Abstract
Phenylketonuria (PKU) is an inherited metabolic disease characterized by abnormally high concentrations of the essential amino acid L-phenylalanine (Phe) in blood plasma caused by reduced activity of phenylalanine hydroxylase (PAH). While numerous studies have shown association between high plasma Phe concentration and intellectual impairment, it is not clear whether increased Phe fluctuations also observed in PKU affect the brain as well. To investigate this, time-resolved in vivo data on Phe and competing large neutral amino acid (LNAA) concentrations in neurons are needed, but cannot be acquired readily with current methods. We have used in silico modeling as an alternative approach to characterize the interactive dynamics of Phe and competing LNAAs (CL) in the neurovascular unit (NVU). Our results suggest that plasma Phe fluctuations can propagate into the NVU cells and change there the concentration of LNAAs, with the highest magnitude of this effect observed at low frequency and high amplitude-to-mean ratio of the plasma Phe concentration fluctuations. Our model further elucidates the effect of therapeutic LNAA supplementation in PKU, showing how abnormal concentrations of Phe and CL in the NVU move thereby toward normal physiologic levels.
Highlights
Phenylketonuria (PKU) is the most common disorder of amino acid (AA) metabolism, resulting from severely reduced activity of the liver enzyme phenylalanine hydroxylase (PAH), which leads to abnormal accumulation of the essential amino acid L-phenylalanine (Phe) in the blood plasma (Güttler et al, 1969; Madden, 2004; Regier and Greene, 2017)
Phe is transported across the blood brain barrier (BBB) into the neurovascular unit (NVU), where abnormal increase in its concentration leads to imbalance of large neutral amino acid (LNAA) levels in brain interstitial fluid (ISF), astrocytes and neurons, as a consequence of the competition for NVU-LNAA transporters
Given that animal species are different in terms of NVU geometry and kinetic characteristics of LNAA transporters (Smith et al, 1987; Hargreaves and Pardridge, 1988; Martynyuk et al, 2010), a 1:1 comparison between species cannot be provided for concentration behavior of LNAA in the brain
Summary
Phenylketonuria (PKU) is the most common disorder of amino acid (AA) metabolism, resulting from severely reduced activity of the liver enzyme phenylalanine hydroxylase (PAH), which leads to abnormal accumulation of the essential amino acid L-phenylalanine (Phe) in the blood plasma (Güttler et al, 1969; Madden, 2004; Regier and Greene, 2017). The results were not conclusive: while in some studies IQ was found to be more often associated with the level of Phe fluctuations in the plasma rather than with its mean value (Hood et al, 2014; Romani et al, 2017), the opposite was reported in others (Viau et al, 2011; Hood et al, 2015), while no differentiation was possible in yet another one (Burgard et al, 1996) The reasons for this inconsistency are not clear, but could be, in part, a reflection of how fluctuations in plasma Phe concentration translate in individual patients to effects on AA homeostasis in the brain (Cleary et al, 2013)
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