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PubMed1997

Acyltransferases and transacylases involved in fatty acid remodeling of phospholipids and metabolism of bioactive lipids in mammalian cells.

Over 100 different phospholipid molecular species are known to be present in mammalian cells and tissues. Fatty acid remodeling systems for phospholipids including acyl-CoA: lysophospholipid acyltransferases, CoA-dependent and CoA-independent transacylation systems and lysophospholipase/transacylase are involved in the biosynthesis of these molecular species. Acyl-CoA:1-acyl-2-lysophospholipid acyltransferase prefers polyunsaturated fatty acyl-CoAs as acyl donors while acyl-CoA:2-acyl-1-lysophospholipid acyltransferase prefers saturated fatty acyl-CoAs. Therefore, the acyl-CoA:lysophospholipid acyltransferase system is involved in the synthesis of the phospholipid molecular species containing sn-1 saturated and sn-2 unsaturated fatty acids. The CoA-dependent transacylation system catalyzes the transfer of fatty acids esterified in phospholipids to lysophospholipids in the presence of CoA without the generation of free fatty acids. The CoA-dependent transacylation reaction in rat liver exhibits strict fatty acid specificity, i.e., three types of fatty acids (20:4, 18:2, and 18:0) are transferred. On the other hand, the CoA-independent transacylase catalyzes the transfer of C20 and C22 polyunsaturated fatty acids from diacyl phospholipids to various lysophospholipids, in particular, ether-containing lysophospholipids, in the absence of any cofactors. The CoA-independent transacylase is assumed to be involved in the accumulation of polyunsaturated fatty acids in ether-containing phospholipids and in the removal of deleterious ether-containing lysophospholipids. These acyltransferases and transacylases are involved in not only the remodeling of fatty acids but also the synthesis and degradation of some bioactive lipids and their precursors. In this review, the properties of these fatty acid remodeling systems and their possible roles in the biosynthesis of bioactive lipids are described.

1-Acylglycerophosphocholine O-Acyltransferase↗
PubMed1976

Escherichia coli membrane D-lactate dehydrogenase. Isolation of the enzyme in aggregated from and its activation by Triton X-100 and phospholipids.

D-Lactate dehydrogenase was obtained in an aggregated form consisting of 2 to 3 molecules of the monomer enzyme after removal of most Triton X-100 from the preparation as described previously (1). The aggregate dissociated reversibly to the monomeric form after addition of 0.06% or 1.0% Triton X-100. Formation of these aggregates was confirmed by the finding that the enzyme activity was only partially sensitive to specific antibody. The specific activity of the aggregated enzyme was one-third that of the enzyme with Triton X-100 and it increased approximately 5-fold on addition of phospholipids or cardiolipin of Escherichia coli and lecithin from egg yolk. Both the monomer and micelle forms of Triton X-100 caused activation of the enzyme. The activity of the aggregates after preincubation with Triton X-100 or phospholipids was completely inhibited by specific antibody. The difference in the properties of the aggregated enzyme after preincubation with Triton X-100 and with phospholipids suggested that its interaction with phospholipids was stronger than with Triton X-100. Kinetic studies also suggested a difference between the interactions of the enzyme with phospholipids and with Triton X-100. Aggregated enzyme had an apparent Km value for D-lactate similar to that of membrane-bound enzyme after preincubation with phospholipids.

Cell Membrane↗
PubMed2006

Autophagy is not a main contributor to the degradation of phospholipids in tobacco cells cultured under sucrose starvation conditions.

Net degradation of cellular components occurs in plant cells cultured under starvation conditions, and autophagy contributes to the degradation of intracellular proteins. In this study, we investigated the degradation of membrane phospholipids by autophagy in cultured tobacco (Nicotiana tabacum) cells. The amounts of total phospholipids and a major phospholipid, phosphatidylcholine (PC), decreased, whereas phosphorylcholine, a degradation product of PC, increased in response to deprivation of sucrose. The addition of glycerol to the culture medium inhibited both the degradation of phospholipids and the concomitant increase of phosphorylcholine. Glycerol, however, did not block autophagy, which was assessed by the accumulation of autolysosomes in the presence of a cysteine protease inhibitor. On the other hand, 3-methyladenine, an inhibitor of autophagy, did not affect the net degradation of PC. We labeled intracellular phospholipids by loading cells with a fluorochrome-labeled fatty acid and chased it under sucrose-free conditions. Glycerol slowed down the decrease in the amount of fluorochrome-labeled PC, suggesting that it inhibits the degradation process of PC. These results show that phospholipids are degraded by mechanisms different from autophagy in tobacco cells cultured under sucrose-free conditions.

Adenine↗
PubMed2006

Annexin A5 binding to giant phospholipid vesicles is differentially affected by anti-beta2-glycoprotein I and anti-annexin A5 antibodies.

OBJECTIVES: Anti-phospholipid antibodies have been recognized to play a role in vascular thrombosis and pregnancy morbidity. They were first thought to be directed to phospholipids, but it is now known that the majority of pathogenic antibodies recognizes epitopes on phospholipid-binding plasma proteins such as beta2-glycoprotein I (beta2GPI) or possibly also annexin A5 (ANXA5). The mechanism of their prothrombotic action is still not completely understood. The aim of the present study was to observe the effect of antibodies against ANXA5 (aANXA5) and antibodies against beta2GPI (abeta2GPI) on the binding of ANXA5 to the negatively charged phospholipid membrane. METHODS: Giant phospholipid vesicles (GPVs) were used as a simple model of the membrane surface. GPVs composed of phosphatidylserine and phosphatidylcholine were produced in an aqueous medium. A single GPV was transferred to the solution containing ANXA5 conjugated with Alexa Fluor 488 (FANXA5) and (i) aANXA5 or abeta2GPI and (ii) different concentrations of abeta2GPI together with beta2GPI. The emission of the fluorescent light from the GPV surface, as the result of FANXA5 binding, was measured. RESULTS: Beta2GPI together with abeta2GPI reduced the binding of FANXA5 to GPVs. On the contrary, aANXA5 enhanced the binding of ANXA5 to the GPV surface. CONCLUSIONS: Our results point to the competition between FANXA5 and complexes of beta2GPI-abeta2GPI for the same binding sites and therefore support the hypothesis of the disruption of the ANXA5 protective shield on procoagulant phospholipid surface. The influence of increased cell surface ANXA5 concentration in the presence of aANXA5 on coagulation needs to be further studied.

Annexin A5↗
PubMed2004

The metabolism of phospholipids oscillates rhythmically in cultures of fibroblasts and is regulated by the clock protein PERIOD 1.

The mammalian circadian timing system is composed of countless cell oscillators distributed throughout the body and central pacemakers regulating temporal physiology and behavior. Peripheral clocks display circadian rhythms in gene expression both in vivo and in culture. We examined the biosynthesis of phospholipids as well as the expression of the clock gene period 1 (Per1) and its potential involvement in the regulation of the phospholipid metabolism in cultured quiescent NIH 3T3 cells synchronized by a 2 h serum shock. A 30 min pulse of radiolabeled precursor was given at phases ranging from 0.5 to 62 h after serum treatment. We observed a daily rhythm in the phospholipid labeling that persisted at least for two cycles, with levels significantly decreasing 29 and 58 h after treatment. Per1 expression exhibited a rapid and transient induction and a daily rhythmicity in antiphase to the lipid labeling. After Per1 expression knockdown, the rhythm of phospholipid labeling was lost. Furthermore, in cultures of CLOCK mutant fibroblasts--cells with a clock mechanism impairment--PER1 was equally expressed at all times examined and the phospholipid labeling did not oscillate. The results demonstrate that the biosynthesis of phospholipids oscillates daily in cultured fibroblasts by an endogenous clock mechanism involving Per1 expression.

3T3 Cells↗
PubMed1997

Phospholipid metabolism in cholesterol-loaded macrophages.

Macrophage foam cells in atherosclerotic lesions accumulate free cholesterol as well as cholesteryl ester. In addition, these cells have an increased rate of phospholipid biosynthesis and accumulate intracellular phospholipid-containing membrane structures ('whorls'). Studies with cultured macrophages have revealed the possible molecular mechanism and biological relevance of these observations. A rate-limiting enzyme of phosphatidylcholine biosynthesis, cytidine triphosphate: phosphocholine cytidylyltransferase, is post-translationally activated in response to the accumulation of free cholesterol in macrophages. This leads to an increase in phosphatidylcholine mass and the appearance of membrane whorls in these cells. We have advanced the hypothesis that this alteration in cellular phospholipid metabolism is an adaptive response to prevent the cellular free cholesterol: phospholipid ratio from reaching cytotoxic levels. Support for this hypothesis was obtained by demonstrating a direct relationship between the free cholesterol: phospholipid ratio and cellular necrosis in cultured macrophages, especially under conditions in which the phosphatidylcholine response was experimentally blunted. We propose that the eventual inability of this phospholipid response to keep up with free cholesterol accumulation in lesional macrophages in vivo may be an important cause of macrophage necrosis and, thus, plaque progression and clinical events in advanced atherosclerotic lesions.

Animals↗
PubMed1994

Phospholipids of Mycobacterium intracellulare inhibit T cell blastogenesis.

A crude lipid fraction obtained from Mycobacterium intracellulare (MI whole lipids) suppressed concanavalin A (Con A)-induced blastogenesis of murine spleen cells (SPCs). Among three lipid fractions, the phospholipid fraction possessed the highest inhibitory activity, followed by the polar mycoside fraction, but the apolar mycoside fraction showed no activity. Since MI whole lipid and phospholipid fractions inhibited the Con A-induced proliferative response of SPCs which had been treated with Con A before the addition of the lipid fractions, their action is not due to hindrance of Con A binding to T cells. These two MI lipid fractions reduced IL-2-producing ability, acquisition of IL-2 reactivity, and expression of IL-2 receptors in Con A-stimulated T cells. However, they did not affect IL-2-induced proliferation of an IL-2-dependent cytotoxic T cell line, CTLL-2. When SPCs were pretreated with either MI whole lipid or phospholipid fraction for 24 h, an irreversible reduction in Con A responsiveness was seen only in the phospholipid-treated SPCs. The action of these MI lipid fractions was phase-dependent and they exhibited considerably decreased but still significant inhibitory activity against Con A blastogenesis of SPCs, even when they were added at 24 h after the initiation of SPC culture with Con A. MI whole lipids and the three lipid fractions (polar mycoside, apolar mycoside, and phospholipid fractions) did not exhibit suppressor cell-inducing activity, while MI whole lipid fraction antagonized the Con A-mediated generation of suppressor cells. Silica gel thin layer chromatography of the phospholipid fraction showed four spots containing phosphate and one spot without.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1977

Incorporation of 32PO4 into phospholipids of blood platelets.

Human or rabbit platelets in an artificial medium without phosphate were incubated with carrier-free [32P] orthophosphate for I h, washed and resuspended in Tyrode-albumin solution containing unlabelled phosphate. Aliquots of platelet suspension were subjected to lipid extraction at various times and the extracted phospholipids were separated by thin layer chromatography. The specific radioactivities of triphosphoinositide (TPI) and diphosphoinositide (DPI) were highest during the labelling period and then declined rapidly after the platelets were resuspended in the medium containing unlabelled phosphate. The percentage of total phospholipid 32P in TPI and DPI decreased from over 95% at 1 h to less than 50% at 12 h with either rabbit or human platelets. The specific radioactivity of monophosphoinositide (MPI) reached its greatest value 6-8 h after labelling. In the in vitro incubation studies, phosphatidylcholine (PC), phosphatidylserine (PS) and phosphatidylethanolamine (PE) were negligibly labelled in the initial hours but at 12 h (rabbit or human platelets) PC contained more than 30% of the radioactivity. PE and PS contained less than 10% of the total phospholipid-bound radioactivity at the end of the incubation period. The pattern of incorporation of [32P]orthophosphate into the inositol phospholipids, PC, PS and PE that had been found in the in vitro studies was confirmed by an in vivo study in which rabbit platelets labelled with 32P in vitro were infused into rabbits and harvested after 35 h. These findings indicate that the phosphates of all the phospholipids studied in these experiments turn over in vitro and in vivo but the phosphates of the inositol phospholipids turn over most rapidly.

Animals↗
PubMed1977

Phospholipid binding and self-association of the major apoprotein of human and baboon high-density lipoproteins.

The purpose of this study was to establish a relationship between self-association and phospholipid binding of the human and the baboon apoA-I protein. The enthalpy changes on binding dimyristoyl lecithin and lysolecithin to either the human or the baboon native apoA-I protein were measured in a microcalorimeter. An endothermal process, most pronounced for the human apoprotein, was observed at low phospholipid levels. At higher phospholipid to protein ratios the binding was exothermal. Gel filtration experiments on Sephadex G-200 showed that the native apoprotein of both species consists of dimers and tetramers. The baboon native apoA-I protein contained a higher amount of dimers. After preincubation of the apoA-I protein with lysolecithin, the enthalpy changes measured on subsequent binding of dimyristoyl lecithin were shifted towards more exothermal values compared to the curve for the native apoprotein. The amplitude of this shift corresponds to that of the endothermal process observed on binding dimyristoyl lecithin to the native apoprotein. This process was attributed to a phospholipid-induced disaggregation of the apoA-I protein. Gel filtration data showed a decreased extent of aggregation in the apoA-I protein preincubated with lysolecithin. This sample consisted exclusively of dimers. Ultracentrifugal flotation of the complexes formed between the apoA-I protein, and respectively dimyristoyl lecithin and sphingomyelin indicated that preincubation with lysolecithin increased the extent of complex formation. These results suggest that the dimeric form of the apoA-I protein possesses the highest affinity for phospholipids. Any dissociation of higher polymers enhances the phospholipid-binding capacity of the human and the baboon apoA-I protein.

Animals↗
PubMed1984

Binding of adriamycin-Fe3+ complex to membrane phospholipids.

Binding of adriamycin-Fe3+ complex to phospholipids has been examined by phase partitioning in a hexane-water system. Formation of a stable ternary adriamycin-Fe3+-lipid complex with the negatively charged phospholipids cardiolipin and phosphatidylglycerol (both isolated from Escherichia coli) and synthetic dioleoyl glycerophosphoglycerol is demonstrated. Binding of adriamycin-Fe3+ complex to phospholipid bilayers was assessed by incubation of the complex with aqueous phospholipid dispersions prepared from synthetic dimyristoyl glycerophosphocholine, E. coli phosphatidylethanolamine or E. coli cardiolipin and from mixtures of these lipids. Binding of the complex to the phospholipids took place with an affinity for cardiolipin greater than phosphatidylethanolamine greater than phosphatidylcholine. The ternary adriamycin-Fe3+-ADP complex formed in the presence of 1 mM ADP (ADP in 25-fold molar excess to adriamycin) showed low affinity for binding to phospholipid.

Cardiolipins↗
PubMed1992

Identification of two domains which mediate the binding of activating phospholipids to the plasma-membrane Ca2+ pump.

The stimulation of the purified human erythrocyte calcium pump by acidic phospholipids was investigated using synthetic peptides corresponding to a putative phospholipid-responsive domain [Zvaritch, E., James, P., Vorherr, T., Falchetto, R., Modyanov, N. & Carafoli, E. (1990) Biochemistry 29, 8070-8076] and to the calmodulin-binding domain of the pump. The peptides interfered with the activation of the enzyme by phosphatidylserine and phosphatidic acid in competition assays. The peptide corresponding to the calmodulin-binding domain was found to be the most efficient antagonist. Direct binding measurements using fluorescent derivatives of the peptides confirmed the interaction between the acidic phospholipids and the peptides, and fluorescence titrations of dansylated calmodulin with the purified ATPase showed a direct effect of acidic phospholipids on calmodulin binding. A proteolyzed preparation of the Ca(2+)-ATPase lacking the calmodulin-binding domain confirmed that the phospholipid-induced stimulation is mediated by two sites, one located in the C-terminal portion of the previously identified 44-amino-acid phospholipid-responsive domain, the other in the calmodulin-binding domain.

Amino Acid Sequence↗
PubMed1994

Surface potential regulation of phospholipid composition and in-out translocation in yeast.

In yeast cells the anionic phospholipids, phosphatidylinositol and phosphatidylserine, determine to a large extent the magnitude of the negative surface charge density (sigma) [Cerbón, J. & Calderón, V. (1990) Biochim. Biophys. Acta 1028, 261-267]. We now report further findings. (a) When the yeast phi out was reduced by increasing the concentration of monovalent (C+) or divalent (C2+) cations in the culture medium, the relative amount of anionic phospholipids increased (45-52%). (b) For each such increment, a corresponding increase in the external surface charge density (sigma) was found, due to the translocation from the cytoplasmic side to the exoplasmic side of the plasma membrane. (c) These changes were reversed when the phi out was increased by reducing the concentration of cations in the culture medium. (d) When the phi out was reduced and phosphatidylserine decarboxylation or phosphatidylinositol degradation were inhibited, to measure synthesis of anionic phospholipids, a 1.4 times further increase in the anionic/zwitterionic phospholipid ratio occurred. As a consequence, a similar increase in the external surface charge (sigma) was found. (e) Under all the conditions studied, the percentage of anionic phospholipid at the external surface of the plasma membrane calculated from the sigma values was 2.3-3.0 times less than that in the cells, indicating that the asymmetric composition (more inside) was maintained. A model for the regulation of the anionic phospholipid composition of the yeast membranes is proposed.

Cell Membrane↗
PubMed1990

Clinical evaluation of a direct colorimetic method for determination of amniotic phospholipids.

Evaluation of amniotic phospholipids, which are a parameter of fetal lung maturation, is important in the management of premature infants. The method available for measuring the lecithin/sphingomyelin (L/S) ratio, which appears to provide an index to fetal lung maturity, is laborious, involving determinations of phospholipids, and so is unsuitable for rapid quantitative measurement of phospholipids in the amniotic fluid in the perinatal period. We developed a simple, sensitive colorimetric assay for phospholipids without their extraction. This assay is based on the fact that phospholipids form stable hydrophobic complexes with Co(SCN)4, Fe(SCN)2- and Fe(SCN)3 within about 1 hr. Amniotic fluid samples (n = 115) were collected from women with normal and abnormal pregnancies in week 16-41 of pregnancy, and these samples were examined both by thin layer chromatography (TLC) and by our method of phospholipid determination. Good correlations were observed between the L/S ratio determined by TLC and the values obtained by this method. Moreover the distributions of the dipalmitoylphosphatidylcholine (DPPC) content and DPPC/sphingomyelin (SM) ratio were similar to those of the PC content and L/S ratio. This method was proved to be more accurate than other methods such as TLC and the shake test for predicting neonatal RDS.

Amniotic Fluid↗
PubMed1981

Turnover of axonally transported phospholipids in nerve endings of retinal ganglion cells.

We have investigated the metabolic turnover of axonally transported phospholipids in myelinated axons (optic tract) and nerve endings (superior colliculus) of retinal ganglion cells. One week following intraocular injection of [2-3H]glycerol, turnover rates for individual phospholipid classes in the retina (which contains a number of other cell types in addition to the ganglion cells) were all very similar to each other, with apparent half-lives of approximately 7 days. Apparent half-lives of labeled phospholipids in superior colliculus (presumably primarily in retinal ganglion cell nerve endings) were 10 days for both choline and inositol phosphoglycerides and 13 days for both serine and diacylethanolamine phosphoglycerides. Subcellular fractionation data obtained from superior colliculus at various times after injection suggested that apparent turnover rates determined for nerve ending phospholipids probably were not significantly affected by transfer of axonally transported 3H lipids into myelin. Apparent half-lives for phospholipids in optic tract were somewhat longer than in superior colliculus, ranging from 11 to 18 days. The slower turnover rates in optic tract may, in part, reflect the transfer of some axonal lipids to the more metabolically stable pool of lipids in the myelin ensheathing the retinal ganglion cell axons. In both optic tract and superior colliculus, apparent half-lives for axonally transported phospholipids labeled with [32P]phosphate were only slightly longer than for [2-3H]glycerol, while those for [14C]choline and [3H]acetate were markedly longer, indicating differing degrees of metabolic conservation or reutilization of these precursors relative to glycerol.

Acetates↗
PubMed1985

Does phospholipid methylation play a role in the primary mechanism of action of nerve growth factor?

Nerve growth factor (NGF)-untreated (naive) and neurite-bearing NGF-treated ("primed") PC12 rat pheochromocytoma cells were used as model system to study the role of phospholipid methylation in the NGF mechanism of action. The neurite-bearing cultures were deprived of NGF for 3 h before experimentation. Under both experimental conditions, the cells were labelled with [methyl-3H]methionine and then challenged with NGF for time periods ranging from 5 s to 30 min. Methylated phospholipids were extracted and then resolved and identified by TLC as phosphatidyl mono-, di-, and trimethyl ethanolamine. Quantification of the amount of radioactivity incorporated into each of the phospholipids indicated that NGF does not significantly alter phospholipid methylation either in naive or in neurite-bearing cells. Furthermore, using a methyltransferase inhibitor, it was found that neurite outgrowth still occurs when phospholipid methylation is almost completely blocked. These results indicate that phospholipid methylation does not play a primary role in the mechanism of action of NGF.

Animals↗
PubMed1985

Normal myelin composition and phospholipid synthesis in adrenalectomized rats with reduced brain myelin and glycerol 3-phosphate dehydrogenase activity.

The composition of CNS myelin was investigated in rats adrenalectomized at day 14 and killed 7 days later, previously shown to result in a 25% reduction in the amount of bulk-isolated myelin and a 40% decrease in brain glycerol 3-phosphate dehydrogenase activity. The proportions of the major myelin proteins, as well as the specific activity of 2',3'-cyclic nucleotide 3'-phosphohydrolase, were the same in the myelin from both adrenalectomized and control animals. The amount of total phospholipid and the proportions of individual phospholipids were also normal in myelin from the adrenalectomized animals. The amount of nonmyelin phospholipid in whole brain was unchanged by adrenalectomy. Labeling studies carried out 4 days after adrenalectomy of 14-day-old animals showed no change in the synthesis rates of the major myelin phospholipids as compared with the synthesis rate of nonmyelin phospholipids. Furthermore, incorporation of [1,(3)-14C]glycerol into the glycerol moiety of ethanolamine plasmalogen, which requires glycerol 3-phosphate dehydrogenase, was also normal, showing that the reduced oligodendroglial glycerol 3-phosphate dehydrogenase activity following adrenalectomy was not rate-limiting for myelin phospholipid synthesis.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
PubMed1987

Phospholipid metabolism in mouse sciatic nerve in vivo.

To probe the activities of various pathways of lipid metabolism in peripheral nerve, six phospholipid-directed precursors were individually injected into the exposed sciatic nerves of adult mice, and their incorporation into phospholipids and proteins was studied over a 2-week period. Tritiated choline, inositol, ethanolamine, serine, and glycerol were mainly used in phospholipid synthesis; in contrast, methyl-labeled methionine was primarily incorporated into protein. Phosphatidylcholine was the main lipid formed from tritiated choline, glycerol, and methionine precursors. Phosphatidylserine, phosphatidylethanolamine, and phosphatidylinositol were the main lipids formed from serine, ethanolamine, and inositol, respectively. With time there was a shift in label among phospholipids, with higher proportions of choline appearing in sphingomyelin, glycerol in phosphatidylserine, ethanolamine in phosphatidylethanolamine (plasmalogen), and inositol in polyphosphoinositides, especially phosphatidylinositol 4,5-bisphosphate. We suggest that the delay in formation of these phospholipids, which are concentrated in peripheral nerve myelin, may, at least in part, be due to their formation at a site(s) distant from the sites where the bulk of Schwann cell lipids are made. We propose that separating the synthesis of these myelin-destined lipids to near the Schwann cell's plasma membrane would facilitate their concentration in peripheral nerve myelin sheaths. At earlier labeling times, ethanolamine and glycerol were more actively incorporated into phosphatidylcholine and phosphatidylinositol, respectively, than later. The transient labeling of these phospholipids may reflect some unique role in peripheral nerve function.

Animals↗
PubMed2004

Phospholipid synthesis is decreased in neuronal tissue in a mouse model of Sandhoff disease.

Sandhoff disease is a progressive neurodegenerative disorder caused by mutations in the HEXB gene which encodes for the beta-subunit of beta-hexosaminidase A and B, resulting in ganglioside GM(2) accumulation in the brain. We now demonstrate that phospholipid metabolism is altered in both cultured neurons and in brain tissue from a mouse model of Sandhoff disease, the Hexb-/- mouse. Metabolic labelling using [methyl-(14)C]choline and l-[3-(3)H]serine demonstrated reduced incorporation of [methyl-(14)C]choline into phospholipids in brain tissue but not in liver or spleen. Phospholipid mass was also reduced in brain. The activities of CTP : phosphocholine cytidylyltransferase (CCT) and phosphatidylserine synthase were also reduced in brain tissue from Hexb-/- mice, probably because of post-translational modification as no changes were observed in levels of enzyme expression. The relevance of these findings to Sandhoff disease in human patients is strengthened by observations made over 30 years ago on autopsy tissue of Tay Sachs and Sandhoff disease patients, in which reduced phospholipid levels were observed. We suggest that changes in phospholipid metabolism are not simply because of loss of neuronal tissue as a result of degeneration but rather may cause degeneration, and we discuss the possible effects that changes in phospholipid metabolism could play in the neuropathophysiology of Sandhoff disease.

Animals↗