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

Yao Wei, Ming Lu, Meng Mei, Haoran Wang, Zhitao Han, Miaomiao Chen, Hang Yao, Nanshan Song, Xiao Ding, Jianhua Ding, Ming Xiao and Gang Hu ()
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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

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14788-x

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