Department of Neurology in the Center for Translational Neuromedicine, University of Rochester, Rochester, NY 14642, USA.
Proc Natl Acad Sci U S A. 2011 Dec 20;108(51):20766-71. doi: 10.1073/pnas.1115141108. Epub 2011 Dec 5.
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.
除草剂百草枯（PQ）在越来越多的流行病学研究中被报道可增强帕金森病（PD）的发病风险。此外，病例对照研究报告称，当接触 PQ 时，多巴胺转运体（DAT，SLC6A）存在遗传变异的个体患 PD 的风险更高。然而，PQ 是否可以通过 DAT 进入多巴胺（DA）神经元仍然是一个争论的话题。我们在这里报告了 PQ 通过 DAT 转运的一种机制：在其天然二价阳离子状态下，PQ(2+)不是 DAT 的底物；然而，当被微胶质细胞中的还原剂或 NADPH 氧化酶转化为单价阳离子 PQ(+)时，它成为 DAT 的底物并在 DA 神经元中积累，在那里它诱导氧化应激和细胞毒性。在培养细胞和突变小鼠中 DAT 功能受损显著减轻了 PQ(+)诱导的神经毒性。除了 DAT，PQ(+)也是有机阳离子转运体 3（Oct3，Slc22a3）的底物，后者在黑质纹状体区域的非 DA 细胞中大量表达。在 Oct3 缺陷的小鼠中，在 PQ 处理后检测到纹状体损伤增加。这种敏感性增加可能是由于非 DA 细胞的缓冲能力降低，导致更多的 PQ(+)可被 DA 神经元摄取。这项研究提供了 DAT 和 Oct3 调节 PQ(2+)/PQ(+)氧化还原循环诱导的黑质纹状体损伤的机制。
