Phenylketonuria: Direct and indirect effects of phenylalanine

Schlegel, Gudrun; Scholz, Ralf; Ullrich, Kurt; Santer, René; Rune, Gabriele M.

doi:10.1016/j.expneurol.2016.04.013

Cited by 21 publications

(19 citation statements)

References 39 publications

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“…How these PKU-related changes can result in a different functional outcome is not clear. Concerning raised Phe concentrations, in in vitro models of PKU, increased Phe concentrations seems to affect post- and presynaptic markers, proteins involved in cytoskeleton organization, and neuronal morphology (Zhang and Gu, 2005; Hörster et al, 2006; Zhang et al, 2007; Li et al, 2010; Horling et al, 2015; Schlegel et al, 2016). In vivo , although both strains show changes in different markers related to synaptic functioning, both BTBR PKU and B6 PKU show affected synaptic plasticity and overall neuronal functioning (Andolina et al, 2011; Liang et al, 2011; Horling et al, 2015; Bruinenberg et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background

Bruinenberg

Goot

Vliet

et al. 2016

Front. Behav. Neurosci.

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To unravel the role of gene mutations in the healthy and the diseased state, countless studies have tried to link genotype with phenotype. However, over the years, it became clear that the strain of mice can influence these results. Nevertheless, identical gene mutations in different strains are often still considered equals. An example of this, is the research done in phenylketonuria (PKU), an inheritable metabolic disorder. In this field, a PKU mouse model (either on a BTBR or C57Bl/6 background) is often used to examine underlying mechanisms of the disease and/or new treatment strategies. Both strains have a point mutation in the gene coding for the enzyme phenylalanine hydroxylase which causes toxic concentrations of the amino acid phenylalanine in blood and brain, as found in PKU patients. Although the mutation is identical and therefore assumed to equally affect physiology and behavior in both strains, no studies directly compared the two genetic backgrounds to test this assumption. Therefore, this study compared the BTBR and C57Bl/6 wild-type and PKU mice on PKU-relevant amino acid- and neurotransmitter-levels and at a behavioral level. The behavioral paradigms were selected from previous literature on the PKU mouse model and address four domains, namely (1) activity levels, (2) motor performance, (3) anxiety and/or depression-like behavior, and (4) learning and memory. The results of this study showed comparable biochemical changes in phenylalanine and neurotransmitter concentrations. In contrast, clear differences in behavioral outcome between the strains in all four above-mentioned domains were found, most notably in the learning and memory domain. The outcome in this domain seem to be primarily due to factors inherent to the genetic background of the mouse and much less by differences in PKU-specific biochemical parameters in blood and brain. The difference in behavioral outcome between PKU of both strains emphasizes that the consequence of the PAH mutation is influenced by other factors than Phe levels alone. Therefore, future research should consider these differences when choosing one of the genetic strains to investigate the pathophysiological mechanism underlying PKU-related behavior, especially when combined with new treatment strategies.

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Section: Discussionmentioning

confidence: 99%

The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background

Bruinenberg

Goot

Vliet

et al. 2016

Front. Behav. Neurosci.

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“…Horster and colleagues found that phenylalanine reduces synaptic density and simultaneously inhibits pyruvate kinase in mixed cortical cultures (Hörster et al 2006). Another study by Schlegel et al demonstrated decreased dendritic arborization of hippocampal neurons in dispersion cultures and loss of synapses in hippocampal slice cultures upon phenylalanine treatment (Schlegel et al 2016). Moreover, Li et al observed that phenylalanine inhibits neurite outgrowth and induces neuronal death of the cultured cortical neurons by decreasingB D N Fe x p r e s s i o na tb o t h mRNA and protein levels (Li et al 2010).…”

Section: Introductionmentioning

confidence: 99%

AMP‐activated protein kinase activation in mediating phenylalanine‐induced neurotoxicity in experimental models of phenylketonuria

Xiao-ming

Xiao

et al. 2017

J of Inher Metab Disea

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Phenylketonuria (PKU), one of the most prevalent autosomal recessive disorders of amino acid metabolism, is characterized by abnormal accumulation of phenylalanine, which can lead to intellectual disability. The main pathologic changes in the central nervous system of untreated phenylketonuric patients are reductions in the number of axons, dendrites, and synapses in the brain. Such alterations are thought to be mainly associated with the toxic effects caused by phenylalanine. However, the underlying molecular mechanisms have not been fully elucidated. The present study shows that a high concentration of phenylalanine remarkably inhibited neuronal neurite formation in vitro. Interestingly, AMP-activated protein kinase (AMPK), the energy status sensor, was activated in cultured cerebral cortical neurons upon phenylalanine treatment. Pretreatment with an AMPK inhibitor ameliorated the reduction of neurite formation caused by phenylalanine. In addition, the levels of the phosphorylated AMPK, the active form of AMPK, were significantly higher in the cerebral cortices of PKU mice with elevated phenylalanine levels in this brain region compared to those in wild-type control mice, whereas the density of dendritic spines on basal secondary dendrites of pyramidal neurons in prefrontal cortices of PKU mice was significantly decreased. Collectively, these findings indicate that AMPK activation is a key event in impaired neuronal dendritic development in PKU and consequently, a potential therapeutic target for developing neuroprotective strategies against phenylalanine-evoked brain injury in PKU.

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“…So far, there has been no permanent treatment to this disease [2,3]. Due to its harmful effects on the developing brain of newborns, early diagnosis and treatment is crucial to the normal development of the patients [4,5].…”

Section: Introductionmentioning

confidence: 99%

Benzene Derivatives from Ink Lead to False Positive Results in Neonatal Hyperphenylalaninemia Screening with Ninhydrin Fluorometric Method

Feng

Mei

et al. 2020

IJNS

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Ninhydrin-based fluorometric quantification of phenylalanine is one of the most widely used methods for hyperphenylalaninemia (HPA) screening in neonates due to its high sensitivity, high accuracy, and low cost. Here we report an increase of false positive cases in neonatal HPA screening with this method, caused by contamination of blood specimen collection devices during the printing process. Through multiple steps of verification, the contaminants were identified from ink circles printed on the collection devices to indicate the positions and sizes of blood drops. Blood specimens from HPA-negative persons collected on these contaminated collection devices showed positive results in the fluorometric tests, but negative results in tandem mass spectroscopy (MS/MS) experiments. Contaminants on the collection devices could be extracted by 80% ethanol and showed an absorption peak around 245 nm, suggesting that these contaminants may contain benzene derivatives with similar structure to phenylalanine. High-performance liquid chromatography (HPLC) analysis of the ethanol extracts from contaminated collection devices identified two prominent peaks specifically from the devices. Methyl-2-benzoylbenzoate (MBB, CAS#606-28-0) was found as one of the major chemicals from contaminated collection devices. This report aims to remind colleagues in the field of this potential contamination and call for tighter regulation and quality control of specimen collection devices.

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Phenylketonuria: Direct and indirect effects of phenylalanine

Cited by 21 publications

References 39 publications

The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background

The Behavioral Consequence of Phenylketonuria in Mice Depends on the Genetic Background

AMP‐activated protein kinase activation in mediating phenylalanine‐induced neurotoxicity in experimental models of phenylketonuria

Benzene Derivatives from Ink Lead to False Positive Results in Neonatal Hyperphenylalaninemia Screening with Ninhydrin Fluorometric Method

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