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Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU)

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU.

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Abbreviations

PKU:

Phenylketonuria

PAH:

Phenylalanine hydroxylase

NTBC:

2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione

Phe:

L-phenylalanine

Tyr:

L-tyrosine

Trp:

L-tryptophan

LNAA:

Large neutral amino acids

L-DOPA:

L-3,4-dihydroxyphenylalanine

DA:

Dopamine

DOPAC:

L-3,4-dihydroxyphenylacetic acid

3-MT:

3-methoxytyramine

HVA:

Homovanillic acid

5-HTP:

L-5-hydroxytryptophan

5-HIAA:

5-hydroxyindoleacetic acid

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Acknowledgments

This work was supported in part by NIH Grants R01 DK059371 and R01 NS080866 and a grant from the National PKU Alliance (NPKUA, www.npkua.org).

We thank Gloria Baca, Baoyu Lin, Lindsey Stetson, and Katie Cobb for able technical assistance and Dr. Melanie Gillingham for critical review of the manuscript.

Conflict of interest

None declared.

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Authors and Affiliations

  1. Department of Molecular and Medical Genetics, Oregon Health & Science University, Mailstop L-103, 3181 Sam Jackson Park Rd., Portland, OR, 97239, USA

    Cary O. Harding & Shelley R. Winn

  2. Section of Clinical Pharmacology, College of Pharmacy, Washington State University, Spokane, WA, USA

    K. Michael Gibson

  3. Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX, USA

    Erland Arning & Teodoro Bottiglieri

  4. Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA

    Markus Grompe

Authors
  1. Cary O. Harding
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  2. Shelley R. Winn
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  3. K. Michael Gibson
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  4. Erland Arning
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  5. Teodoro Bottiglieri
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  6. Markus Grompe
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Corresponding author

Correspondence to Cary O. Harding.

Additional information

Communicated by: Nenad Blau

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Harding, C.O., Winn, S.R., Gibson, K.M. et al. Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU). J Inherit Metab Dis 37, 735–743 (2014). https://doi.org/10.1007/s10545-013-9675-2

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  • DOI: https://doi.org/10.1007/s10545-013-9675-2

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