Abstract
The core of clinic treatment of Parkinson's disease (PD) is to enhance dopamine (DA) signaling within the brain. The regulation of dopamine transporter (DAT) is integral to this process. This study aims to explore the regulatory mechanism of glial cell line-derived neurotrophic factor (GDNF) on DAT, thereby gaining a profound understanding its potential value in treating PD. Here, we investigated the effects of GDNF on both cells and mice with PD, including the glycosylation and membrane distribution of DAT detected by immunofluorescence and immunoblotting, DA signal measured by neurotransmitter fiber imaging technology, Golgi morphology observed by electron microscopic, as well as cognitive ability assessed by behavior tests. In this study, GDNF enhanced the glycosylation and membrane distribution of DAT of the injured DA neurons both in vivo and invitro, while reversing GRASP65 loss and Golgi fragmentation leading to alleviation of DAT accumulation in the Golgi. Moreover, GRASP65 overexpression increased DAT distribution in PD cells and mice, whereas, the inhibition of GRASP65 could leading to diminished role of GDNF on DAT. In addition, GDNF could enhance the reutilization of neurotransmitter uptake by presynaptic membranes in the PFC and enhance the effective DA release signal after a single electrical stimulation, ultimately improving the cognitive impairment of PD mice. Thus, we proposed that GDNF promotes the glycosylation and membrane distribution of DAT by facilitating Golgi reaggregation, leading to an enhancement of DA signal utilization, ultimately resulting in an improvement in cognitive ability of PD mice. This study illustrates from a new perspective the beneficial role of GDNF in enhancing DA utilization and improving cognition in PD.