Phenylketonuria: modelling cerebral amino acid and neurotransmitter metabolism

Objective Phenylketonuria (PKU) is caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase, which primarily converts phenylalanine into tyrosine. Despite a phenylalanine-deprived diet, many adult PKU patients display deficits in executive functions. These are hypothesised to be caused by high cerebral phenylalanine and a shortage of monoaminergic neurotransmitters. Method To better understand the relationship between plasma and brain amino acid levels and monoaminergic neurotransmitter biochemistry, we constructed a computational model. The model comprises the transport of large neutral amino acids (LNAA) across the blood-brain barrier as well as cerebral amino acid and monoaminergic neurotransmitter metabolism and was validated by direct measurements of brain amino acid concentrations in PKU mice on various diets. Results The model predicts that brain amino acids are positively controlled by the concentrations of the corresponding amino acids in the blood, and to a lesser extent negatively by other amino acids competing for the transport systems. The model suggests that brain levels of monoaminergic neurotransmitters are controlled more by phenylalanine, probably through non-competitive inhibition of the hydroxylases rather than by their precursor amino acids. Therefore, the model predicts that the decrease of neurotransmitters in PKU cannot be fully rescued by the addition of tyrosine and tryptophan alone, but also benefits from a reduction of the phenylalanine level. Thereby, the model substantiates the experimental data of the synergistic effect of both brain phenylalanine reduction and increased precursor amino acid availability to improve brain neurotransmitters in PKU mice. Conclusion We present the first complete model of the LNAA transport through the blood-brain barrier and subsequent brain neurotransmitter metabolism in PKU. The model leads to a better understanding of the pathophysiological mechanisms and the influence of individual amino acids in the diet on the underlying brain dysfunction in PKU. Moreover, it identifies gaps in our current knowledge about the LNAA transport across the blood-brain barrier. Furthermore, the model can be readily applied in studies of other neurological disorders in which the relation between diet, gene activities, brain amino acids, and neurotransmitters is important. ### Competing Interest Statement Agnieszka B. Wegrzyn reports financial support was provided by Marie Curie Initial Training Networks (ITN) action PerFuMe, project number 316723. Barbara M. Bakker reports financial support was provided by the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 812968. Francjan van Spronsen reports a relationship with Agios, AlltRNA, Arla Food Int, BioMarin, Eurocept, Homology, Illumina, LogicBio, Lucane, Nestle-Codexis Alliance, Moderna, Nutricia, Orphan Europe, Origin Biosciences, Travere, Ultragenyx, and Sanofi that includes: board membership. Francjan van Spronsen reports a relationship with BioMarin, ESPKU, NPKUA, NPKUV, Nutricia, Sobi, Tyrosinemia Foundation, and ZonMW that includes: funding grants. Francjan van Spronsen reports a relationship with Applied Pharma Research SA, Alexion, Axcella, BioMarin, LogicBio, Nutricia, Orphan Europe, Pluvia Biotech, and PTC that includes: consulting or advisory. Francjan van Spronsen reports a relationship with BioMarin, Nutricia, Vitaflo, and Applied Pharma Research SA that includes: speaking and lecture fees. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.