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Abstract
ObjectivePhenylketonuria (PKU) is an inherited metabolic disease characterized by plasma hyperphenylalaninemia and several neurological symptoms that can be controlled by rigorous dietetic treatment. The cellular mechanisms underlying impaired brain functions are still unclear. It has been proposed, however, that phenylalanine interference in cognitive functions depends on impaired dopamine (DA) transmission in the prefrontal cortical area due to reduced availability of the precursor tyrosine. Here, using Pahenu2 (ENU2) mice, the genetic murine model of PKU, we investigated all metabolic steps of catecholamine neurotransmission within the medial preFrontal Cortex (mpFC), availability of the precursor tyrosine, synthesis and release, to find an easy way to reinstate normal cortical DA neurotransmission.Methods and resultsAnalysis of blood and brain levels of tyrosine showed reduced plasma and cerebral levels of tyrosine in ENU2 mice. Western blot analysis demonstrated deficient tyrosine hydroxylase (TH) protein levels in mpFC of ENU2 mice. Cortical TH activity, determined in vivo by measuring the accumulation of l-3,4-dihydroxyphenylalanine (L-DOPA) in mpFC after inhibition of L-aromatic acid decarboxylase with NSD-1015, was reduced in ENU2 mice. Finally, a very low dose of L-DOPA, which bypasses the phenylalanine-inhibited metabolic steps, restored DA prefrontal transmission to levels found in healthy mice.ConclusionThe data suggests that a strategy of using tyrosine supplementation to treat PKU is unlikely to be effective, whereas small dose L-DOPA administration is likely to have a positive therapeutic effect.
Highlights
Phenylketonuria (PKU; McKusick 2610600) is an inherited metabolic disease caused by a deficiency of the enzyme phenylalanine hydroxylase, which is necessary to convert phenylalanine to tyrosine
The data suggests that a strategy of using tyrosine supplementation to treat PKU is unlikely to be effective, whereas small dose L-DOPA administration is likely to have a positive therapeutic effect
Phenylalanine blood/brain ratio was significantly reduced, and tyrosine blood/brain ratio was not significantly different, in ENU2 compared with WT mice
Summary
Phenylketonuria (PKU; McKusick 2610600) is an inherited metabolic disease caused by a deficiency of the enzyme phenylalanine hydroxylase, which is necessary to convert phenylalanine to tyrosine. This results in accumulation of phenylalanine (> 20 mg/dl), known as hyperphenylalaninemia, and reduction of tyrosine concentrations in the blood and brain. Compliance with a rigid low phenylalanine diet is difficult (Giovannini et al 2007; MacDonald 2000), and it is still unknown when or if the diet can be safely interrupted (De Roche and Welsh 2008; Stemerdink et al 2000; Diamond et al 1994). Evidence indicates that even mildly elevated blood phenylalanine levels induce deficits in cognitive functions involving the prefrontal cortical area
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