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Oxidative stress in phenylketonuria—evidence from human studies and animal models, and possible implications for redox signaling

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Abstract

Phenylketonuria (PKU) is one of the commonest inborn error of amino acid metabolism. Before mass neonatal screening was possible, and the success of introducing diet therapy right after birth, the typical clinical finds in patients ranged from intellectual disability, epilepsy, motor deficits to behavioral disturbances and other neurological and psychiatric symptoms. Since early diagnosis and treatment became widespread, usually only those patients who do not strictly follow the diet present psychiatric, less severe symptoms such as anxiety, depression, sleep pattern disturbance, and concentration and memory problems. Despite the success of low protein intake in preventing otherwise severe outcomes, PKU’s underlying neuropathophysiology remains to be better elucidated. Oxidative stress has gained acceptance as a disturbance implicated in the pathogenesis of PKU. The conception of oxidative stress has evolved to comprehend how it could interfere and ultimately modulate metabolic pathways regulating cell function. We summarize the evidence of oxidative damage, as well as compromised antioxidant defenses, from patients, animal models of PKU, and in vitro experiments, discussing the possible clinical significance of these findings. There are many studies on oxidative stress and PKU, but only a few went further than showing macromolecular damage and disturbance of antioxidant defenses. In this review, we argue that these few studies may point that oxidative stress may also disturb redox signaling in PKU, an aspect few authors have explored so far. The reported effect of phenylalanine on the expression or activity of enzymes participating in metabolic pathways known to be responsive to redox signaling might be mediated through oxidative stress.

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Abbreviations

ADMA:

asymmetric dimethylarginine

CAT:

catalase

Q10:

coenzyme ubiquinone-10

ERK:

extracellular signal-regulated kinase

ETC:

electron transport chain

GPx:

glutathione peroxidase

GSH:

reduced glutathione

GSSG:

glutathione disulfide

HPA:

hyperphenylalaninemia

MAPK:

mitogen-activated protein kinase

MDA:

malondialdehyde

mtROS:

mitochondrial ROS

NOS:

nitric oxide synthase

Nrf2:

nuclear factor erythroid 2-related factor 2

PAH:

phenylalanine hydroxylase

Phe:

phenylalanine

PKU:

phenylketonuria

ROS:

reactive oxygen species

SOD:

superoxide dismutase

αMePhe:

α-methyl-L-phenylalanine

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Funding

The authors would like to thank the Department of Biochemistry, the Institute of Basic Health Sciences of the Federal University of Rio Grande do Sul, and the funding agencies CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), and FINEP (Financiadora de Estudos e Projetos)- Rede Instituto Brasileiro de Neurociência.

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Authors and Affiliations

  1. Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos 2600-Anexo, Porto Alegre, RS, CEP 90.035-003, Brazil

    Vanessa Trindade Bortoluzzi, Carlos Severo Dutra Filho & Clovis Milton Duval Wannmacher

Authors
  1. Vanessa Trindade Bortoluzzi
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  2. Carlos Severo Dutra Filho
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  3. Clovis Milton Duval Wannmacher
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Contributions

VB and CD independently screened the titles and abstracts and extracted data from the selected studies. VB wrote the manuscript and CD and CW revised it. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Vanessa Trindade Bortoluzzi.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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Bortoluzzi, V.T., Dutra Filho, C.S. & Wannmacher, C.M.D. Oxidative stress in phenylketonuria—evidence from human studies and animal models, and possible implications for redox signaling. Metab Brain Dis 36, 523–543 (2021). https://doi.org/10.1007/s11011-021-00676-w

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  • DOI: https://doi.org/10.1007/s11011-021-00676-w

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