# Novel therapy for monoamine neurotransmitter deficiency in PKU

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $383,779

## Abstract

PROJECT SUMMARY
The overall goal of this project is to investigate the etiology of cognitive deficits and neuropsychiatric symptoms
associated with phenylketonuria (PKU), one of the most common inborn errors of metabolism detected through
neonatal screening. Many adolescents and adults with PKU struggle with adherence to recommended dietary
therapy. Chronic hyperphenylalaninemia is frequently associated with anxiety, depression, and impaired
executive function such as difficulties with concentration and short-term memory. Deficiencies of the
monoamine neurotransmitters, dopamine and serotonin, in brain have been implicated as probable proximal
causes of neurobehavioral difficulties in PKU. In our recent work with the Pahenu2 mouse, a model of human
PKU that exhibits both a memory deficit and anxiety, we have found that brain dopamine content is relatively
undisturbed but that serotonin is severely deficient in untreated adult mice. The most likely mechanism causing
brain serotonin deficiency in Pahenu2 mice is phenylalanine-mediated competitive inhibition of TPH activity
leading to impaired serotonin synthesis. Correction of hyperphenylalaninemia following administration of either
a phenylalanine restricted diet or liver-directed gene therapy leads to increased brain serotonin content and
improved anxiety behaviors but no change in memory. These outcomes are similar to those seen in adult
humans with PKU who were late treated and suffered irreversible damage to the brain early in life prior to the
initiation of dietary therapy. Our hypotheses are that anxiety in hyperphenylalaninemic mice is caused by
CNS serotonin deficiency but that the memory deficit is a result of other more permanent abnormalities
of brain development resulting from long standing hyperphenylalaninemia beginning in infancy. In the
first aim of our project, we will continue to explore the relationship between brain serotonin and anxiety in
Pahenu2/enu2 mice and to evaluate novel therapeutic approaches directed at this complication. In the second aim
of our project, we will develop and characterize a novel model of PKU, more analogous to the status of
contemporary adults with PKU who were detected by newborn screening, received dietary treatment early in
life, but subsequently lost dietary control, by treating Pahenu2/enu2 neonates with recombinant phenylalanine
ammonia lyase (PAL, Pegvaliase) to control blood phenylalanine throughout infancy and into adulthood. We
will compare behavioral outcomes, neuropathology and neurochemistry between PAL-treated and untreated
Pahenu2/enu2 mice and furthermore will study the consequences of remerging hyperphenylalaninemia upon
discontinuation of PAL treatment. We propose that PAL-treated Pahenu2/enu2 mice will more effectively model the
current status of contemporary PKU treatment and will provide novel insights into the nature of PKU-
associated neurocognitive deficits.

## Key facts

- **NIH application ID:** 9930656
- **Project number:** 5R01NS080866-09
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Cary O. Harding
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $383,779
- **Award type:** 5
- **Project period:** 2012-09-30 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9930656

## Citation

> US National Institutes of Health, RePORTER application 9930656, Novel therapy for monoamine neurotransmitter deficiency in PKU (5R01NS080866-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9930656. Licensed CC0.

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