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PubMed2000

Evidence for forebrain cholinergic neuronal loss in congenital ornithine transcarbamylase deficiency.

Congenital ornithine transcarbamylase (OTC) deficiency in humans results in failure to thrive, hypotonia, seizures and mental retardation. Neuropathologic evaluation reveals significant cerebral cortical atrophy, delayed myelination and Alzheimer type II astrocytosis. Using an animal model of congenital OTC deficiency, the sparse fur (spf) mouse, studies reveal convincing evidence of a loss of forebrain cholinergic neurons in this condition. Evidence includes (i) reduced activities of the cholinergic nerve terminal enzyme choline acetyltransferase (ChAT), (ii) a 25% loss of ChAT immunostaining, (iii) reduced high affinity transport of [3H]choline by cortical synaptosomes and (iv) a selective reduction in densities of presynaptic muscarinic M2 binding sites, in spf mouse brain compared to controls. A partial correction of the cholinergic deficit was observed following treatment with acetyl-L-carnitine. Possible mechanisms responsible for cholinergic neuronal loss in congenital OTC deficiency include decreased synthesis of the ChAT substrate acetyl CoA, impaired cerebral energy metabolism and NMDA receptor-mediated excitotoxicity. Loss of forebrain cholinergic neurons is consistent with the severe cognitive impairment characteristic of congenital OTC deficiency.

Animals↗
PubMed1999

Lysosomal phospholipase activity is decreased in mucolipidosis II and III fibroblasts.

Mucolipidosis (ML) II and III are rare autosomal recessively inherited diseases characterized by deficiency of multiple lysosomal enzymes and, as a result, a generalized storage of macromolecules in lysosomes of cells of mesenchymal origin. In ML II and ML III fibroblasts, most, but not all, newly synthesized lysosomal enzymes are secreted into the medium instead of being targeted correctly to lysosomes. Defects in the enzyme UDP-N-acetylglucosamine:lysosomal enzyme N-acetylglucosamine-1-phosphotransferase underlie this effect. It is unknown how lysosomal phospholipases are targeted to the lysosomes of fibroblasts. In the present study lysosomal phospholipase activity was determined in delipidated fibroblast homogenates and plasma from ML II and ML III patients and controls using a [3H]choline-labeled phosphatidylcholine. After incubation, residual phosphatidylcholine and its labeled degradation products (lysophosphatidylcholine, glycerophosphorylcholine and choline phosphate) were quantified. We found that ML II and ML III fibroblasts are deficient in lysosomal phospholipase A and C activity. These enzymes were present in elevated amounts in plasma of ML II and ML III patients. These data indicate that phospholipases, like most other lysosomal enzymes in these diseases, are secreted into the blood instead of being targeted specifically to lysosomes. Thus, the mannose-6-phosphate receptor pathway is needed for proper delivery of lysosomal phospholipases to lysosomes. We also found that production of labeled choline phosphate was mainly due to the activity of acid sphingomyelinase instead of phospholipase C under the assay conditions used. Other active lipolytic enzymes were phospholipase A and lysophospholipase. No evidence for phospholipase D activity was found.

Biological Transport, Active↗
PubMed2003

Deficiency in ethanolamine plasmalogen leads to altered cholesterol transport.

Plasmalogens are a major sub-class of ethanolamine and choline phospholipids in which the sn-1 position has a long chain fatty alcohol attached through a vinyl ether bond. These phospholipids are proposed to play a role in membrane fusion-mediated events. In this study, we investigated the role of the ethanolamine plasmalogen plasmenylethanolamine (PlsEtn) in intracellular cholesterol transport in Chinese hamster ovary cell mutants NRel-4 and NZel-1, which have single gene defects in PlsEtn biosynthesis. We found that PlsEtn was essential for specific cholesterol transport pathways, those from the cell surface or endocytic compartments to acyl-CoA/cholesterol acyltransferase in the endoplasmic reticulum. The movement of cholesterol from the endoplasmic reticulum or endocytic compartments to the cell surface was normal in PlsEtn-deficient cells. Also, vesicle trafficking was normal in PlsEtn-deficient cells, as measured by fluid phase endocytosis and exocytosis, as was the movement of newly-synthesized proteins to the cell surface. The mutant cholesterol transport phenotype was due to the lack of PlsEtn, since it was corrected when NRel-4 cells were transfected with a cDNA encoding the missing enzyme or supplied with a metabolic intermediate that enters the PlsEtn biosynthetic pathway downstream of the defect. Future work must determine the precise role that plasmalogens have on cholesterol transport to the endoplasmic reticulum.

Biological Transport↗
PubMed1961

Latent viral infection of cells in tissue culture. VII. Role of water-soluble vitamins in psittacosis virus propagation in L cells.

A study of the metabolic requirements for the growth of psittacosis virus in L cells has been extended to the water-soluble vitamins. In a system in which a balanced salt solution was used to deplete the cells of their vitamin constituents, only thiamine was essential for psittacosis virus production. Extended depletion of cells with media deficient in specific vitamins demonstrated that pantothenate, niacin (niacinamide), pyridoxine (pyridoxal), and choline, in addition to thiamine, were essential for maximal growth of psittacosis virus. No requirement for biotin, inositol, folic acid, or riboflavin was demonstrated, although the possibility of incomplete vitamin depletion of the cells has not been eliminated. In most cases in which a specific vitamin requirement was shown the decreased yield of virus was correlated with a delay in the cytopathic effects produced in the cell cultures by psittacosis virus.

Chlamydophila psittaci↗
PubMed1985

New tools for the study of Niemann-Pick disease: analogues of natural substrate and Epstein-Barr virus-transformed lymphoid cell lines.

Acid sphingomyelinase activity was determined in Epstein-Barr virus-transformed lymphoid cell lines (LCL) established from patients affected with Niemann-Pick disease (NPD) using several substrates: sphingomyelin derivatives, radiolabeled [14C]sphingomyelin (SM), fluorescent N-(10-(1-pyrene)decanoyl)sphingomyelin (P10-SM) or colored trinitrophenylaminolauryl-sphingomyelin, and the chromogenic non-natural substrate 2-N-(hexadecanoyl)amino-4-nitrophenylphosphoryl-choline. LCL from NPD Type A and Type B showed a severe deficiency of acid sphingomyelinase determined using either substrate, whereas LCL from normal subjects had an activity close to that of blood leukocytes. Sphingomyelinase in normal LCL had the same pH optimum (5.0-5.2) and molecular form (pI 5.8) as the enzyme from other sources; identical profiles and activity levels were obtained using the various analogues of sphingomyelin. However, among these derivatives, the assay using P10-SM appeared as the most useful and sensitive for enzymatic diagnosis of NPD. Electron microscopy of NPD LCL demonstrated the lysosomal storage. These results prove the validity of LCL as an experimental model system for NPD.

Cell Line↗
PubMed1993

Cloning and sequencing of a cDNA encoding Saccharomyces cerevisiae carnitine acetyltransferase. Use of the cDNA in gene disruption studies.

cDNA encoding for carnitine acetyltransferase (CAT) of yeast S. cerevisiae was isolated by screening a yeast cDNA lambda gt11 library with antibody. The whole coding sequence was obtained from the cDNA and from a YEP 13 DNA clone identified using the cDNA as probe. The coding sequence consists of 670 residues, which amounts to a molecular mass of 77,300 kDa. This cDNA was used successfully to disrupt the gene for the mitochondrial isoenzyme of CAT, which was shown by measuring the enzyme activity and by immunoblot. The acetylcarnitine content of these cells decreased significantly. A search in the PIR protein data base revealed that besides the known carnitine acyltransferases, choline acyltransferases are highly homologous to yeast CAT. The mitochondrial CAT-deficient (CAT-) cells were able to grow on different fermentable and nonfermentable carbon sources, even on acetate at the same rate as the parental strain. In contrast to these, 13C NMR studies revealed significant differences between parental and CAT- cells. In CAT-cells [3-13C]pyruvate was converted mainly to lactate and acetate, whereas in the parental cells alanine and tricarboxylic acid cycle intermediates were found as the main products of pyruvate metabolism beside acetate. These results suggest diminished flux through the pyruvate dehydrogenase complex in the absence of mitochondrial CAT in yeast cells.

Amino Acid Sequence↗
PubMed1996

Central muscarinic cholinergic M1 and M2 receptor changes in congenital ornithine transcarbamylase deficiency.

Congenital ornithine transcarbamylase (OTC) deficiency results in neuropathologic damage to the cerebral cortex, basal ganglia, and thalamus. However, the precise nature of the cell loss, as well as the pathophysiologic mechanisms responsible for it, have not been fully elucidated. In the present study, densities of the M1 and M2 subclasses of muscarinic cholinergic binding sites were assessed using quantitative receptor autoradiography in the brains of sparse-fur (spf) mice with congenital OTC deficiency and in age-matched CD-1 controls. Densities of binding sites for the muscarinic M1 subtype ligand [3H]pirenzepine were reduced by 24-54% (p < 0.01) in frontal cortex, caudate/ putamen, and hippocampal CA1 and CA2 areas. Since muscarinic M1 sites are localized presynaptically, their selective loss, together with a previous report of reduced activities of the presynaptic cholinergic enzyme choline acetyltransferase, confirms that loss of cholinergic neurons is an important feature of congenital OTC deficiency. Densities of binding sites for the predominantly postsynaptic muscarinic M2 subtype ligand 3H-AFDX 384 were increased by up to 60% (p < 0.01) in cerebral cortex, hippocampus, globus pallidus, as well as thalamic and hypothalamic structures of OTC-deficient mice. Increased M2 sites in the cerebral cortex, hippocampus, and thalamus are most likely the result of up-regulation of these sites after the loss of the presynaptic neuron. These findings support the presence of a central muscarinic cholinergic lesion in congenital OTC deficiency.

Animals↗
PubMed1977

Oral choline administration to patients with tardive dyskinesia.

We gave pharmacologic doses of choline to patients with tardive dyskinesia in an attempt to suppress involuntary facial movements. Choline is the physiologic precursor of acetylcholine, and its administration elevates brain acetylcholine levels in laboratory animals and, possibly, in human beings. Hence, we thought that its use could benefit patients with diseases like tardive dyskinesia, which is believed to result from deficient central cholinergic tone. Twenty patients with stable baccal-lingual-masticatory movements took oral doses of choline for two weeks according to a double-blind crossover protocol. Plasma choline levels rose from 12.4 +/- 1.0 to 33.5 +/- 2.5 nmol per milliliter (mean +/- S.E.M.; P less than 0.001) during this period. Choreic movements decreased in nine patients, worsened in one and were unchanged in 10. Thus, oral doses of choline can be useful in neurologic diseases in which an increase in acetylcholine release is desired.

Administration, Oral↗
PubMed1974

The pancreatic beta-cell recognition of insulin secretagogues. Effects of calcium and sodium on glucose metabolism and insulin release.

The transport and oxidation of glucose, the content of fructose 1,6-diphosphate, and the release of insulin were studied in microdissected pancreatic islets of ob/ob mice incubated in Krebs-Ringer bicarbonate medium. Under control conditions glucose oxidation and insulin release showed a similar dependence on glucose concentration with the steepest slope in the range 5-12mm. The omission of Ca(2+), or the substitution of choline ions for Na(+), or the addition of diazoxide had little if any effect on glucose transport. However, Ca(2+) or Na(+) deficiency as well as diazoxide (7-chloro-3-methyl-1,2,4-benzothiadiazine 1,1-dioxide) or ouabain partially inhibited glucose oxidation. These alterations of medium composition also increased the islet content of fructose 1,6-diphosphate, as did the addition of adrenaline. Phentolamine [2-N-(3-hydroxyphenyl)-p-toluidinomethyl-2-imidazoline] counteracted the effects of adrenaline and Ca(2+) deficiency on islet fructose 1,6-diphosphate. After equilibration in Na(+)-deficient medium, the islets exhibited an increase in basal insulin release whereas the secretory response to glucose was inhibited. The inhibitory effects of Na(+) deficiency on the secretory responses to different concentrations of glucose correlated with those on (14)CO(2) production. When islets were incubated with 17mm-glucose, the sudden replacement of Na(+) by choline ions resulted in a marked but transient stimulation of insulin release that was not accompanied by a demonstrable increase of glucose oxidation. Galactose and 3-O-methylglucose had no effect on glucose oxidation or on insulin release. The results are consistent with a metabolic model of the beta-cell recognition of glucose as insulin secretagogue and with the assumption that Ca(2+) or Na(+) deficiency, or the addition of adrenaline or diazoxide, inhibit insulin release at some step distal to stimulus recognition. In addition the results suggest that these conditions create a partial metabolic block of glycolysis in the beta-cells. Hence the interrelationship between the processes of stimulus recognition and insulin discharge may involve a positive feedback of secretion on glucose metabolism.

Animals↗
PubMed2003

Homocysteine-betaine interactions in a murine model of 5,10-methylenetetrahydrofolate reductase deficiency.

Hyperhomocysteinemia, a proposed risk factor for cardiovascular disease, is also observed in other common disorders. The most frequent genetic cause of hyperhomocysteinemia is a mutated methylenetetrahydrofolate reductase (MTHFR), predominantly when folate status is impaired. MTHFR synthesizes a major methyl donor for homocysteine remethylation to methionine. We administered the alternate choline-derived methyl donor, betaine, to wild-type mice and to littermates with mild or severe hyperhomocysteinemia due to hetero- or homozygosity for a disruption of the Mthfr gene. On control diets, plasma homocysteine and liver choline metabolite levels were strongly dependent on the Mthfr genotype. Betaine supplementation decreased homocysteine in all three genotypes, restored liver betaine and phosphocholine pools, and prevented severe steatosis in Mthfr-deficient mice. Increasing betaine intake did not further decrease homocysteine. In humans with cardiovascular disease, we found a significant negative correlation between plasma betaine and homocysteine concentrations. Our results emphasize the strong interrelationship between homocysteine, folate, and choline metabolism. Hyperhomocysteinemic Mthfr-compromised mice appear to be much more sensitive to changes of choline/betaine intake than do wild-type animals. Hyperhomocysteinemia, in the range of that associated with folate deficiency or with homozygosity for the 677T MTHFR variant, may be associated with disturbed choline metabolism.

Animals↗
PubMedDate not supplied

[Mechanism of the effect of varying saturation of the rat organism with thiamine on membrane-bound succinate dehydrogenase activity].

The properties of the membrane-bound succinate dehydrogenase (SDH) of rat liver mitochondria were studied in the presence of thiamine excess and deficiency in the body. In acute oxythiamine B1-avitaminosis, the content of phosphatidyl choline in the mitochondria fell and SDH activity was suppressed. After incubation of such mitochondria with a sonicated phospholipid emulsion from egg yolk the activity of the enzyme virtually returned to control values. Incubation of the mitochondria from control rats and animals given thiamine contained by phospholipid emulsion did not affect SDH activity.

Animals↗
PubMed1983

Biosynthesis of phosphatidylcholine from serum phospholipids in Chinese hamster ovary cells deprived of choline.

We report that Chinese hamster ovary cells assemble membrane phospholipids from choline-linked lipid present in fetal calf serum. This was examined by testing the ability of various serum preparations to satisfy the choline requirement of the cells. Chinese hamster ovary cells divided in growth medium containing lipoprotein-deficient serum and approximately 8 microM lysolecithin. Identical results were obtained in growth medium supplemented with solvent-extracted (delipidated) serum reconstituted with purified egg lysolecithin and the uptake of lipid was inhibited by the addition of bovine serum albumin. Analysis of the phospholipid composition of cells incubated with 32Pi and egg lysolecithin in place of choline revealed that approximately 30% of the phosphorus moieties of the cellular phospholipids were derived from the added lipid, while in the presence of choline less than 10% arose in this fashion. Choline starvation enhanced the formation of lecithin from [32P]lysolecithin without affecting phospholipid turnover and labeled lecithin was converted to other phospholipids, especially sphingomyelin and phosphatidylserine. Unlike endogenous serum lysolecithin, lipoproteins obtained from human and fetal calf sera failed to satisfy the choline requirement of Chinese hamster ovary cells, even though 95% of the lipoprotein phospholipid was phosphatidylcholine and sphingomyelin. Together, these results demonstrate that animal cells can derive all of the choline required for membrane phospholipid synthesis from serum lysolecithin and that its conversion to lecithin within the cell is regulated by the availability of choline. In contrast, serum lipoproteins do not normally serve as a major source of choline moieties.

Animals↗
PubMed1986

Choline+: a substrate of the neuronal noradrenaline carrier in the rat vas deferens.

The effects of choline+ (10-40 mmol/l) on 3H-noradrenaline uptake by, and 3H-noradrenaline efflux from, noradrenergic neurones were studied in vasa deferentia of reserpine-pretreated rats at an external Na+ concentration of 100 mmol/l. Monoamine oxidase and catechol-O-methyltransferase were inhibited. Choline+ (20 and 40 mmol/l) competitively inhibited the neuronal uptake of 3H-noradrenaline. From the choline+-induced changes in the apparent Km for 3H-noradrenaline transport, a Ki of 35 mmol/l was obtained. Choline+ (10, 20 and 40 mmol/l) accelerated the neuronal efflux of 3H-noradrenaline in a concentration-dependent manner. This acceleration of efflux was greatly reduced in the presence of 1 mumol/l desipramine, indicating that choline+ is capable of eliciting "accelerative exchange diffusion". Choline+ (40 mmol/l) and (-)noradrenaline (4.5 mumol/l) (i.e., concentrations about equivalent to the Ki and Km for choline+ and (-)noradrenaline, respectively) produced virtually identical increases in the neuronal efflux of 3H-noradrenaline. Choline+ (3-300 mmol/l) inhibited the specific binding of 3H-desipramine to plasma membranes derived from cultured rat phaeochromocytoma (PC-12) cells. The Ki for this interaction was 48 mmol/l. This results suggest that choline+ acts as alternative substrate of the neuronal noradrenaline transport system and should, therefore, not be used in transport studies with noradrenaline as substitute for Na+ in Na+-deficient media.

Animals↗
PubMed1998

M1 muscarinic agonist treatment reverses cognitive and cholinergic impairments of apolipoprotein E-deficient mice.

Recent studies suggest that apolipoprotein E (apoE) plays a specific role in brain cholinergic function and that the E4 allele of apoE (apoE4), a major risk factor for Alzheimer's disease (AD), may predict the extent of cholinergic dysfunction and the efficacy of cholinergic therapy in this disease. Animal model studies relevant to this hypothesis revealed that apoE-deficient (knockout) mice have working memory impairments that are associated with distinct dysfunction of basal forebrain cholinergic neurons. Cholinergic replacement therapy utilizing M1-selective muscarinic agonists has been proposed as effective treatment for AD patients. In the present study, we examined whether the memory deficits and brain cholinergic deficiency of apoE-deficient mice can be ameliorated by the M1-selective agonist 1-methylpiperidine-4-spiro-(2'-methylthiazoline), [AF150(S)]. Treatment of apoE-deficient mice with AF150(S) for 3 weeks completely abolished their working memory impairments. Furthermore, this reversal of cognitive deficit was associated with a parallel increase of histochemically determined brain choline acetyltransferase and acetylcholinesterase levels and with the recovery of these cholinergic markers back to control levels. These findings show that apoE deficiency-related cognitive and cholinergic deficits can be ameliorated by M1-selective muscarinic treatment. They also provide a novel model system for development and evaluation of therapeutic strategies directed specifically at the AD patients whose condition is attributed to the apoE genotype.

Acetylcholinesterase↗
PubMed2004

Phosphatidylethanolamine is not essential for growth of Sinorhizobium meliloti on complex culture media.

In addition to phosphatidylglycerol (PG), cardiolipin (CL), and phosphatidylethanolamine (PE), Sinorhizobium meliloti also possesses phosphatidylcholine (PC) as a major membrane lipid. The biosynthesis of PC in S. meliloti can occur via two different routes, either via the phospholipid N-methylation pathway, in which PE is methylated three times in order to obtain PC, or via the phosphatidylcholine synthase (Pcs) pathway, in which choline is condensed with CDP-diacylglycerol to obtain PC directly. Therefore, for S. meliloti, PC biosynthesis can occur via PE as an intermediate or via a pathway that is independent of PE, offering the opportunity to uncouple PC biosynthesis from PE biosynthesis. In this study, we investigated the first step of PE biosynthesis in S. meliloti catalyzed by phosphatidylserine synthase (PssA). A sinorhizobial mutant lacking PE was complemented with an S. meliloti gene bank, and the complementing DNA was sequenced. The gene coding for the sinorhizobial phosphatidylserine synthase was identified, and it belongs to the type II phosphatidylserine synthases. Inactivation of the sinorhizobial pssA gene leads to the inability to form PE, and such a mutant shows a greater requirement for bivalent cations than the wild type. A sinorhizobial PssA-deficient mutant possesses only PG, CL, and PC as major membrane lipids after growth on complex medium, but it grows nearly as well as the wild type under such conditions. On minimal medium, however, the PE-deficient mutant shows a drastic growth phenotype that can only partly be rescued by choline supplementation. Therefore, although choline permits Pcs-dependent PC formation in the mutant, it does not restore wild-type-like growth in minimal medium, suggesting that it is not only the lack of PC that leads to this drastic growth phenotype.

CDPdiacylglycerol-Serine O-Phosphatidyltransferase↗
PubMed2006

Diagnosis and management of trimethylaminuria (FMO3 deficiency) in children.

Persistent trimethylaminuria in children is caused by autosomal recessively inherited impairment of hepatic trimethylamine (TMA) oxidation due to deficiency of flavin monooxygenase 3 (FMO3) secondary to mutations in the FMO3 gene. Trimethylaminuria or 'fish odour syndrome' is due to excessive excretion into body fluids and breath of TMA derived from the enterobacterial metabolism of dietary precursors. The disorder is present from birth but becomes apparent as foods containing high amounts of choline or of trimethylamine N-oxide (TMAO) from marine (sea or saltwater) fish are introduced into the diet. In our experience, trimethylaminuria (FMO3 deficiency) in children is rare. We have compared the dynamics and diagnostic efficacy of choline loading with marine fish meals in six children with trimethylaminuria. Loading with a marine fish meal provides a simple and acceptable method for confirmation of diagnosis of suspected trimethylaminuria in children, with the effects being cleared more quickly than with a choline load test. However, oral loading with choline bitartrate allows estimation of residual oxidative capacity in vivo and is a useful adjunct to molecular studies. Patients homozygous for the 'common' P153L mutation in the FMO3 gene showed virtual complete lack of residual TMA N-oxidative capacity, consistent with a nonfunctional or absent FMO3 enzyme, whereas a patient with the M82T mutation showed some residual oxidative capacity. A patient compound heterozygous for two novel mutations, G193E and R483T, showed considerable residual N-oxidative capacity. A further patient, heterozygous for two novel sequence variations in the FMO3 gene, consistently showed malodour and elevated urinary TMA/TMAO ratios under basal conditions but a negative response to both choline and marine fish meal loading. Comparison of the effects of administration of antibiotics (metronidazole, amoxicillin, neomycin) on gut bacterial production of trimethylamine from choline showed they all reduced TMA production to a limited extent, with neomycin being most effective. 'Best-practice' diagnostic and treatment guidelines are summarized.

Adult↗