Preferential resistance of dopaminergic neurons to the toxicity of glutathione depletion is independent of cellular glutathione peroxidase and is mediated by tetrahydrobiopterin

Depletion of glutathione in the substantia nigra is one of the earliest cha nges observed in Parkinson's disease (PD) and could initiate dopaminergic n euronal degeneration, Nevertheless, experimental glutathione depletion does not result in preferential toxicity to dopaminergic neurons either in vivo or in vitro. Moreover, dopaminergic neurons in culture are preferentially resistant to the toxicity of glutathione depletion, possibly owing to diffe rences in cellular glutathione peroxidase (GPx1) function. However, mesence phalic cultures from GPx1 -knockout and wild-type mice were equally suscept ible to the toxicity of glutathione depletion, indicating that glutathione also has GPx1-independent functions in neuronal survival. In addition, dopa minergic neurons were more resistant to the toxicity of both glutathione de pletion and treatment with peroxides than nondopaminergic neurons regardles s of their GPx1 status. To explain this enhanced antioxidant capacity, we h ypothesized that tetrahydrobiopterin (BH4) may function as an antioxidant i n dopaminergic neurons. In agreement, inhibition of BH4 synthesis increased the susceptibility of dopaminergic neurons to the toxicity of glutathione depletion, whereas increasing BH4 levels completely protected nondopaminerg ic neurons against it. Our results suggest that BH4 functions as a compleme ntary antioxidant to the glutathione/glutathione peroxidase system and that changes in BH4 levels may contribute to the pathogenesis of PD.