Dopamine-dependent cytotoxicity of tetrahydrobiopterin: a possible mechanism for selective neurodegeneration in Parkinson's disease

Parkinson's disease is a neurodegenerative disorder associated with selective loss of dopaminergic neurons in the substantia nigra. While the underlying cause of this cell death is poorly understood, oxidative stress is thought to play a role. We have previously shown that tetrahydrobiopterin (BH4), an obligatory co-factor for tyrosine hydroxylase (TH), exerts selective toxicity on dopamine-producing cells and that this is prevented by antioxidants. This study shows that BH4-induced dopaminergic cell death is primarily mediated by dopamine, evidenced by findings that (i) BH4 toxicity is increased in proportion to cellular dopamine content; (ii) non-dopaminergic cells become susceptible to BH4 upon exposure to dopamine; and (iii) depletion of dopamine attenuates BH4 toxicity in dopamine-producing cells. BH4 causes lipid peroxidation, suggesting involvement of oxidative stress but the toxicity does not require enzymatic oxidation of dopamine. Instead, it seems to involve formation of quinone product(s) because (i) the cell death is attenuated by exposure to or induction of quinone reductase and (ii) BH4-treated cells show increased formation of protein-bound quinones, which is inhibited by thiol antioxidants. These data taken together suggest that the presence of both BH4 and dopamine is important in rendering dopaminergic cells vulnerable and that this involves formation of reactive dopamine quinone products.