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Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection

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  • Yao Wei

    (Nanjing University of Chinese Medicine)

  • Ming Lu

    (Nanjing Medical University)

  • Meng Mei

    (Nanjing University of Chinese Medicine)

  • Haoran Wang

    (Nanjing Medical University)

  • Zhitao Han

    (Nanjing University of Chinese Medicine)

  • Miaomiao Chen

    (Nanjing Medical University)

  • Hang Yao

    (Nanjing Medical University)

  • Nanshan Song

    (Nanjing Medical University)

  • Xiao Ding

    (Nanjing University of Chinese Medicine)

  • Jianhua Ding

    (Nanjing Medical University)

  • Ming Xiao

    (Nanjing Medical University)

  • Gang Hu

    (Nanjing University of Chinese Medicine
    Nanjing Medical University
    Nanjing Normal University)

Abstract

Oxidative stress is a major pathogenic mechanism in Parkinson’s disease (PD). As an important cellular antioxidant, glutathione (GSH) balances the production and incorporation of free radicals to protect neurons from oxidative damage. GSH level is decreased in the brains of PD patients. Hence, clarifying the molecular mechanism of GSH deficiency may help deepen our knowledge of PD pathogenesis. Here we report that the astrocytic dopamine D2 receptor (DRD2) regulates GSH synthesis via PKM2-mediated Nrf2 transactivation. In addition we find that pyridoxine can dimerize PKM2 to promote GSH biosynthesis. Further experiments show that pyridoxine supplementation increases the resistance of nigral dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in wild-type mice as well as in astrocytic Drd2 conditional knockout mice. We conclude that dimerizing PKM2 may be a potential target for PD treatment.

Suggested Citation

  • Yao Wei & Ming Lu & Meng Mei & Haoran Wang & Zhitao Han & Miaomiao Chen & Hang Yao & Nanshan Song & Xiao Ding & Jianhua Ding & Ming Xiao & Gang Hu, 2020. "Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14788-x
    DOI: 10.1038/s41467-020-14788-x
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    1. Tian Lan & Fengwei Gao & Yunshi Cai & Yinghao Lv & Jiang Zhu & Hu Liu & Sinan Xie & Haifeng Wan & Haorong He & Kunlin Xie & Chang Liu & Hong Wu, 2025. "The protein circPETH-147aa regulates metabolic reprogramming in hepatocellular carcinoma cells to remodel immunosuppressive microenvironment," Nature Communications, Nature, vol. 16(1), pages 1-22, December.

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