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Gene expression profiles in the brain of phenylketonuria mouse model reversed by the low phenylalanine diet therapy

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Abstract

To gain insight into the potential protective mechanisms of low phenylalanine diet (LPD) in phenylketonuria (PKU), gene expression profiles were studied in the cerebral cortex and hippocampus of a PKU mouse model (BTBR-Pahenu2). PKU mice were fed with low Phe diet (LPD-PKU group) and normal diet (PKU group). Wild-type mice were treated with normal diet (WT group) as control. After 12 weeks, we detected gene expression in the cerebral cortex and hippocampus of the three groups by RNA-sequencing, and then screened the differentially-expressed genes (DEGs) among the groups by bioinformatics analyses. We found that the transcriptional profiles of both cerebral cortex and hippocampus changed markedly between PKU and WT mice. Furthermore, LPD changed the transcriptional profiles of the cerebral cortex and the hippocampus of PKU mice significantly, especially in the cerebral cortex, with overlaps of genes that changed with the disease and altered by LPD treatment. In the cerebral cortex, hundreds of DEGs enriched in a wide spectrum of biological processes, molecular function, and cellular component, including nervous system development, axon development and guidance, calcium ion binding, modulation of chemical synaptic transmission, and regulation of protein kinase activity. In the hippocampus, the overlapping genes were enriched in positive regulation of long term synaptic, negative regulation of excitatory postsynaptic potential, positive regulation of synapse assembly. Our results showed that genes impaired in PKU and then rescued by LPD might indicate the potential protective capability of LPD in the PKU brain.

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Data availability

The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

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Funding

This work was supported by Shanghai Municipal Health Commission (No.202040448) and the National Natural Science Foundation of China (No.81600701).

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Author notes

  1. Sha Hong and Tianwen Zhu contributed equally to this work.

Authors and Affiliations

  1. Department of Neonatal Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Sha Hong, Tianwen Zhu & Simin Zheng

  2. Department of Pediatric Endocrinology and Genetic Metabolism, Shanghai Institute for Pediatric Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Kongjiang Road 1665#, Shanghai, 200092, China

    Xia Zhan, Feng Xu, Xuefan Gu & Lili Liang

Authors
  1. Sha Hong
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  2. Tianwen Zhu
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  3. Simin Zheng
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  4. Xia Zhan
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  5. Feng Xu
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  6. Xuefan Gu
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  7. Lili Liang
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Contributions

LL and XG conceived and designed the study. SH, TZ and SZ prepared an analytical plan, analyzed data, and drafted the initial manuscript. SH and LL collaborated in the revision and interpretation of the data and results, and revised the manuscript. SH, TZ, SZ involved in data collection, manuscript review and revision, XZ and FX contributed to the detection of the blood Phe concentration, the management of animals and tissue extraction. All authors commented on the manuscript and approved the final manuscript as submitted.

Corresponding authors

Correspondence to Xuefan Gu or Lili Liang.

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All procedures were carried out in accordance with the National Regulations on the Administmiceion of Labomiceory Animals. Ethical approval was obtained from the Ethics Committee of Xinhua Hospital.

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The authors declare that they have no competing interests.

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Hong, S., Zhu, T., Zheng, S. et al. Gene expression profiles in the brain of phenylketonuria mouse model reversed by the low phenylalanine diet therapy. Metab Brain Dis 36, 2405–2414 (2021). https://doi.org/10.1007/s11011-021-00818-0

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