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PubMed1981

Use of leukocytes in diagnosis of Krabbe disease and detection of carriers.

The optimal conditions for the assay of the cerebroside-beta-galactosidase deficiency in Krabbe disease were studied. Labelled galactosylceramides and lactosylceramides isolated from natural sources were both suitable substrates provided that the lipophilic moieties were identical in labelled and unlabelled portions. Galactosylceramides and lactosylceramides with uniform fatty acid compositions were also tested. The highest specific cerebroside-beta-galactosidase activities were obtained with N-palmitoyl galactosyl- and lactosylceramides. The chromogenic substrate 2-hexadecanoyl-amino-4-nitrophenyl-beta-D-galactopyranoside (HNGal) was shown to be an unreliable substrate requiring large amounts of enzyme protein and giving false normal results. Krabbe disease was diagnosed in 45 patients. With galactosylceramides as substrates the residual cerebroside-beta-galactosidase activity was 7%, with lactosylceramides 8%, and there was no overlap in enzyme activity between the 45 patients and 42 parents. Approximately 50% of the obligate carriers had values within the range for the normal controls, independently of which substrate was used.

Adolescent↗
PubMed1989

Lipid metabolism in Trichuris globulosa (Nematoda).

Adult males and females of Trichuris globulosa, an intestinal nematode parasite of goats, were studied for their lipid composition, capability of incorporation of (Na)-1-14C-acetate into different lipid classes and the activity of certain key enzymes of lipid metabolism. The parasite possesses a large variety of lipids including certain complex lipids. These are phosphatidylcholine (PC), diphosphatidylglycerol (cardiolipin), lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), phosphatidylserine (PS), phosphatidylinositol (PI), plasmalogens (choline + ethanolamine), mono-, di- and triacylglycerols, free and esterified cholesterol, non-esterified fatty acids (NEFA), gangliosides, cerebrosides (glycosyl ceramide) and sulphuric acid esters of cerebrosides (sulphatides). The females contain more lipids than males, particularly the acylglycerols and phospholipids, possibly to meet the energy requirement and structural entities for the daily production of large numbers of eggs. Incorporation studies of labelled substrate, sodium-1-14C acetate demonstrate that the adult female has extremely active mechanisms for biosynthesizing these lipids. Most of the labels are found in PC, PE, SM, acylglycerols, NEFA, gangliosides, cerebrosides and sulphatides. Cholesterol, although a minor component of the parasitic lipids, incorporates large amount of label and also undergoes fast turnover. Kinetic analysis of the incorporation by measuring the rate constant (k) and half life (t1/2) reveals that gangliosides are the fastest biosynthesizing and turning over lipids, although they constitute only 0.1% of the total lipids. The presence of important enzymes of lipid biosynthesis, glucose-6-phosphate dehydrogenase, malate dehydrogenase and hydroxymethyl glutaryl-CoA reductase and an enzyme of lipid ester hydrolysis, triacylglycerol lipase, is also established in T. globulosa. Michaelis-Menten kinetic characteristics of the parasitic enzymes (Km, Vmax, v and the first order rate constant, k) are comparable with those of rat liver homogenates.

Animals↗
PubMed1997

NMR study of the conformation of galactocerebroside in bilayers and solution: galactose reorientation during the metastable-stable gel transition.

Conformations of two types of bovine brain cerebroside containing normal and alpha-hydroxy-fatty acids (NFA-CER and HFA-CER, respectively) in solution and in bilayers were investigated using 1H and 13C NMR in solution and in the solid state. The analysis of vicinal 1H-1H coupling constants and NOE measurements in solution indicated that in both cerebrosides the predominant conformation about the O1-C1, C1-C2, and C2-C3 bonds is ap/-sc/ap, respectively. The remarkable similarity in the 13C NMR chemical shifts in solution and in hydrated liquid-crystalline bilayers indicated that both cerebrosides in bilayers assume conformation essentially identical to those in solution. The obtained 13C NMR spectra in solution were used as a reference for comparison with the variable-temperature 13C CP-MAS NMR spectra in the metastable and stable gel phases. The lack of chemical shift changes of polar carbon atoms upon cooling the HFA-CER bilayers below the Tm strongly suggests that the liquid-crystalline-metastable gel transition is not associated with a conformational change of the head group. The observed line broadening can be interpreted in terms of the hydrocarbon chain crystallization and slow dynamics of the head group in the metastable phase. On the other hand, the relaxation of the metastable gel phase of HFA-CER caused profound changes in the 13C spectra, primarily of the signals of the galactose C1, the ceramide C2, C4, and C5, and the carbonyl group. These changes are interpreted using the known dependence of the chemical shifts of anomeric carbon on the conformation about the O1-C1 bond to suggest that the gel phase relaxation involves a significant reorientation of the galactose moiety caused by a change in the rotation of the O1-C1 bond from the ap to -sc conformer. Similar changes of chemical shifts were observed in the case of NFA-CER during the transition from the liquid-crystalline phase to the stable gel phase.

Animals↗
PubMed1992

Additional biochemical findings in a patient and fetal sibling with a genetic defect in the sphingolipid activator protein (SAP) precursor, prosaposin. Evidence for a deficiency in SAP-1 and for a normal lysosomal neuraminidase.

It has been shown that sphingolipid activator proteins (SAPs) 1 and 2 are encoded on the same gene along with two other putative activator proteins [Fürst, Machleidt & Sandhoff (1988) Biol. Chem. Hoppe-Seyler 369, 317-328 and O'Brien, Kretz, Dewji, Wenger, Esch & Fluharty (1988) Science 241, 1098-1101]. We have undertaken further biochemical investigations on a patient and fetal sibling, who were previously shown to have a unique sphingolipid storage disorder associated with an SAP-2 deficiency [Harzer, Paton, Poulos, Kustermann-Kuhn, Roggendorf, Grisar & Popp (1989) Eur. J. Pediatr. 149, 31-39]. The severity of their disorder suggested that other products of the SAP precursor or prosaposin gene may also be deficient. The turnover of cerebroside sulphate and globotriaosylceramide were investigated and were both impaired in fibroblasts from the patient and fetus. However, the activities of cerebroside sulphate sulphatase and globotriaosylceramide alpha-galactosidase in vitro were normal in cells from the fetus and patient respectively. In addition, there was an increase in cerebroside sulphate concentration in the kidney of the affected fetus. These results indicate that, in addition to the SAP-2 deficiency, there was a defect in SAP-1 function in this disorder. Additional increases in the concentration of monohexosyl- and dihexosyl-ceramide in the fetal kidney probably reflect the deficiency of SAP-2 in the case of monohexosylceramides, and the combined activator deficiency in the case of dihexosylceramides. Lactosylceramide-loading studies confirmed that there was a defect in the turnover of this lipid in fibroblasts from the affected patient and fetus but not from a patient with an isolated SAP-1 deficiency, or from patients with Krabbe disease, GM1 gangliosidosis or galactosialidosis. It has been suggested [Potier, Lamontagne, Michaud & Tranchemontagne (1990) Biochem. Biophys. Res. Commun. 173, 449-456] that the prosaposin gene also codes for lysosomal neuroaminidase. However, we found normal neuraminidase activity in fibroblasts from our patient, using assay conditions which are diagnostic for sialidosis patients. The role of prosaposin gene products in sphingolipid metabolism is discussed in view of our biochemical findings in this genetic disorder.

Cells, Cultured↗
PubMed1990

Biochemical pathogenesis of demyelination in globoid cell leukodystrophy (Krabbe's disease): the effects of psychosine upon oligodendroglial cell culture.

The effects of psychosine on the metabolism of myelin associated glycolipids such as galactocerebroside and sulfatide in mouse brain cell cultures were investigated in order to clarify the mechanism of demyelination in globoid cell leukodystrophy (Krabbe's disease). The incorporation of 3H-galactose into cerebroside and sulfatide was studied in the presence of psychosine (1-3 micrograms/ml medium). These data indicated that psychosine inhibited the incorporation of 3H-galactose into cerebroside and sulfatide not in astroglial cell culture but in oligodendroglial cell culture. Oligodendrocytes produce myelin in the central nervous system, and cerebroside and sulfatide are major components of myelin. These results suggest that psychosine influences the lipid metabolisms of myelin and subsequently leads to the demyelination in Krabbe's disease.

Animals↗
PubMed1981

Neutral glycosphingolipids and ceramide composition of ethylnitrosourea-induced rat neural tumors: accumulation of ceramide in tumors.

Experimental rat neural tumors in offspring were induced transplacentally by a single injection of a chemical carcinogen, ethylnitrosourea, 20 mg/kg body weight, in the tail vein of the mother. The neutral glycosphingolipid, sulfatide, and ceramide composition of the tumors and the normal tissues from which the tumors originated is described. The content of nonhydroxy fatty acid (NFA) and hydroxy fatty acid (HFA) containing ceramide in all the neural tumors so far examined was significantly increased compared with the corresponding normal neural tissue. Some 8 to 18 mol% of total neutral glycolipids was as ceramide in neurinomas, oligodendrogliomas, and meningiomas. Lactosylceramide in normal neural tissues was about 1 mol% of the total neutral glycosphingolipids. In various neural tumors lactosylceramide increased up to 8 mol%. NFA- and HFA-containing cerebrosides constitute 94-100% of the neutral glycosphingolipids in normal neural tissues. In various neural tumors the mol percent of cerebrosides was significantly reduced. A high performance liquid chromatographic method was modified to analyze simultaneously ceramides, cerebrosides, and higher neutral glycosphingolipids.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1993

Lipid and fatty acid composition of brain tissue from adrenoleukodystrophy patients.

White matter and active plaque tissue from adrenoleukodystrophy (ALD) patients were analysed for lipid class and fatty acid compositions and the results compared with white matter from normal brain. ALD white matter was characterised by increased levels of cholesteryl esters and decreased levels of phosphatidylethanolamine, including phosphatidylethanolamine plasmalogen, in comparison with normal brain white matter. In addition to even higher levels of cholesteryl esters, ALD plaque tissue had reduced levels of cerebrosides as well as phosphatidylethanolamines. The loss of phosphatidylethanolamine plasmalogen is indicative of early demyelination. Total lipid from ALD white matter and ALD plaque tissue contained nearly five times and seven times, respectively, more 26:0 than total lipid from normal brain white matter. The 26:0 in ALD white matter was elevated in all lipid classes except phosphatidylinositol, but was located mainly in cerebrosides, phosphatidylcholine, sphingomyelin, and sulfatides. Most of the 26:0 in ALD plaque tissue was present in cholesteryl esters, followed by phosphatidylcholine and sphingomyelin, with reduced amounts in cerebrosides as compared with ALD white matter. The results are consistent with an initial accumulation of very-long-chain fatty acids in ALD white matter, primarily in sphingolipids and phosphatidylcholine, and subsequent accumulation of very-long-chain fatty acids in cholesteryl esters during demyelination. In addition, it was notable that the sphingolipids, especially sphingomyelin in ALD brain, had decreased levels of 24:1 and increased levels of 18:0, as well as increased levels of very-long-chain fatty acids. The extent to which the data shed light on mechanisms of demyelination in ALD is discussed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenoleukodystrophy↗
PubMed1990

Brain damage and recovery in hyperphenylalaninemic rats.

Rats were made hyperphenylalaninemic by injecting a mixture of alpha-methylphenylalanine and phenylalanine. Brain development was measured by biochemical, histological and 31-P nuclear magnetic resonance (NMR) methods. In 17-day-old hyperphenylalaninemic rats, brain myelinogenesis was disturbed. Compared to controls, test animals had lower body weights, brain weights, cerebrosides, sulfatides, myelin basic protein (MBP) and reduced cerebroside sulfotransferase (CST) and 2'3'-cyclic nucleotide-3'-phosphohydrolase (CNP) activities. No changes were found in total proteins, total lipids, total phospholipids, phosphatidylethanolamine and phosphorylethanolamine. In the brain of 17-day-old hyperphenylalaninemic rats no changes in phosphomonoesters, phosphodiester and phosphocreatine were found using in vivo 31-P NMR spectroscopy. Because body weights of hyperphenylalaninemic rats were significantly lower than those of controls, we compared them with undernourished rats. Undernourished rats had lower body weights, brain weights and CNP activity. No other changes were found. Therefore, we conclude that hyperphenylalaninemia per se and not undernutrition affected myelinogenesis in test animals. After treatment was discontinued, test rats recovered completely within 6 weeks with regard to biochemical and histological measurements; at 59 days they had normal body weights, cerebrosides, sulfatides, MBP, total proteins, total lipids, total phospholipids, phosphatidylethanolamine, phosphorylethanolamine and normal CST and CNP activities. Brain weights were significantly reduced.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2002

Isolation and structure determination of six glucocerebrosides from the starfish Luidia maculata.

Two new glucocerebrosides, luidiacerebroside A (2) and B (6), were isolated from the cerebroside molecular species obtained from the less polar fraction of the CHCl3/MeOH extract of the starfish Luidia maculata using HPLC. Four known cerebrosides, CE-2b (1), astrocerebroside B (3), acanthacerebroside B (4), and CE-3-2 (5) have also been isolated and characterized. The structures of these cerebrosides were determined on the basis of chemical and spectroscopic evidence. Mass spectrometry of dimethyl disulfide derivatives was useful for the determination of the double-bond position in the long-chain base.

Animals↗
PubMed2002

[Chemo-pharmaceutical studies on the glycosphingolipid constituents from echinoderm, sea cucumbers, as the medicinal materials].

Glycosphingolipids (GSLs), together with glycopeptides, are typical constitutents of various cell membranes in a wide variety of organisms. In particular, it is known that GSLs have numerous physiological functions due to variations in the sugar chain, in spite of the very small quantity of constituents. Those are classified into cerebrosides, sulfatides, ceramide oligohexosides, globosides, and gangliosides based on the constituent sugars. Gangliosides, sialic acid-containing GSLs, are especially enriched in the brain and nervous tissues and are involved in the regulation of many cellular events. Recently, a number of GSLs have been isolated from marine invertebrates such as echinoderms, poriferans, and mollusks. We have also been researching biologically active GSLs from echinoderms to elucidate the structure-function relationships of GSLs and to develop novel medicinal resources. This review summarizes the structures and biological activities of GSLs from sea cucumbers. This study showed that the characteristics of GSLs and structure-activity relationships had neuritogenic activity toward the rat pheochromocytoma cell line PC12. That is, most of the cerebroside constituents of the sea cucumber are same glucocerebrosides as in other animals, except for some constituents, while the ganglioside constituents were unique in that a sialic acid directly binds to the glucose of cerebroside, they are mutually connected in tandem, and some are located in the internal parts of the sugar chain. It also became apparent that sialic acid is indispensable for the neuritogenic activities.

Animals↗
PubMedDate not supplied

[Metabolism of glycolipids in the rat brain during acute and chronic ethanol administration].

Increase in content of sulfatides I and II and a decrease in cerebrosides was found in brain of rats after acute alcoholization with 25% ethanol, 4 g/kg, intragastric administration. In this case incorporation of 1,2-14C-ethanol into cerebrosides II and III was decreased. Content of sulfatides I was increased, while specific radioactivity of cerebrosides III--decreased as a result of chronic alcohol intoxication (25% ethanol, intragastric administration, 7 g/kg daily within 21 days).

Alcoholic Intoxication↗
PubMed1981

Genetic control of developmental patterns of cerebral enzyme activities: further differences between C3H and ICR strains of mice.

We have investigated developmental changes in activity for five enzymes associated with different cerebral metabolic systems in two separate strains of mice. The enzymes studied were acid beta-galactosidase, arylsulfatase A, cerebroside beta-galactosidase, cerebroside sulfotransferase, and glutamate decarboxylase. The two strains of mice were C3H/SWV and ICR/SWV. We confirm the experiments of Meisler, Paigen, and colleagues showing higher acid beta-galactosidase activity throughout development in C3H mice. In addition we have demonstrated higher arylsulfatase A activity throughout development in C3H mice. The shape of the developmental curve for arylsulfatase A activity in brain in the two strains was similar. There were no differences in developmental changes of activity between the two strains for the other three enzymes studied.

Animals↗
PubMed1980

Developmental dissociation of myelin synthesis and "myelin-associated" enzyme activities in the shiverer mouse.

Developmental changes in three enzymes associated with myelin lipids were studied in the shiverer mouse, a murine mutant showing a severe deficiency of CNS myelin. Age-related changes in cerebroside sulfotransferase (measured in brain) and arylsulfatase A and cerebroside B-galactosidase (measured in brain and liver) were the same for shiverer and control mice. The shiverer mouse, therefore, demonstrates a dissociation between the genetic mechanisms regulating myelination in the CNS and developmental changes in enzyme activities thought to be closely related to the synthesis of myelin. In addition, we found no defect in the shiverer mouse in the incorporation of glycine-labeled basic protein into CNS myelin, indicating an important metabolic difference between the morphologically similar shiverer and quaking mutants.

Aging↗
PubMed1979

Sulphatase A: an arylsulphatase and a glycosulphatase.

Sulphatase A was first described as an arylsulphatase but was subsequently shown to have cerebroside sulphatase activity, bydrolysing galactose 3-sulphate residues in certain lipids. A characteristic feature of the arylsulphatase activity is the substrate-induced inactivation of the enzyme which occurs during the catalytic reaction. Present views of the course of this modification are considered. A similar modification of the enzyme does not occur during the cerebroside sulphatase reaction and the fall in velocity noted during most such assays can be explained by disappearance of substrate and accumulation of sulphate. Possible reasons for the difference between the two types of activity are considered. Sulphatase A also hydrolyses hexose sulphates at rates comparable to those of aryl sulphates. The specificity of sulphatase A towards its natural substrates, sulpholipids, is considered in the light of these findings.

Animals↗
PubMed1986

Type 2 and type 3 Gaucher disease: a morphological and biochemical study.

Glucocerebroside levels were measured in the brains of patients with neuronopathic forms (types 2 and 3) of Gaucher disease and compared to those obtained from control brain. Nine separate brain regions (frontal, temporal, occipital, and cerebellar cortices; thalamus; corpus striatum; pons; medulla; and dentate nuclei) were analyzed. In all the Gaucher brains studied, the greatest glucocerebroside accumulation occurred within the occipital cortex, with lesser amounts in the temporal and frontal areas. The cerebellar cortex, corpus striatum, and thalamus in Gaucher brains had mildly increased levels of glucocerebroside, especially when the values were expressed as a percentage of total non-hydroxy fatty-acid cerebroside. Brainstem structures (pons and medulla) and dentate nuclei did not have increased glucocerebroside levels when compared to levels from similar control areas. However, when glucocerebroside concentration was expressed as a percentage of total non-hydroxy fatty-acid cerebroside, the type 2 Gaucher brainstem structures did show a slight increase in glucocerebroside levels over control levels. Neuropathological studies demonstrated the presence of Gaucher cells, gliosis, and microglial nodules within the type 2 brains. The neuropathological findings correlated with the glucocerebroside accumulation in the type 2 brains. Despite the similar pattern of glucocerebroside accumulation in the type 3 brain, no neuropathological abnormalities were seen. Thus, this study demonstrated that within several brain regions, both neuronopathic forms of Gaucher disease have elevated glucocerebroside levels, and that in the type 2 brains, the glucocerebroside accumulation correlated positively with the neuropathological findings.

Brain↗
PubMed1994

Molecular genetics of metachromatic leukodystrophy.

Metachromatic leukodystrophy is an autosomal recessive inherited lysosomal storage disease. It can be caused by mutations in two different genes, the arylsulfatase A and the prosaposin gene. These genes encode two proteins that are needed for the proper degradation of cerebroside sulfate, a glycolipid mainly found in the myelin membranes. Deficiency of arylsulfatase A or of a proteolytic product of prosaposin leads to the accumulation of cerebroside sulfate, which causes a lethal progressive demyelination. Mutations in the arylsulfatase A gene are far more frequent than those of the prosaposin gene. So far 31 amino acid substitutions, one nonsense mutation, three small deletions, three splice donor site mutations, and one combined missense/splice donor site mutation have been identified in the arylsulfatase A gene. Two of these mutant alleles are frequent, accounting for about one-half of all mutant alleles, whereas the remainder are heterogeneous. Amino acid substitutions cluster in exons 2 and 3, a region that shows a high degree of conservation among sulfatases of different function and origin. Different mutations are associated with phenotypes of different severity, but there is a remarkable variability of severity when patients with identical genotypes are compared. Demonstration of an arylsulfatase A deficiency is not a proof of metachromatic leukodystrophy, since a substantial deficiency without any clinical consequences is frequent in the general population. This deficiency is caused by an arylsulfatase A allele, which due to certain mutations encodes greatly reduced amounts of functional enzyme. However, these amounts are sufficient to sustain a normal phenotype. In the diagnosis and genetic counseling, these deficiencies must be differentiated from those causing metachromatic leukodystrophy. So far only six patients with mutations in the prosaposin gene have been described, in which three defective alleles two with amino acid substitutions and one with a 33-bp insertion have been identified.

Cerebroside-Sulfatase↗
PubMed1985

Purification and characterization of cultures of oligodendroglia from rat brain.

It is possible to purify small dark cells from rat brain which by ultrastructural criteria are oligodendroglia. The modified technique involves the use of an isolation medium less damaging to the initial cell suspension and then differential plating of a stratified primary cell culture obtained from 1-3-day-old rat brain which has been described. Five percent serum encourages the growth of oligodendroglia. In this system, the oligodendroglia can be harvested several times from the primary cultures. To retain the homogeneous populations of oligodendroglia, it is necessary to constantly manipulate the cultures by hitting the flasks and replating the suspended cells. Electron microscopy reveals that the small dark cells are differentiated oligodendroglia with prominent microtubules. Immunofluorescence staining of the cells shows that the majority of the cells are negative for known surface markers which include cerebrosides and 04 antigen (markers for oligodendroglia), glial fibrillary acidic protein, and fibronectin. Interestingly, it is possible to increase the number of 04-positive cells by the addition of dibutyryl cyclic AMP to the medium. Rat oligodendroglia are able to incorporate about 20% of the radioactivity into cerebrosides, using the substrate, [3H]galactose; this is a biochemical feature unique to oligodendroglia. The expression of all the oligodendroglial antigens should be remarkably enhanced when the cells are induced to produce myelin.

Animals↗
PubMed1998

A mushroom fruiting body-inducing substance inhibits activities of replicative DNA polymerases.

We found and isolated two natural products in the extract from a basidiomycete, Ganoderma lucidum, as eukaryotic DNA polymerase inhibitors. The compounds were identified as cerebrosides, (4E,8E)-N-D-2'-hydroxypalmitoyl- 1-O-beta-D-glucopyranosyl-9-methyl-4,8-sphingadienine and (4E,8E)-N-D-2'-hydroxystearoyl-1-O-beta-D-glucopyranos yl-9-methyl- 4,8-sphingadienine and were found to be identical to the mushroom fruiting body-inducing substances (FIS) reported. These cerebrosides selectively inhibited the activities of replicative DNA polymerases, especially the alpha-type, from phylogenetically broad eukaryotic species, whereas they hardly influenced the activities of DNA polymerase beta, prokaryotic DNA polymerases, terminal deoxynucleotidyl transferase, HIV reverse transcriptase, RNA polymerase, deoxyribonuclease I, and ATPase. The inhibition of another replicative polymerase, the delta-type, was moderate. The inhibitions of the replicative polymerases were dose-dependent, and the IC50 for animal or mushroom DNA polymerase alpha was achieved at approximately 12 micrograms/ml (16.2 microM) and for animal DNA polymerase delta at 57 micrograms/ml (77.2 microM). FIS is possibly a DNA polymerase inhibitor specific to the replicative enzyme group, and the fruiting body formation may be required for the suppression of the DNA replication or the vegetative growth of the mycelium.

Animals↗