Oxidative stress is a major pathogenic mechanism in Parkinsons disease (PD). As an important cellular antioxidant, glutathione (GSH) balances the production and incorporation of free radicals to protect neurons from oxidative damage. Unfortunately, the GSH level is greatly 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. Besides, 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. Given that dopamine agonist treatment in PD is limited by their intolerable side effects and diminished effectiveness over time, we anticipate dimerizing PKM2 to be a new strategy for PD treatment. SOURCE: Yao Wei (yaowei@njucm.edu.cn) -  Nanjing University of Chinese medicine

Pluto Bioinformatics

GSE143164: Pyridoxine induces glutathione synthesis via PKM2-mediated Nrf2 transactivation and confers neuroprotection