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Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3.

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.

Pubmed ID: 22143804


  • Rappold PM
  • Cui M
  • Chesser AS
  • Tibbett J
  • Grima JC
  • Duan L
  • Sen N
  • Javitch JA
  • Tieu K


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

December 20, 2011

Associated Grants

  • Agency: NIA NIH HHS, Id: AG040903
  • Agency: NIDA NIH HHS, Id: DA022413
  • Agency: NIDA NIH HHS, Id: DA12408
  • Agency: NIEHS NIH HHS, Id: ES0017470-01S1
  • Agency: NIEHS NIH HHS, Id: ES014899
  • Agency: NIEHS NIH HHS, Id: ES020081
  • Agency: NIEHS NIH HHS, Id: ES17470
  • Agency: NIA NIH HHS, Id: F30 AG040903
  • Agency: NIDA NIH HHS, Id: K05 DA022413
  • Agency: NCRR NIH HHS, Id: KL2 RR024136
  • Agency: NIGMS NIH HHS, Id: T32 GM07356
  • Agency: NCRR NIH HHS, Id: TL1 RR024135
  • Agency: NCRR NIH HHS, Id: TL1RR 024135
  • Agency: NCRR NIH HHS, Id: UL1 RR024160

Mesh Terms

  • Animals
  • Cations
  • Cell Survival
  • Dopamine Plasma Membrane Transport Proteins
  • Dose-Response Relationship, Drug
  • Mice
  • Mice, Transgenic
  • Microdialysis
  • NADPH Oxidase
  • Neurodegenerative Diseases
  • Neurotoxicity Syndromes
  • Neurotoxins
  • Organic Anion Transporters, Sodium-Independent
  • Oxidation-Reduction
  • Oxidative Stress
  • Paraquat
  • Substantia Nigra