Metabolomics analysis reveals perturbations of cerebrocortical metabolic pathways in the Pah^enu2 mouse model of phenylketonuria

Abstract

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.

Investigating the Impact of SN-38 on Mouse Brain Metabolism Based on Metabolomics

“…Branched-chain amino acids(BCAAs), key metabolic precursors, play a role in neurotransmitter synthesis and amino acid metabolism in the brain. 33 Studies show reduced valine and isoleucine levels in the cortical tissue of SN-38-treated mice compared to controls, indicating an effect on BCAA biosynthesis. This suggests that SN-38 could negatively impact brain function by disrupting the synthesis of vital proteins, neurotransmitters, and metabolites.…”

Transcriptome and metabolome analyses reveal the regulation of peel coloration in green, red Chinese prickly ash (Zanthoxylum L.)

“…The sample extraction analysis, metabolite identification and quantification were conducted at MetWare Biotechnology Co., Ltd. (www.metware.cn; Wuhan, China) following their standard procedures ( Lu et al, 2020 , Yang et al, 2008 , Zhang et al, 2017 ). The analysis of metabolite data was performed using Analyst 1.6.1 software (AB SCIEX, Ontario, Canada).…”

“…The experimental process of transcription group sequencing included RNA extraction, RNA detection, and the construction of cDNA libraries, as performed previously (Chai et al, 2017; Lu et al, 2020 ). The libraries were sequenced on an Illumina HiSeq platform, and 150 bp paired-end reads were generated.…”

Understanding Inborn Errors of Metabolism through Metabolomics

“…The metabolic origins of neurological dysfunction in PKU were examined by Lu et al in cerebral cortices from homozygous Pah enu2−/− mice (PKU mice) compared with wild-type mice (WT mice) [ 44 ]. First, a metabolomics screening revealed that 35 metabolic compounds were significantly altered in the brain tissue of PKU mice compared to WT.…”