Unraveling correlative roles of dopamine transporter (DAT) and Parkin in Parkinson's disease (PD) - A road to discovery?

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.