Abstract
Introduction
Parkinson’s Disease (PD) is characterized by loss of substantia nigra (SN) dopaminergic neurons, resulting in reduced CNS dopamine transmission. PD is widely thought to start in the periphery; however, whether and how PD affects peripheral dopamine transmission remains unknown. Peripheral immune cells express key dopaminergic proteins, including dopamine transporter (DAT) and tyrosine hydroxylase (TH). Therefore, it is possible that the peripheral dopamine system is affected by PD pathology.
Objective
We hypothesized that peripheral immune cells of PD patients exhibit dysregulated dopamine homeostasis.
Methods/Results
Using flow cytometry we found human peripheral blood mononuclear cells (PBMCs) constitutively express DAT and TH with 90% of CD14+ cells expressing both markers. Upon examining PBMCs of PD patients receiving a variety of treatments, we found that DAT/TH positive PBMCs are elevated in PD patients compared to healthy controls (n=67 independent biological replicates, P<0.05) irrespective of the treatment modality applied. Importantly, in drug naïve patients diagnosed with PD we observed the highest increase in DAT/TH positive monocytes (n=5, P<0.05) compared to both treated PD patients and healthy individuals, suggesting observed changes correlate with disease pathology and not treatment interventions. Collectively, these data suggest a system-wide dysregulation of the dopamine system on peripheral immune cells in PD. To further understand the functional consequences of increased DAT+/TH+ PBMCs, we asked if DAT function was altered on PD monocyte-derived cells. Live cell fluorescence microscopy and biochemical analysis confirmed healthy human monocyte-derived macrophages (MDM) express membrane-localized, canonically functional DAT (Km=3.2mM). Surprisingly, relative to healthy age-matched controls, PD patients’ MDMs exhibited dramatically elevated DAT-mediated substrate uptake and increased membrane localization (p<0.0001, n=5 biological replicates).
Conclusions
Taken together, these data are consistent with the interpretation that in PD, peripheral dopamine homeostasis is dysregulated. Importantly, this presents PBMC DAT/TH as a potential biomarker for PD and suggests the peripheral dopamine system is functionally linked to the CNS dopamine system. Future work will aim to validate this biomarker and investigate the mechanistic connection between peripheral-CNS dopamine systems to elucidate the pathophysiological role of dysregulated monocyte dopamine transmission in PD.