Phenylketonuria: Brain Phenylalanine Concentrations Relate Inversely to Cerebral Protein Synthesis

Abstract

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.

A Multiplatform Metabolomics Approach to Characterize Plasma Levels of Phenylalanine and Tyrosine in Phenylketonuria

“…METPA analysis highlighted the involvement of Arg, Pro, and Ala, Asp, Glu metabolism. One of the most described pathophysiological ways in PKU is the defect in central nervous system protein synthesis (de Groot et al 2015). Numerous authors highlighted a significant negative correlation between plasma Phe levels and the cerebral protein synthesis rate, based on positron emission tomography in PKU patients, and experiments in animal or in vitro models (Schuck et al 2015).…”

Large Neutral Amino Acid Supplementation Exerts Its Effect through Three Synergistic Mechanisms: Proof of Principle in Phenylketonuria Mice

“…Based on both the increased Phe and the decreased non-Phe LNAA transport across the BBB, different brain biochemical disturbances underlie brain dysfunction in PKU [ 3 , 9 ]. High brain Phe concentrations have been found to be neurotoxic and to affect brain metabolism [ 10 – 14 ], while reduced brain availability of non-Phe LNAA has been related to impaired cerebral protein synthesis [ 6 , 15 ]. In addition, impaired cerebral monoaminergic neurotransmitter synthesis may result from outcompeted brain uptake of their amino acid precursors tyrosine and tryptophan [ 16 ], and/or from an inhibitory effect of high brain Phe concentrations on tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) [ 17 ].…”

White matter disturbances in phenylketonuria: Possible underlying mechanisms

“…Decreased rates of protein synthesis and transport of large neutral amino acids into the CNS, formation of Phe oligomers and fibrils, as well as impaired energy metabolism and myelination have been shown under HPA conditions (Adler-Abramovich et al, 2012;Berti et al, 2012;Hoeksma et al, 2009;Landvogt et al, 2008). Studies evidenced that a reduction in brain protein synthesis is at least partially related to impaired transport of tyrosine to the CNS via blood-brain barrier, therefore decreasing the incorporation of this amino acid into proteins (de Groot et al, 2013;de Groot, Sijens, Reijngoud, Paans, & Spronsen, 2014). Formation of Phe amyloid-like fibrils was shown in PKU mouse models and PKU patients (Adler-Abramovich et al, 2012).…”