Parkinson's disease (PD) is a neurodegenerative disorder accompanied by depletion of dopamine(DA) and loss of dopaminergic (DAergic) neurons in the brain that is believed to be responsible for the motor and non-motor symptoms of PD. Dopamine Transporter (DAT) is essential for reuptake of DA into the presynaptic terminal, thereby controlling the availability and spatial activity of released DA. Parkin interacts with proteins involved in the endosomal pathway, suggesting that presynaptic Parkin could regulate the expression of DAT in the plasma membrane. Parkin mutations lead to early synaptic damage and it appears as a crucial gene having a vast functioning area. PD-specific induced pluripotent stem cells (iPSCs) derived DA neurons exist as a potential tool for in-vitro modeling of PD, as they can recapitulate the pathological features of PD. The exact mechanism of PARKIN influenced DAT variations and changes in DA reuptake by DAT remain unknown. Hence, DAT and PARKIN mutated PD-specific iPSCs-derived DA neurons could provide important clues for elucidating the pathogenesis and mechanism of PD. This mysterious and hidden connection may prove to be a boon in disguise, hence, here we review the influence of PARKIN and DAT on DA mechanism and will discuss how these findings underpin the concept of how downregulation or upregulation of DAT is influenced by PARKIN. We conclude that the establishment of new model for PD with a combination of DAT and PARKIN would have a high translational potential, which includes the identification of drug targets and testing of known and novel therapeutic agents.

中文翻译：

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解开多巴胺转运蛋白 (DAT) 和帕金森在帕金森病 (PD) 中的相关作用——一条发现之路？

帕金森病 (PD) 是一种神经退行性疾病，伴随着大脑中多巴胺 (DA) 的耗竭和多巴胺能 (DAergic) 神经元的丧失，被认为是导致 PD 运动和非运动症状的原因。多巴胺转运蛋白 (DAT) 对于 DA 再摄取到突触前末端至关重要，从而控制释放的 DA 的可用性和空间活动。Parkin 与参与内体通路的蛋白质相互作用，表明突触前 Parkin 可以调节质膜中 DAT 的表达。Parkin 突变会导致早期突触损伤，它似乎是一个具有广阔功能区域的关键基因。PD 特异性诱导多能干细胞 (iPSC) 衍生的 DA 神经元作为 PD 体外建模的潜在工具存在，因为它们可以概括 PD 的病理特征。PARKIN 影响 DAT 变异和 DAT 对 DA 再摄取变化的确切机制仍然未知。因此，DAT 和 PARKIN 突变的 PD 特异性 iPSC 衍生的 DA 神经元可以为阐明 PD 的发病机制和机制提供重要线索。这种神秘而隐藏的联系可能被证明是变相的恩惠，因此，在这里，我们回顾了 PARKIN 和 DAT 对 DA 机制的影响，并将讨论这些发现如何支持 PARKIN 如何影响 DAT 的下调或上调的概念。我们得出结论，结合 DAT 和 PARKIN 建立新的 PD 模型将具有很高的转化潜力，其中包括确定药物靶点以及测试已知和新型治疗剂。