Effect of phenylalanine on protein synthesis in the developing rat brain.
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ABSTRACT:
SUBMITTER: Agrawal HC
PROVIDER: S-EPMC1178865 | biostudies-other | 1970 Apr
REPOSITORIES: biostudies-other
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Project description:Increasing the plasma phenylalanine concentration to levels as high as 0.560-0.870 mM (over ten times normal levels) had no detectable effect on the rate of brain protein synthesis in adult rats. The average rates for 7-week-old rats were: valine, 0.58 +/- 0.05%/h, phenylalanine, 0.59 +/- 0.06%/h, and tyrosine, 0.60 +/- 0.09%/h, or 0.59 +/- 0.06%/h overall. Synthesis rates calculated on the basis of the specific activity of the tRNA-bound amino acid were slightly lower (4% lower for phenylalanine) than those based on the brain free amino acid pool. Similarly, the specific activities of valine and phenylalanine in microdialysis fluid from striatum were practically the same as those in the brain free amino acid pool. Thus the specific activities of the valine and phenylalanine brain free pools are good measures of the precursor specific activity for protein synthesis. In any event, synthesis rates, whether based on the specific activities of the amino acids in the brain free pool or those bound to tRNA, were unaffected by elevated levels of plasma phenylalanine. Brain protein synthesis rates measured after the administration of quite large doses of phenylalanine (> 1.5 mumol/g) or valine (15 mumol/g) were in agreement (0.62 +/- 0.01 and 0.65 +/- 0.01%/h respectively) with the rates determined with infusions of trace amounts of amino acids. Thus the technique of stabilizing precursor-specific activity, and pushing values in the brain close to those of the plasma, by the administration of large quantities of precursor, appears to be valid.
| S-EPMC1137270 | biostudies-other
Project description:In phenylketonuria, elevated plasma phenylalanine concentrations may disturb blood-to-brain large neutral amino acid (LNAA) transport and cerebral protein synthesis (CPS). We investigated the associations between these processes, using data obtained by positron emission tomography with l-[1-(11)C]-tyrosine ((11)C-Tyr) as a tracer. Blood-to-brain transport of non-Phe LNAAs was modeled by the rate constant for (11)C-Tyr transport from arterial plasma to brain tissue (K1), while CPS was modeled by the rate constant for (11)C-Tyr incorporation into cerebral protein (k3). Brain phenylalanine concentrations were measured by magnetic resonance spectroscopy in three volumes of interest (VOIs): supraventricular brain tissue (VOI 1), ventricular brain tissue (VOI 2), and fluid-containing ventricular voxels (VOI 3). The associations between k3 and each predictor variable were analyzed by multiple linear regression. The rate constant k3 was inversely associated with brain phenylalanine concentrations in VOIs 2 and 3 (adjusted R(2)=0.826, F=19.936, P=0.021). Since brain phenylalanine concentrations in these VOIs highly correlated with each other, the specific associations of each predictor with k3 could not be determined. The associations between k3 and plasma phenylalanine concentration, K1, and brain phenylalanine concentrations in VOI 1 were nonsignificant. In conclusion, our study shows an inverse association between k3 and increased brain phenylalanine concentrations.
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Project description:Fetal alcohol syndrome is a neurological and developmental disorder caused by exposure of developing brain to ethanol. Administration of osmotin to rat pups reduced ethanol-induced apoptosis in cortical and hippocampal neurons. Osmotin, a plant protein, mitigated the ethanol-induced increases in cytochrome c, cleaved caspase-3, and PARP-1. Osmotin and ethanol reduced ethanol neurotoxicity both in vivo and in vitro by reducing the protein levels of cleaved caspase-3, intracellular [Ca(2+)]cyt, and mitochondrial transmembrane potential collapse, and also upregulated antiapoptotic Bcl-2 protein. Osmotin is a homolog of adiponectin, and it controls energy metabolism via phosphorylation. Adiponectin can protect hippocampal neurons against ethanol-induced apoptosis. Abrogation of signaling via receptors AdipoR1 or AdipoR2, by transfection with siRNAs, reduced the ability of osmotin and adiponectin to protect neurons against ethanol-induced neurodegeneration. Metformin, an activator of AMPK (adenosine monophosphate-activated protein kinase), increased whereas Compound C, an inhibitor of AMPK pathway, reduced the ability of osmotin and adiponectin to protect against ethanol-induced apoptosis. Osmotin exerted its neuroprotection via Bcl-2 family proteins and activation of AMPK signaling pathway. Modulation of AMPK pathways by osmotin, adiponectin, and metformin hold promise as a preventive therapy for fetal alcohol syndrome.
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Project description:The brains of 3--16-day-old rats that were rendered hyperphenylalaninaemic by daily injections of alpha-methylphenylalanine plus phenylalanine were subjected to biochemical analysis. Fluctuations throughout the treatment period in the concentrations of branched-chain amino acids, methionine and serotonin were in agreement with the known interference of excess plasma phenylalanine with transport. The glycine content, however, became abnormal only by day 5, remained so through the treatment, and the elevation was equally apparent at 4, 8 or 24 h after the last daily injections. On the last day of treatment there were small increases in the taurine, glutamate, aspartate and 4-aminobutyrate concentrations, attributable mainly to the diencephalon or brain stem. After day 3 of treatment there were persistent elevations in the specific activity of phosphoserine phosphatase and glycine synthase (but not serine hydroxymethyltransferase) of the brain in each of the regions analysed. The observations indicate that chronic hyperphenylalaninaemia interferes with the normal regulation of intracerebral glycine metabolism during a critical period of early postnatal development, and suggest that the resulting excess in this amino acid (particularly marked in the cortex) contributes to the behavioural abnormalities that these animals exhibit in later life.
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Project description:Energy use in the brain constrains its information processing power, but only about half the brain's energy consumption is directly related to information processing. Evidence for which non-signalling processes consume the rest of the brain's energy has been scarce. For the first time, we investigated the energy use of the brain's main non-signalling tasks with a single method. After blocking each non-signalling process, we measured oxygen level changes in juvenile rat brain slices with an oxygen-sensing microelectrode and calculated changes in oxygen consumption throughout the slice using a modified diffusion equation. We found that the turnover of the actin and microtubule cytoskeleton, followed by lipid synthesis, are significant energy drains, contributing 25%, 22% and 18%, respectively, to the rate of oxygen consumption. In contrast, protein synthesis is energetically inexpensive. We assess how these estimates of energy expenditure relate to brain energy use in vivo, and how they might differ in the mature brain.
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Project description:In spite of intense interest in how altered epigenetic processes including DNA methylation may contribute to psychiatric and neurodevelopmental disorders, there is a limited understanding of how methylation processes change during early postnatal brain development. The present study used in situ hybridization to assess mRNA expression for the three major DNA methyltranserases (DNMTs)--DNMT1, DNMT3a and DNMT3b--in the developing rat brain at seven developmental timepoints: postnatal days (P) 1, 4, 7, 10, 14, 21, and 75. We also assessed 5-methylcytosine levels (an indicator of global DNA methylation) in selected brain regions during the first three postnatal weeks. DNMT1, DNMT3a and DNMT3b mRNAs are widely expressed throughout the adult and postnatal developing rat brain. Overall, DNMT mRNA levels reached their highest point in the first week of life and gradually decreased over the first three postnatal weeks within the hippocampus, amygdala, striatum, cingulate and lateral septum. Global DNA methylation levels did not follow this developmental pattern; methylation levels gradually increased over the first three postnatal weeks in the hippocampus, and remained stable in the developing amygdala and prefrontal cortex. Our results contribute to a growing understanding of how DNA methylation markers unfold in the developing brain, and highlight how these developmental processes may differ within distinct brain regions.
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Project description:Liver phenylalanine hydroxylase (PheH) is an allosteric enzyme that requires activation by phenylalanine for full activity. The location of the allosteric site for phenylalanine has not been established. NMR spectroscopy of the isolated regulatory domain (RDPheH(25-117) is the regulatory domain of PheH lacking residues 1-24) of the rat enzyme in the presence of phenylalanine is consistent with formation of a side-by-side ACT dimer. Six residues in RDPheH(25-117) were identified as being in the phenylalanine-binding site on the basis of intermolecular NOEs between unlabeled phenylalanine and isotopically labeled protein. The location of these residues is consistent with two allosteric sites per dimer, with each site containing residues from both monomers. Site-specific variants of five of the residues (E44Q, A47G, L48V, L62V, and H64N) decreased the affinity of RDPheH(25-117) for phenylalanine based on the ability to stabilize the dimer. Incorporation of the A47G, L48V, and H64N mutations into the intact protein increased the concentration of phenylalanine required for activation. The results identify the location of the allosteric site as the interface of the regulatory domain dimer formed in activated PheH.
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Project description:1. The effects of treatment with thyroid hormone (tri-iodothyronine) and of neonatal thyroidectomy on the cerebral metabolism of [U-(14)C]leucine were investigated during the period of functional maturation of the rat brain extending from 9 to 25 days after birth. 2. Age-dependent changes in the labelling of brain constituents under normal conditions appear to depend on changes in the availability of blood-borne [(14)C]leucine resulting from differential rates of growth of body and brain; but developmental changes in the pool size of free leucine and in the rates of protein synthesis and oxidation of leucine are also involved. 3. Treatment with thyroid hormone had no significant effect on the conversion of leucine carbon into proteins and lipids; and the age-dependent changes in the concentration and specific radioactivity of leucine were similar to controls. On the other hand there was an acceleration in the conversion of leucine carbon into amino acids associated with the tricarboxylic acid cycle. These observations indicate that leucine oxidation was the process mainly affected. 4. The specific radioactivity of glutamine relative to that of glutamate was used as an index of metabolic compartmentation in brain tissue. Treatment with thyroid hormone advanced the development of metabolic compartmentation. 5. Neonatal thyroidectomy led to a marked decrease in the conversion of leucine carbon into proteins and lipids and to a significant increase in the amount of (14)C combined in the amino acids associated with the tricarboxylic acid cycle. The age-dependent increase in the glutamate/glutamine specific-radioactivity ratio was strongly retarded. 6. The increased conversion of leucine carbon into cerebral amino acids applied to glutamate and aspartate, but not to glutamine and gamma-aminobutyrate. This observation facilitated the understanding of the effects of thyroid deprivation on brain metabolism and provided new evidence for the allocation of morphological structures to the metabolic compartments in brain tissue. 7. In contrast with the marked effects of the thyroid state on metabolic compartmentation, it had relatively little effect on the developmental changes in the concentration of amino acids in the brain. 8. The rate of conversion of leucine carbon into the ;cycle amino acids' both under normal conditions and in thyroid deficiency indicated a special metabolic relationship between glutamate and aspartate on the one hand, and glutamine and gamma-aminobutyrate on the other.
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Project description:Microglia are the resident immune cells within the brain and their production of immune molecules such as cytokines and chemokines is critical for the processes of normal brain development including neurogenesis, axonal migration, synapse formation, and programmed cell death. Notably, sex differences exist in many of these processes throughout brain development; however, it is unknown whether a sex difference concurrently exists in the colonization, number, or morphology of microglia within the developing brain. We demonstrate for the first time that the number and morphology of microglia throughout development is dependent upon the sex and age of the individual, as well as the brain region of interest. Males have overall more microglia early in postnatal development [postnatal day (P) 4], whereas females have more microglia with an activated/amoeboid morphology later in development, as juveniles and adults (P30-60). Finally, gene expression of a large number of cytokines, chemokines and their receptors shifts dramatically over development, and is highly dependent upon sex. Taken together, these data warrant further research into the role that sex-dependent mechanisms may play in microglial colonization, number, and function, and their potential contribution to neural development, function, or potential dysfunction.
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