The Parkinsonism-inducing drug 1-methyl-4-phenylpyridinium triggers intracellular dopamine oxidation - A novel mechanism of toxicity

Uptake of the Parkinsonism-inducing toxin, 1-methyl-4-phenylpyridinium (MPP +), into dopaminergic terminals is thought to block Complex I activity lead ing to ATP loss and overproduction of reactive oxygen species (ROS). The pr esent study indicates that MPP+-induced ROS formation is not mitochondrial in origin but results from intracellular dopamine (DA) oxidation. Although a mean lethal dose of MPP+ led to ROS production in identified dopaminergic neurons, toxic doses of the Complex I inhibitor rotenone did not. Concurre nt with ROS formation, MPP+ redistributed vesicular DA to the cytoplasm pri or to its extrusion from the cell by reverse transport via the DA transport er. MPP+-induced DA redistribution was also associated with cell death. Dep leting cells of newly synthesized and/or stored DA significantly attenuated both superorxide production and cell death, whereas enhancing intracellula r DA content exacerbated dopaminergic sensitivity to MPP+. Lastly, depletin g cells of DA in the presence of succinate completely abolished MPP+-induce d cell death. Thus, MPP+ neurotoxicity is a multi-component process involvi ng both mitochondrial dysfunction and ROS generated by vesicular DA displac ement. These results suggest that in the presence of a Complex I defect, mi sregulation of DA storage could lead to the loss of nigrostriatal neurons i n Parkinson's disease.