Multicompartment analysis of protein-restricted phenylketonuric mice reveals amino acid imbalances in brain
- 304 Downloads
The mainstay of therapy for phenylketonuria (PKU) remains dietary protein restriction. Developmental and neurocognitive outcomes for patients, however, remain suboptimal. We tested the hypothesis that mice with PKU receiving protein-restricted diets would reveal disruptions of brain amino acids that shed light on these neurocognitive deficits.
Phenylalanine hydroxylase-deficient (PKU) mice and parallel controls (both wild-type and heterozygous) were fed custom diets containing 18, 6, and 4 % protein for 3 weeks, after which tissues (brain, liver, sera) were collected for amino acid analysis profiling.
Phenylalanine (phe) was increased in all tissues (p < 0.0001) of PKU mice and improved with protein restriction. In sera, decreased tyrosine (p < 0.01) was corrected (defined as not significantly different from the level in control mice receiving 18 % chow) with protein restriction, whereas protein restriction significantly increased many other amino acids. A similar trend for increased amino acid levels with protein restriction was also observed in liver. In brain, the effects of protein restriction on large neutral amino acids (LNAAs) were variable, with some deficit correction (threonine, methionine, glutamine) and no correction of tyrosine under any dietary paradigm. Protein restriction (4 % diet) in PKU mice significantly decreased lysine, arginine, taurine, glutamate, asparagine, and serine which had been comparable to control mice under 18 % protein intake.
Depletion of taurine, glutamate, and serine in the brain of PKU mice with dietary protein restriction may provide new insight into neurocognitive deficits of PKU.
KeywordsTaurine Amino Acid Level Protein Restriction Branch Chain Amino Acid Neurocognitive Deficit
Branched chain amino acids (leu, ile, val)
Large neutral amino acids, including phe, tyr, trp, thr, met, gln, his, val, ile, leu
The authors acknowledge the technical assistance of Ms. Erica Thorson.
Compliance with ethical standards
Conflict of interest
All institutional and national guidelines for the care and use of laboratory animals were followed.
- Giller K, Huebbe P, Hennig S, Dose J, Pallauf K, Doering F, Rimbach G (2013) Beneficial effects of a 6-month dietary restriction are time-dependently abolished within 2 weeks or 6 months of refeeding-genome-wide transcriptome analysis in mouse liver. Free Radic Biol Med 61:170–178CrossRefPubMedGoogle Scholar
- Schreiber JM, Pearl PL, Dustin I, Wiggs E, Barrios E, Wassermann EM, Gibson KM, Theodore WH (2016) Biomarkers in a taurine trial for succinic semialdehyde dehydrogenase deficiency. JIMD Rep. doi: 10.1007/8904_2015_524
- van Vliet D, Bruinenberg VM, Mazzola PN, van Faassen MH, de Blaauw P, Kema IP, Heiner-Fokkema MR, van Anholt RD, van der Zee EA, van Spronsen FJ (2015) Large neutral amino acid supplementation exerts its effect through three synergistic mechanisms: proof of principle in phenylketonuria mice. PLoS ONE 10(12):e0143833CrossRefPubMedPubMedCentralGoogle Scholar
- Vogel KR, Ainslie GR, Phillips B, Arning E, Bottiglieri T, Shen DD, Gibson KM (2015) Physiological competition of brain phenylalanine accretion: initial pharmacokinetic analyses of aminoisobutyric and methylaminoisobutyric acids in Pahenu2−/− mice. Mol Genet Metab Rep 3:80–87CrossRefPubMedPubMedCentralGoogle Scholar
- Yano S, Moseley K, Fu X, Azen C (2016) Evaluation of tetrahydrobiopterin therapy with large neutral amino acid supplementation in phenylketonuria: effects on potential peripheral biomarkers, melatonin and dopamine, for brain monoamine neurotransmitters. PLoS ONE 11(8):e0160892CrossRefPubMedPubMedCentralGoogle Scholar