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

Julie Lotharius, Karen L. O'Malley

Research output: Contribution to journalArticlepeer-review

275 Scopus citations

Abstract

Uptake of the Parkinsonism-inducing toxin, 1-methyl-4-phenylpyridinium (MPP+), into dopaminergic terminals is thought to block Complex I activity leading to ATP loss and overproduction of reactive oxygen species (ROS). The present 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 rotonone did not. Concurrent with ROS formation, MPP+ redistributed vesicular DA to the cytoplasm prior to its extrusion from the cell by reverse transport via the DA transporter. MPP+-induced DA redistribution was also associated with cell death. Depleting cells of newly synthesized and/or stored DA significantly attenuated both superoxide production and cell death, whereas enhancing intracellular DA content exacerbated dopaminergic sensitivity to MPP+. Lastly, depleting cells of DA in the presence of succinate completely abolished MPP+-induced cell death. Thus, MPP+ neurotoxicity is a multi-component process involving both mitochondrial dysfunction and ROS generated by vesicular DA displacement. These results suggest that in the presence of a Complex I defect, misregulation of DA storage could lead to the loss of nigrostriatal neurons in Parkinson's disease.

Original languageEnglish
Pages (from-to)38581-38588
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number49
DOIs
StatePublished - Dec 8 2000

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