The mechanism of polyribosome disaggregation in brain tissue by phenylalanine

Taub, Floyd; Johnson, Terry C.

doi:10.1042/bj1510173

Cited by 55 publications

(28 citation statements)

References 32 publications

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“…Presumably, these templates alone were responsible for the steady-state synthesis of viral proteins and of those cellular proteins whose translation was not affected by infection. The salt-sensitive 80S subunits induced during infection were devoid of mRNA and presumably composed of "vacant couples" or empty pairings of 40S with 60S (28).…”

Section: Resultsmentioning

confidence: 99%

Cardiovirus 2A Protein Associates with 40S but Not 80S Ribosome Subunits during Infection

Groppo

Palmenberg

2007

J Virol

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Host translation shutoff induced in picornavirus-infected cells is a well-known phenomenon. The mechanisms by which separate genera of the picornavirus family achieve this shutoff differ. This study examined alterations in the cellular translational components in HeLa cells infected with encephalomyocarditis virus (EMCV), a cardiovirus. In agreement with previous reports, EMCV induced a marked decrease in host mRNA translation. The inhibition correlated with the appearance of a significantly enhanced 80S peak in cells and a concomitant decrease in polysome abundance. Characterization of the 80S material revealed that these ribosomes were virtually devoid of mRNA. Viral protein 2A was tightly associated with some of the free 40S ribosome subunits, but it was not present in the 80S pool which accumulated after infection. Expression of 2A protein in cells in the absence infection was able to modulate the cellular translational environment to increase the ratio of internal ribosome entry site-dependent translation to cap-dependent translation of a reporter construct. The results provide further evidence for a role of 2A protein in the mechanism of cardiovirusinduced host translational shutoff.

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Section: Resultsmentioning

confidence: 99%

Cardiovirus 2A Protein Associates with 40S but Not 80S Ribosome Subunits during Infection

Groppo

Palmenberg

2007

J Virol

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“…It is therefore unlikely that phenylalanine loading causes the rise in ribonuclease activity that in turn leads to the disaggregation of polysomes. Taub and Johnson (1975) reported that the effect of phenylalanine on the integrity of brain polysomes is independent of ribonuclease action. This suggests that hyperphenylalaninemia in pregnant rats inhibits protein synthesis, presumably because it disturbs amino acid pools in the fetal heart and brain.…”

Section: Discussionmentioning

confidence: 98%

Effects of phenylalanine loading on protein synthesis in the fetal heart and brain of rat: an experimental approach to maternal phenylketonuria

Okano

Chow

Isshiki

et al. 1985

J of Inher Metab Disea

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Pregnant rats were loaded with L-phenylalanine, and the distributions of [14C]leucine and [14C]urea into fetal plasma and tissues were examined. Uptake of [14C]leucine into the supernatant and protein fractions of fetal plasma and tissues was low in the rats loaded with phenylalanine. In contrast, [14C]urea was distributed identically in both groups, indicating that maternal hyperphenylalaninemia did not affect blood flow across the placenta. Administration of phenylalanine and p-chlorophenylalanine produced amino acid imbalance in fetal tissues. Along with these changes, polysomes of the affected fetal heart and brain disaggregated without changes in the ribonuclease activity. These results indicate that high phenylalanine levels in maternal plasma disturb the active transport of amino acids across the placenta, causing an amino acid imbalance and disaggregation of polysomes in fetal heart and brain. These changes may contribute to the congenital heart disease and mental retardation of maternal phenylketonuria.

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“…Recent findings show that leucine plays a role not only as a substrate for protein synthesis but also as a signalling molecule for translation initiation (mTor complex, see below). Taub and Johnson (1975) had observed that phenylalanine injections led to polyribosome disaggregation in the brain in neonatal mice and concluded that Fthe monomeric (80S) ribosomes were inactive ... with regard to protein synthesis_. Current MRS techniques (at 1.5 T) are not sensitive enough to measure physiological or even decreased concentrations of LNAAs in the low micromolar range and no in vivo data on the brain concentrations of leucine in PKU patients are available to our knowledge.…”

Section: Brain Uptake Velocity Of Leucinementioning

confidence: 97%

Interpretation of plasma amino acids in the follow‐up of patients: The impact of compartmentation

Bachmann

2008

J of Inher Metab Disea

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Results of plasma or urinary amino acids are used for suspicion, confirmation or exclusion of diagnosis, monitoring of treatment, prevention and prognosis in inborn errors of amino acid metabolism. The concentrations in plasma or whole blood do not necessarily reflect the relevant metabolite concentrations in organs such as the brain or in cell compartments; this is especially the case in disorders that are not solely expressed in liver and/or in those which also affect nonessential amino acids. Basic biochemical knowledge has added much to the understanding of zonation and compartmentation of expressed proteins and metabolites in organs, cells and cell organelles. In this paper, selected old and new biochemical findings in PKU, urea cycle disorders and nonketotic hyperglycinaemia are reviewed; the aim is to show that integrating the knowledge gained in the last decades on enzymes and transporters related to amino acid metabolism allows a more extensive interpretation of biochemical results obtained for diagnosis and follow-up of patients and may help to pose new questions and to avoid pitfalls. The analysis and interpretation of amino acid measurements in physiological fluids should not be restricted to a few amino acids but should encompass the whole quantitative profile and include other pathophysiological markers. This is important if the patient appears not to respond as expected to treatment and is needed when investigating new therapies. We suggest that amino acid imbalance in the relevant compartments caused by over-zealous or protocol-driven treatment that is not adjusted to the individual patient's needs may prolong catabolism and must be corrected.

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The mechanism of polyribosome disaggregation in brain tissue by phenylalanine

Cited by 55 publications

References 32 publications

Cardiovirus 2A Protein Associates with 40S but Not 80S Ribosome Subunits during Infection

Cardiovirus 2A Protein Associates with 40S but Not 80S Ribosome Subunits during Infection

Effects of phenylalanine loading on protein synthesis in the fetal heart and brain of rat: an experimental approach to maternal phenylketonuria

Interpretation of plasma amino acids in the follow‐up of patients: The impact of compartmentation

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