title: Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3.
abstract: The herbicide paraquat (PQ) has increasingly been reported in epidemiological studies to enhance the risk of developing Parkinson's disease (PD). Furthermore, case-control studies report that individuals with genetic variants in the dopamine transporter (DAT, SLC6A) have a higher PD risk when exposed to PQ. However, it remains a topic of debate whether PQ can enter dopamine (DA) neurons through DAT. We report here a mechanism by which PQ is transported by DAT: In its native divalent cation state, PQ(2+) is not a substrate for DAT; however, when converted to the monovalent cation PQ(+) by either a reducing agent or NADPH oxidase on microglia, it becomes a substrate for DAT and is accumulated in DA neurons, where it induces oxidative stress and cytotoxicity. Impaired DAT function in cultured cells and mutant mice significantly attenuated neurotoxicity induced by PQ(+). In addition to DAT, PQ(+) is also a substrate for the organic cation transporter 3 (Oct3, Slc22a3), which is abundantly expressed in non-DA cells in the nigrostriatal regions. In mice with Oct3 deficiency, enhanced striatal damage was detected after PQ treatment. This increased sensitivity likely results from reduced buffering capacity by non-DA cells, leading to more PQ(+) being available for uptake by DA neurons. This study provides a mechanism by which DAT and Oct3 modulate nigrostriatal damage induced by PQ(2+)/PQ(+) redox cycling.
authors.affiliation: Department of Neurology in the Center for Translational Neuromedicine, University of Rochester, Rochester, NY 14642, USA.
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Rappold
authors.forename: Mei
authors.initials: M
authors.lastname: Cui
authors.forename: Adrianne S
authors.initials: AS
authors.lastname: Chesser
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Tibbett
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Grima
authors.forename: Lihua
authors.initials: L
authors.lastname: Duan
authors.forename: Namita
authors.initials: N
authors.lastname: Sen
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Javitch
authors.forename: Kim
authors.initials: K
authors.lastname: Tieu
mesh_terms: D000818:Animals; D002412:Cations; D002470:Cell Survival; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis; D019255:NADPH Oxidases / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010269:Paraquat / Q000494:pharmacology*; D013378:Substantia Nigra / Q000378:metabolism
chemical_list: D002412:Cations; D050483:Dopamine Plasma Membrane Transport Proteins; D009498:Neurotoxins; D029362:Organic Anion Transporters, Sodium-Independent; C114338:organic anion transport protein 3; D019255:NADPH Oxidases; D010269:Paraquat