Bu Mengfei, Farrer Matthew J, Khoshbouei Habibeh
Department of Neurology and Fixel Institute, University of Florida, Gainesville, FL, USA.
Department of Neuroscience, University of Florida, Gainesville, FL, USA.
NPJ Parkinsons Dis. 2021 Mar 5;7(1):22. doi: 10.1038/s41531-021-00161-2.
The dopamine transporter (DAT) transports extracellular dopamine into the intracellular space contributing to the regulation of dopamine neurotransmission. A reduction of DAT density is implicated in Parkinson's disease (PD) by neuroimaging; dopamine turnover is dopamine turnover is elevated in early symptomatic PD and in presymptomatic individuals with monogenic mutations causal for parkinsonism. As an integral plasma membrane protein, DAT surface expression is dynamically regulated through endocytic trafficking, enabling flexible control of dopamine signaling in time and space, which in turn critically modulates movement, motivation and learning behavior. Yet the cellular machinery and functional implications of DAT trafficking remain enigmatic. In this review we summarize mechanisms governing DAT trafficking under normal physiological conditions and discuss how PD-linked mutations may disturb DAT homeostasis. We highlight the complexity of DAT trafficking and reveal DAT dysregulation as a common theme in genetic models of parkinsonism.
多巴胺转运体（DAT）将细胞外多巴胺转运到细胞内空间，有助于调节多巴胺神经传递。神经影像学研究表明，帕金森病（PD）中DAT密度降低；在早期有症状的PD患者以及具有导致帕金森综合征的单基因突变异型的无症状个体中，多巴胺周转率升高。作为一种完整的质膜蛋白，DAT的表面表达通过内吞转运进行动态调节，从而能够在时间和空间上灵活控制多巴胺信号，进而对运动、动机和学习行为进行关键调节。然而，DAT转运的细胞机制及其功能意义仍然不明。在这篇综述中，我们总结了正常生理条件下控制DAT转运的机制，并讨论了与PD相关的突变如何扰乱DAT的稳态。我们强调了DAT转运的复杂性，并揭示DAT失调是帕金森综合征遗传模型中的一个共同主题。
