysaccharides react with neuronal gangliosides and paralyze muscle-nerve preparations.

Guillain-Barré syndrome and its variant, Miller-Fisher syndrome, are acute, postinfectious, autoimmune neuropathies that frequently follow Campylobacter jejuni enteritis. The pathogenesis is believed to involve molecular mimicry between sialylated epitopes on C. jejuni LPSs and neural gangliosides. More than 90% of Miller-Fisher syndrome cases have serum anti-GQ1b and anti-GT1a ganglioside antibodies that may also react with other disialylated gangliosides including GD3 and GD1b. Structural studies on LPS from neuropathy-associated C. jejuni strains have revealed GT1a-like and GD3-like core oligosaccharides. To determine whether this structural mimicry results in pathogenic autoantibodies, we immunized mice with GT1a/GD3-like C. jejuni LPS and then cloned mAb's that reacted with both the immunizing LPS and GQ1b/GT1a/GD3 gangliosides. Immunohistology demonstrated antibody binding to ganglioside-rich sites including motor nerve terminals. In ex vivo electrophysiological studies of nerve terminal function, application of antibodies either ex vivo or in vivo via passive immunization induced massive quantal release of acetylcholine, followed by neurotransmission block. This effect was complement-dependent and associated with extensive deposits of IgM and C3c at nerve terminals. These data provide strong support for the molecular mimicry hypothesis as a mechanism for the induction of cross-reactive pathogenic anti-ganglioside/LPS antibodies in postinfectious neuropathies.

Animals↗
PubMed2004

Increased concentration of GM1-ganglioside in cerebrospinal fluid in dogs with GM1- and GM2-gangliosidoses and its clinical application for diagnosis.

GM1- and GM2-gangliosidoses are lethal lysosomal diseases that are caused by a defect of acid hydrolases, resulting in the intralysosomal accumulation of the specific physiological substrates, GM1- and GM2-gangliosides, respectively. In the present study a method for the diagnosis of canine GM1-gangliosidosis was established using canine cerebrospinal fluid (CSF). The concentration of GM1-ganglioside in CSF was determined by thin-layer chromatography-enzyme immunostaining using biotin-conjugated cholera toxin B, which specifically binds with GM1-ganglioside. The concentration of CSF GM1-ganglioside was increased in Shiba dogs with GM1-gangliosidosis, and the increased level was approximately proportional to the age of the dogs. The concentration was high in the affected dog even at 5 months of age, when Shiba dogs with GM1-gangliosidosis first manifest neurologic signs. In addition, the concentration of CSF GM1-ganglioside in a dog with the GM2-gangliosidosis 0 variant (Sandhoff disease) was also 7 times the normal level. From these results it was concluded that this laboratory technique enables a definitive and early diagnosis of canine GM1-gangliosidosis even if tissues and organs cannot be obtained. However, because GM1-ganglioside can also be elevated in cases of GM2-gangliosidosis, it is necessary to assay for specific enzyme deficiencies to definitively separate GM1- from GM2-gangliosidosis.

Animals↗