Voluntary Exercise Prevents Oxidative Stress in the Brain of Phenylketonuria Mice

Mazzola, Priscila Nicolao; Bruinenberg, Vibeke M.; Anjema, Karen; Vliet, Danique van; Dutra-Filho, Carlos Severo; Spronsen, Francjan J. van; Zee, Eddy A. van der

doi:10.1007/8904_2015_498

Cited by 13 publications

(10 citation statements)

References 51 publications

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“…The BB task was used to assess coordination and balance as previously described in Mazzola et al (2016). In short, animals were trained over three distances (10, 40, and 75 cm) to cross a square wooden beam (length 1 m, width 5 mm, height 10 mm, horizontally positioned 50 cm above the underlying surface) to their home cage.…”

Section: Methodsmentioning

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: Methodsmentioning

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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“…Various forced methods have been applied successfully. Available forced strength training methods for rodents include hanging exercise, loaded ladder climbing, weight lifting in an operant chamber, and weight pulling on a treadmill (Cassilhas et al, 2012;Krüger et al, 2013;Mori et al, 2003;Seo et al, 2014;Strickland and Smith, 2016). In the current study, we proposed and tested the use of two potential (novel) methods of voluntary strength training for rodents: burrowing and tower climbing.…”

Section: Lack Of Animal Models Of Voluntary Strength Trainingmentioning

confidence: 99%

Burrowing as a novel voluntary strength training method for mice: A comparison of various voluntary strength or resistance exercise methods

Roemers

Mazzola

Deyn

et al. 2018

Journal of Neuroscience Methods

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“…The elapsed time for a mouse to maintain its balance on a rotating rod is a good indicator of possible neurological deficits, as shown for the Enu2 mouse 39 . As illustrated in Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

The Pah-R261Q mouse reveals oxidative stress associated with amyloid-like hepatic aggregation of mutant phenylalanine hydroxylase

et al. 2021

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Phenylketonuria (PKU) is caused by autosomal recessive variants in phenylalanine hydroxylase (PAH), leading to systemic accumulation of L-phenylalanine (L-Phe) that may reach neurotoxic levels. A homozygous Pah-R261Q mouse, with a highly prevalent misfolding variant in humans, reveals the expected hepatic PAH activity decrease, systemic L-Phe increase, L-tyrosine and L-tryptophan decrease, and tetrahydrobiopterin-responsive hyperphenylalaninemia. Pah-R261Q mice also present unexpected traits, including altered lipid metabolism, reduction of liver tetrahydrobiopterin content, and a metabolic profile indicative of oxidative stress. Pah-R261Q hepatic tissue exhibits large ubiquitin-positive, amyloid-like oligomeric aggregates of mutant PAH that colocalize with selective autophagy markers. Together, these findings reveal that PKU, customarily considered a loss-of-function disorder, can also have toxic gain-of-function contribution from protein misfolding and aggregation. The proteostasis defect and concomitant oxidative stress may explain the prevalence of comorbid conditions in adult PKU patients, placing this mouse model in an advantageous position for the discovery of mutation-specific biomarkers and therapies.

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Voluntary Exercise Prevents Oxidative Stress in the Brain of Phenylketonuria Mice

Abstract: Exercise prevents oxidative stress in the brain of PKU mice without modifying phenylalanine levels. Hence, exercise positively affects the brain, demonstrating its value as an intervention to improve brain quality in PKU.

Cited by 13 publications

References 51 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

Burrowing as a novel voluntary strength training method for mice: A comparison of various voluntary strength or resistance exercise methods

The Pah-R261Q mouse reveals oxidative stress associated with amyloid-like hepatic aggregation of mutant phenylalanine hydroxylase

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