Open AccessMetabolomics analysis reveals perturbations of cerebrocortical metabolic pathways in the Pah enu2 mouse model of phenylketonuria
Author(s) -
Lu LiHua,
Xia ZhengXiang,
Guo JiaLin,
Xiao LingLing,
Zhang YongJun
Publication year - 2020
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.13214
Subject(s) - metabolome , metabolic pathway , phenylalanine , metabolomics , phenylalanine hydroxylase , metabolism , valine , biochemistry , amino acid , biosynthesis , leucine , phenylketonurias , chemistry , endocrinology , metabolite , biology , enzyme , bioinformatics
Aims Phenylketonuria (PKU), which is caused by mutations in the phenylalanine hydroxylase ( PAH ) gene, is one of the most common inherited diseases of amino acid metabolism. Phenylketonuria is characterized by an abnormal accumulation of phenylalanine and its metabolites in body fluids and brain tissues, subsequently leading to severe brain dysfunction. Various pathophysiological and molecular mechanisms underlying brain dysfunction in PKU have been described. However, the metabolic changes and their impacts on the function of cerebral cortices of patients with PKU remain largely unknown. Methods We measured the levels of small molecule metabolites in the cerebrocortical tissues of PKU mice and wild‐type control mice using liquid chromatography‐mass spectrometry (LC‐MS)‐based metabolome analysis. Differential metabolites were further subjected to metabolic pathway and enrichment analysis. Results Metabolome analysis revealed 35 compounds among 143 detected metabolites were significantly changed in PKU mice as compared to those in their wild‐type littermates. Metabolic pathway and enrichment analysis of these differential metabolites showed that multiple metabolic pathways, including phenylalanine, tyrosine, and tryptophan biosynthesis; valine, leucine, and isoleucine biosynthesis; alanine, aspartate, and glutamate metabolism; purine metabolism; arginine and proline metabolism and methionine metabolism, were impacted in the cerebral cortices of PKU mice. Conclusions The data revealed that multiple metabolic pathways in cerebral cortices of PKU mice were disturbed, suggesting that the disturbances of the metabolic pathways might contribute to neurological or neurodevelopmental dysfunction in PKU, which could thus provide new insights into brain pathogenic mechanisms in PKU as well as mechanistic insights for better understanding the complexity of the metabolic mechanisms of the brain dysfunction in PKU.