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PubMedDate not supplied

A study on enzyme activities of some sphingolipidoses.

Enzyme activities were determined in fibroblast cell cultures of eight patients suspected of having a type of sphingolipidosis. The patients were 0 to 4 years of age; four were female and four were male. Thirteen age-matched controls were also included in the study. In one of the cases, hexosaminidase A activity was found to be 0% (43-82%), while in two other cases beta-galactosidase activity was found to be 5 nmol/h/mg protein (100-1035 nmol/h/mg protein) and arylsulfatase activity was found to be 12 nmol/h/mg protein (106-990 nmol/h/mg protein), respectively. Two more enzymes, alpha-galactosidase (11-39 nmol/h/mg protein) and cerebroside beta-galactosidase (3.7-6.9 nmol/h/mg protein), were also evaluated but were found to be in the normal ranges in these patients. Therefore, these patients were considered to have Tay-Sachs disease, GM1 gangliosidosis and metachromatic leukodystrophy, respectively. The remaining five patients were normal in respect to the five enzyme activities determined. For the prenatal diagnosis of metachromatic leukodystrophy, arylsulfatase A activity was determined in one amniotic cell culture. The activity found in this case was lower than normal (34 nmol/h/mg protein versus 387 nmol/h/mg protein found in three control amniotic cell cultures.

Amniotic Fluid↗
PubMed1978

Dysmyelination revisited.

Dysmyelination describes an inborn error of metabolism affecting myelinogenesis that causes it to be abnormal, arrested, or delayed. Abiotrophy or myelin as defined by Gowers, due to metabolic failure of the myelin maintenance system, is yet another feature of dysmyelination. In addition to the leukodystrophies, genetically determined conditions such as infantile amaurotic idiocy, hematosidosis, Niemann-Pick's disease and several of the aminoacidopathies are examples of dysmyelinating diseases. In order to reconcile morphological and neurochemical data in these conditions, it is necessary to reexamine a number of pathogenetic hypotheses based on known enzymatic deficiencies, and the interpretation of fragmentary biochemical analyses. The obligatory role of the neuron and axon in myelin formation and maintenance is reviewed. The hypothesis is advanced that gangliosides and their degradative products constitue precursors for the synthesis of the characteristic myelin sphingolipids cerebrosides, sulfatides, and sphingomyelin. Alterations in axoplasmic flow and of ganglioside metabolism must be condidered as important factors in the pathogenesis of dysmyelination.

Axons↗
PubMed1996

Regulation of brain m calpain Ca2+ sensitivity by mixtures of membrane lipids: activation at intracellular Ca2+ level.

Combinations of certain phospholipids and gangliosides increase the specific activity of m calpain and can activate m calpain at 1 to 10 microM Ca2+ concentration. However, this level of calcium is still greater than the normal intracellular calcium level. We have used combinations of lipids to demonstrate the m calpain activity at the physiological Ca2+ level. GD1a (100 microM) and cerebroside (Cerb; 750 microM; 1:7.5) mixture was the most effective. At 0.5 microM to 1.0 microM Ca2+ concentrations, 15-20% of the maximal activity was detected for the purified myelin and cytosolic m calpains. Other combinations were GD1a (100 microM), GM1 (100 microM), Cerb (750 microM), sulfatide (Sulf; 750 microM), and phosphatidylinositol (PI; 300 microM) at a ratio of 1:1: 7.5:7.5:3, respectively. These lipid mixtures stimulated calpain activity at three- to tenfold less calcium concentration than control. The other mixtures, including GD1a:Sulf (1:9) > GD1a:PI (1:4) > PI:Sulf (1:5) > Cerb:Sulf (1:5) and PI:Cerb (1:2.5), also stimulated calpain activity at 1.0 microM Ca2+ concentration. Triton X-100, oxidized glutathione (GSSG), and calpain activator did not affect the Ca2+ requirement. Liposomes containing GD1a, Cerb, and m calpain also showed recognizable calpain activity at a significantly reduced Ca2+ concentration (0.4 microM), confirming the glycolipid-mediated enzyme modulation. These studies indicate that specific lipid mixtures can stimulate m calpain activity at an intracellular level of Ca2+.

Animals↗
PubMed2000

Filopodial behavior is dependent on the phosphorylation state of neuronal growth cones.

Several lines of evidence suggest that phosphorylation events play an important role in transducing neurite outgrowth signals. Here we tested if such phosphorylation events altered filopodial dynamics on neuronal growth cones and thereby might affect pathfinding decisions. The general protein kinase inhibitor K252a caused an increase in the overall length of filopodia, thereby increasing the action radius of a growth cone. Application of specific kinase inhibitors demonstrated that myosin light chain kinase, Ca/calmodulin-dependent kinase II, and protein kinase A were likely not involved in this filopodial response. Inhibition of protein kinase C (PKC) with calphostin C or cerebroside, however, induced filopodial elongation similar to that seen with K252a. Activation of PKC with the phorbol ester PMA produced the opposite effect, namely filopodial shortening. Consistent with this finding, the protein phosphatase activator C(2)-ceramide resulted in a significant increase in filopodial length, whereas application of the protein phosphatase inhibitor okadaic acid caused the opposite effect, filopodial shortening. Lastly, the tyrosine kinase inhibitor genistein also caused filopodial elongation, and this effect could be negated by the tyrosine phosphatase inhibitor sodium ortho-vanadate. Using the calcium indicator fura-2, we further showed that these drugs did not cause a measurable change in the free intracellular calcium concentration ([Ca(2+)](i)) in growth cones. Taken together, these results suggest that the action radius of a growth cone and its resulting pathfinding abilities could be rapidly altered by contact with extracellular cues, leading to changes in the activity of protein kinases and phosphatases.

Animals↗
PubMed1979

Chronic lead intoxication: effects on developing optic nerve.

The effects of chronic lead intoxication were studied by examining the optic nerve of mice given lead-containing mother's milk from day 1 to day 21 of life. Biochemical assays for myelin basic protein, 2',3'-cyclic nucleotide phosphodieterase, and cerebroside sulfotransferase showed that the total amount of myelin produced by the lead-exposed animals was decreased. Lead exposure did not alter the number of oligodendroglia or the relationship between axons and myelin sheaths. The hypomyelination was paralleled by a reduction in size of optic axons in the lead-exposed animals. The data suggest that chronic exposure to lead in developing mice results in a primary effect on neurons and that hypomyelination is secondary to reduction in axon size.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1982

A variant form of metachromatic leukodystrophy without arylsulfatase deficiency.

The clinical, pathological, and biochemical findings in a young woman with a new variant of metachromatic leukodystrophy (MLD) are reported. The patient showed slow early development and deteriorated further during her first two decades. Nerve conductions were slow, and a sural nerve biopsy showed features of a sulfatide lipidosis. Urinary sulfatide excretion was comparable to that of patients with classic MLD, yet in vitro activity of arylsulfatase A and B and cerebroside sulfatase activity were normal. Skin fibroblasts cultured in medium supplemented with 3H-labeled sulfatide showed accumulation of labeled sulfatide in large amounts, implying a defect in sulfatide hydrolysis in vivo in spite of intact enzyme activity in vitro.

Adult↗
PubMed2004

Dysmyelination and reduced myelin basic protein gene expression by oligodendrocytes of SHP-1-deficient mice.

We have shown previously that myelin-forming oligodendrocytes express the protein tyrosine phosphatase SHP-1 and that myelin formation was decreased in SHP-1-deficient motheaten mice compared to that in normal littermates. These studies suggested a potential importance for SHP-1 in oligodendrocyte and myelin development. To address further this possibility, we analyzed myelin formation by microscopy and myelin basic protein (MBP) gene expression in motheaten mice at ages when myelination occurs in the developing central nervous system (CNS). Furthermore, we correlate these findings with MBP gene expression in oligodendrocytes grown in vitro. We have found that CNS myelination was significantly reduced in SHP-1-deficient mice relative to their normal littermates at multiple times during the active period of myelination. Under electron microscopy, greater numbers of axons in spinal cords of motheaten mice were either unmyelinated or had thinner myelin sheathes compared to those in matched areas of normal littermates. Accordingly, MBP protein and mRNA levels were reduced in SHP-1-deficient mice compared to that in the CNS of normal littermates. In vitro, O1(+) oligodendrocytes from motheaten mice expressed much less MBP than O1(+) oligodendrocytes of normal littermates indicating an alteration in oligodendrocyte differentiation. The latter correlated with reduced MBP mRNA relative to cerebroside galactosyl transferase (CGT) gene mRNA in SHP-1-deficient oligodendrocytes in purified cultures. We propose that SHP-1 is a critical regulator of developmental signals leading to terminal differentiation and myelin sheath formation by oligodendrocytes.

Animals↗
PubMed1981

Synthesis of lipids in mouse brain cell cultures during development.

Several metabolic activities in dissociated cultures of newborn mouse brain were compared to the situation in vivo. The developmental activity pattern of cerebroside-sulfotransferase, cyclic nucleotide phosphohydrolase, and beta-hydroxy-beta-methyl glutaryl-coenzyme A-reductase and the synthesis and deposition of sulfatide and cholesterol in culture were estimated. The enzyme activity patterns in vivo and in culture are the same. Since the cultures show very little myelin formation, the parallel increase of enzyme activities necessary for myelination in vivo and in culture suggest the existence of intrinsic factors regulating the biochemical differentiation. In addition, the formation of the products, determined in culture, follows the patterns of the enzyme activities. Dissociated brain cell cultures are therefore a valid model for the study of biochemical parameters related to the synthesis of brain lipids during development.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1978

Brain reaggregate cultures: biochemical evidence for myelin membrane synthesis.

Myelin membrane synthesis was studied using mechanically dissociated fetal rodent CNS which formed spherical reaggregates while being maintained in rotating culture flasks. These reaggregate cultures exhibited myelinogenesis in vitro after precisely the same period of time needed for myelin synthesis to commence in vivo. The myelin membrane related enzymes, 2', 3' cyclic nucleotide phosphohydrolase (CNP) and cerebroside sulfotransferase (CST), appear similar in their specific activities and follow the same developmental patterns that these enzymes exhibit in vivo. In addition, phosphorylation of myelin basic protein occurs by the third week in vitro which agrees with previously published in vivo studies. These experiments indicate that this nerve-cell culture system may be a appropriate model for studying the biological regulation of myelinogenesis as well as a variety of other nervous-system functions.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1998

Determination of galactose and galactocerebroside using a galactose oxidase column and electrochemical detector.

A method has been developed to measure galactose and galactocerebroside using galactose oxidase immobilized on a solid resin. Galactose oxidase converts galactose and galactocerebroside to their corresponding aldehydes and hydrogen peroxide, the latter being electroactive and measurable by electrochemical detection using DC amperometric detection. The minimal detection limits of galactose and galactocerebroside were 1 and 2 microM, respectively. The linear response to galactose and galactocerebroside was to at least 300 microM. About 100 samples can be measured per hour using flow injection analysis. The activity of sulfatidase (cerebroside-3-sulfate-3-sulfohydrolase), which converts sulfatide (sulfogalactocerebroside) to galactocerebroside, was measured, and its inhibition by O-phospho-L-tyrosine was determined.

Biosensing Techniques↗
PubMed1978

Lipid and fatty acid composition of human cerebral myelin during development.

A development study of major lipid fatty acids in human brain myelin was undertaken and compared to those in cerebral white matter of the same region. The myelin was isolated from 23 subjects at ages from newborn to old age. The proportions of cholesterol and galactolipids increased in myelin during the first 6 months of age and up to 2 years of age in cerebral white matter. During the same periods the individual phospholipids also showed marked variations. Serine phosphoglycerides and especially sphingomyelins increased, and choline phosphoglycerides decreased. The fatty acid patterns of ethanolamine phosphoglycerides (EPG) and sphingomyelins underwent the largest maturation changes. The proportions of saturated fatty acids in EPG diminished rapidly with a corresponding increase of monoenoic acids. Fatty acids of the linoleic acid series showed a peak between 4 months and 12 months of age, and then their proportion slowly diminished to old age. The fatty acid changes in serine phosphoglycerides were much less pronounced than in EPG but of similar type. In sphingomyelin the proportion of saturated long-chain fatty acids diminished while the proportion of monoenoic acids increased--this increase continued at least to the age of 15 years. The same fatty acid changes occurred in cerebrosides and sulfatides as in the sphingomyelins, but they were less pronounced. The fatty acid changes during development were much more pronounced in white matter than in myelin but already from 1-2 years of age the lipids of myelin and white matter had the same patterns--in the galactolipids from 2 months of age. The individual variations of the lipid fatty acid patterns were small except for at the youngest ages and the variations found for this period might depend on the difficulties in determining the gestational age.

Adolescent↗
PubMed1976

Polyunsaturated fatty acid lipidosis: a new nosological entity.

Lipid analyses in the terminal stage of the disease polyunsaturated fatty acid lipidosis (PFAL), showed a brain very poor in lipids. The concentration of sphingolipids was particularly low: gangliosides of cerebral cortex was only 10% of the control value, and cerebrosides of white matter only 2%. Of the gangliosides, GM1 and GD1 a were reduced more than any other ganglioside fraction. The fatty acid compositions of the phosphoglycerides were the same in cerebral cortex and white matter. Compared with what was found in the controls, ethanolamine phosphoglycerides had much higher proportions of 18:1 and 20:4 (n-6) and much lower proportions of 22:4 (n-6) and 22:6 (n-6) and 22:6 (n-3) in the cerebral cortex. Similar changes in the fatty acid patterns were found in the other phosphoglycerides. It is assumed that in PFAL there is a primary disturbance in the metabolism of arachidonic acid, which leads to a series of secondary changes. The results suggested that the gangliosides GM1 and GD1a, sialidase and phosphoglycerides with dokosahexaenoic acid are confined to the nerve endings.

Brain↗
PubMed1978

Toxicology of triethyllead, methylmercury and cadmium, determined in chick embryo brain cell cultures.

The toxicology of water soluble chemical compounds may be investigated in tissue culture systems. The toxicology of triethyllead chloride, methylmercury chloride and cadmium acetate was studied in chick embryo brain cell cutlures. Tetraethyllead is added to petrol as an anti-knock agent. When tetraethyllead is absorbed by the organism, it is converted to triethyllead which cause the symptoms of tetraethyllead poisoning. Chick embryo brain cell cultures derived from cerebrum of 11-day-old chick embryos developed both neurons and glial cells. The neurons formed nerve processes and synapsis in the cultures. The effect of triethyllead chloride was investigated by addition of triethyllead chloride to the nutrient medium. The median tissue culture lethal dose, TCLD50 = 1.9 mg/l, was determined as the concentration of triethyllead chloride at which the confluent layer of glial cells was destroyed in 50% of the cultures. The neurons lost their processes at even lower concentration, TCED50 = 0.57 mg/l. Electron microscopy revealed cells with swollen Golgi apparatus and dilated endoplasmic reticulum in chick embryo brain cell cultures which were treated with triethyllead chloride, 1.0 mg/l. Studies with radioactive labelled precursors revealed that triethyllead chloride inhibited the synthesis of DNA, sulfatides and cerebrosides without hydroxyfatty acids.

Animals↗
PubMed1984

Atypical metachromatic leukodystrophy? Problems with the biochemical diagnosis.

A 3 1/2-year-old slightly retarded boy with marked deficiency of arylsulfatase A (ASA) activity in leucocytes and fibroblasts and almost no cerebroside sulfatase (CS) activity in fibroblasts was tested with the sulfatide-loading test. On this test his fibroblasts showed impaired degradation. A pathological excretion of sulfatides was seen in his urine. Nerve conduction velocity, visual evoked potential, auditory brain stem evoked response, and somatosensory evoked potential were all normal. His father and older brother had similarly low levels of ASA in leucocytes and fibroblasts and 1.7-2% residual CS activity in fibroblasts. Although both were clinically normal, their fibroblasts accumulated increased amounts of sulfatides when challenged in the sulfatide-loading test. In this family, this test thus will be of no value in prenatal diagnosis to discriminate among low ASA fetuses with pseudoarylsulfatase A deficiency and fetuses with this unusual ASA deficiency variant.

Adult↗
PubMed1980

Biochemical, psychometric, and neuropsychological studies in heterozygotes for various lipidoses. Preliminary results.

A sample of 38 clinically unaffected carriers for various lipidoses and their noncarrier relatives was studied with biochemical, psychological, and neuropsychological tests under blind conditions. The largest group of carriers was that for metachromatic leucodystrophy (MLD). The mean activity of arylsulphatase A or cerebroside sulphatase in the obligate carriers was 25%-30% of the control values, some heterozygotes showing little more activity than MLD patients. It was found that compared with the controls all heterozygotes (both obligate and facultative) differ unfavourably in some personality traits and in WISA subtests, including capacity for spatial cognition. These differences are especially obvious in a group of seven MLD carriers from the same family. With respect to reaction times, performance was significantly slower in MLD carriers, and particularly in those with enzyme activity lower than 30% of the control values.

Adolescent↗
PubMed1977

[Adult metachromatic leukodystrophy manifested as schizophrenic psychosis (author's transl)].

An autopsy case of adult metachromatic leukodystrophy (MLD) manifested clinically as schizophrenic psychosis is reported. A 50-year-old man developed progressive mental changes 10 years before his death, and later manifested a schizophrenic syndrome without neurologic deficits or EEG changes. After his death from uremia neuropathology disclosed MLD with demyelination accentuated in the frontal lobes and abundant metachromatic deposits in the preserved areas of cerebral white matter. Neurochemical examination of the demyelinated frontal area showed reduced concentration of cerebrosides and sulfatides, decreased amounts of total lipids in the tissue, and an increase of sulfatides, and particularly of their cerebron fractions in lipid extract. The problems of adult forms of MLD with prolonged course are discussed with special reference to cases showing mainly psychiatric syndromes.

Atrophy↗
PubMed1988

Multiple sulfatase deficiency with a novel biochemical presentation.

Deficient activities of cerebroside-sulfatase, N-Acetylgalactosamine-4-sulfatase and iduronide 2-sulfatase in the lymphocytes of a patient suspected of metachromatic leukodystrophy, established the diagnosis of multiple sulfatase deficiency (MSD). Cultured skin fibroblasts (of early passage) from the patient had normal levels of activity for the three sulfatases. One week after the first examination, the activities of the three sulfatases in the fibroblasts of the patient declined and within a month were 4%-29% of normal. Total urinary glycosaminoglycans were within normal range. However, further examination showed an increase in the concentration of heparan sulfate, which comprised more than 50% of the total, compared with less than 20% in normal controls. Urinary sulfatides, cholesterol esters, cholesterol, and triglycerides were increased. The results from the study of this unique case of MSD suggest that time-dependent changes affect the activities of sulfatases in MSD. These results also demonstrate the necessity of assaying the sulfatases in both lymphocytes and fibroblasts from suspected cases of MSD.

Acetylgalactosamine↗