Choline and Cholinergic Neurons

Blusztajn, Jan Krzysztof; Wurtman, Richard J.

doi:10.1126/science.6867732

Cited by 420 publications

(163 citation statements)

References 129 publications

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“…The high-affinity uptake of choline appears to be unique for cholinergic nerve endings and is not present in perikarya (38). The carrier is employed by cholinergic terminals to sequester the choline derived from hydrolysis of ACh released into the synaptic cleft (39). Uptake of choline via this pathway seems to be the rate-limiting, regulatory step for ACh synthesis (40), and is thus of particular importance in cholinergic synaptic function.…”

Section: Kineticsmentioning

confidence: 99%

Cholinergic Nerve Terminals in the Central Nervous System of Insects

Sattelle

Breert

1990

J Neuroendocrinology

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Section: Kineticsmentioning

confidence: 99%

Cholinergic Nerve Terminals in the Central Nervous System of Insects

Sattelle

Breert

1990

J Neuroendocrinology

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“…Additionally, we found significant elevations in cortical levels of the PtdCho catabolite GPC. GPC is generated by deacylation of PtdCho (17). It is therefore likely that the accumulation of GPC in AD brain reflects increased activity of the deacylation pathways mediated by phospholipase A and lysophospholipase (see Fig.…”

mentioning

confidence: 99%

“…Decreased levels of choline and ethanolamine in AD brain could also imply reduced availability of the precursors for PtdCho and PtdEtn synthesis. Furthermore, a decrease in choline levels may slow acetylcholine synthesis because of the high Km of choline acetyltransferase for choline as substrate (30-100 gM) (17), and thus contribute to the cholinergic deficit in AD.…”

mentioning

confidence: 99%

Evidence for a membrane defect in Alzheimer disease brain.

Nitsch

Blusztajn

Pittas

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

488

267

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To determine whether neurodegeneration in Alzheimer disease brain is associated with degradation of structural cell membrane molecules, we measured tissue levels of the major membrane phospholipids and their metabolites in three cortical areas from postmortem brains of Alzheimer disease patients and matched controls. Among phospholipids, there was a significant (P < 0.05) decrease in phosphatidylcholine and phosphatidylethanolamine. There were significant (P < 0.05) decreases in the initial phospholipid precursors choline and ethanolamine and increases in the phospholipid deacylation product glycerophosphocholine. The ratios of glycerophosphocholine to choline and glycerophosphoethanolamine to ethanolamine were significantly increased in all examined Alzheimer disease brain regions. The activity of the glycerophosphocholine-degrading enzyme glycerophosphocholine cholinephosphodiesterase was normal in Alzheimer disease brain. There was a near stoichiometric relationship between the decrease in phospholipids and the increase of phospholipid catabolites. These data are consistent with increased membrane phospholipid degradation in Alzheimer disease brain. Similar phospholipid abnormalities were not detected in brains of patients with Huntington disease, Parkinson disease, or Down syndrome. We conclude that the phospholipid abnormalities described here are not an epiphenomenon of neurodegeneration and that they may be specific for the pathomechanism of Alzheimer disease.Brain lesions characteristic of Alzheimer disease (AD) include amyloid deposition, the formation of neurofibrillary tangles, and neuronal degeneration. The etiology and pathophysiology of neuronal death in AD are unknown. Cell membrane lipid abnormalities have been described in AD brain, and it has been hypothesized that these contribute to amyloid deposition (1, 2) and neuronal dysfunction (3). Initial evidence for a biochemical abnormality in the metabolism of phospholipids came from in vitro 31P NMR spectroscopic studies showing that the ratio of glycerophosphocholine (GPC) to glycerophosphoethanolamine (GPE) as well as levels of glycerophosphodiesters and phosphomonoesters were increased in AD brain (4-6). Quantitative HPLC analysis has demonstrated that the increase in glycerophosphodiesters was due to accumulation of the phospholipid catabolites GPC and GPE (7, 8). The biochemical mechanisms accounting for the increase of phospholipid catabolites are unknown. To investigate the abnormalities in the phospholipid metabolic pathways, we examined levels of the parent phospholipids, their precursors, and their catabolites (see Fig. 1) in three cortical brain areas obtained at autopsy from AD patients and matched controls. To rule out the possibility that the elevation in GPC reflects a slowing in its degradation,

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“…Upon consumption of a choline-deficient (CD) 1 diet for 3 weeks, humans develop incipient liver dysfunction, particularly when adequate levels of methionine and folate are also lacking (5). In addition, choline has been proposed to play an important function in brain development (7,8), probably because in cholinergic neurons choline is a precursor of the neurotransmitter acetylcholine (6,9). Choline is also a precursor of the abundant membrane phospholipids phosphatidylcholine (PC), sphingomyelin, and choline plasmalogens in eukaryotic cells.…”

mentioning

confidence: 99%

A Choline-deficient Diet in Mice Inhibits neither the CDP-choline Pathway for Phosphatidylcholine Synthesis in Hepatocytes nor Apolipoprotein B Secretion

Kulinski

Vance

2004

Journal of Biological Chemistry

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Phosphatidylcholine is a major component of very low density lipoproteins (VLDLs) secreted by the liver. Hepatic phosphatidylcholine is synthesized from choline via the CDP-choline pathway and from the phosphatidylethanolamine N-methyltransferase pathway. Elimination of the methyltransferase in male mice reduces hepatic VLDL secretion. Our objective was to determine whether inhibition of the CDP-choline pathway for phosphatidylcholine synthesis (by restricting the supply of choline) also impaired VLDL secretion. In mice fed a choline-deficient (CD), compared with a cholinesupplemented, diet for 21 days, the amounts of plasma apolipoproteins (apo) B100 and B48 were reduced and the liver triacylglycerol content was increased. Hepatocytes were isolated from male mice that had been fed the CD diet for 3 or 21 days, and the cells were incubated with or without choline. The secretion of apoB100 and B48 from CD hepatocytes was not reduced, and triacylglycerol secretion was only modestly decreased, compared with that from cells supplemented with choline. Remarkably, in light of widely held assumptions, the rate of phosphatidylcholine synthesis from the CDPcholine pathway was not decreased in CD hepatocytes. Rather, there was a trend toward increased phosphatidylcholine synthesis that might be explained by enhanced CTP:phosphocholine cytidylyltransferase activity. Although the concentration of phosphocholine in CD hepatocytes was reduced, the size of the phosphocholine pool remained well above the K m for the cytidylyltransferase. Moreover, the amount and activity of the cytidylyltransferase and methyltransferase were increased. The reduction in plasma apoB in mice deprived of dietary choline cannot, therefore, be attributed to decreased apoB secretion.In 1998, choline was classified as an essential nutrient for humans and a minimum dietary intake was recommended (53). Choline is ubiquitously present in animals and plants and is essential for survival and normal growth of cultured cells (1-4). Choline also appears to be an essential nutrient for humans (5, 6). Upon consumption of a choline-deficient (CD) 1 diet for 3 weeks, humans develop incipient liver dysfunction, particularly when adequate levels of methionine and folate are also lacking (5). In addition, choline has been proposed to play an important function in brain development (7, 8), probably because in cholinergic neurons choline is a precursor of the neurotransmitter acetylcholine (6, 9). Choline is also a precursor of the abundant membrane phospholipids phosphatidylcholine (PC), sphingomyelin, and choline plasmalogens in eukaryotic cells. In all nucleated eukaryotic cells, PC is synthesized from choline via the CDP-choline pathway (10). In the liver, an additional PC biosynthetic pathway, the phosphatidylethanolamine N-methyltransferase (PEMT) pathway (11, 12), which utilizes S-adenosylmethionine, generates ϳ30% of hepatic PC (13-15).Choline deprivation has been widely reported to be an effective tool for specifically inhibiting the CDP-choline pathway for PC...

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Choline and Cholinergic Neurons

Cited by 420 publications

References 129 publications

Cholinergic Nerve Terminals in the Central Nervous System of Insects

Cholinergic Nerve Terminals in the Central Nervous System of Insects

Evidence for a membrane defect in Alzheimer disease brain.

A Choline-deficient Diet in Mice Inhibits neither the CDP-choline Pathway for Phosphatidylcholine Synthesis in Hepatocytes nor Apolipoprotein B Secretion

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