DAT and TH expression marks human Parkinson’s disease in peripheral immune cells

Abstract

Parkinson’s disease (PD) is marked by a loss of dopamine neurons, decreased dopamine transporter (DAT) and tyrosine hydroxylase (TH) expression. However, this validation approach cannot be used for diagnostic, drug effectiveness or investigational purposes in human patients because midbrain tissue is accessible postmortem. PD pathology affects both the central nervous and peripheral immune systems. Therefore, we immunophenotyped blood samples of PD patients for the presence of myeloid derived suppressor cells (MDSCs) and discovered that DAT+/TH+ monocytic MDSCs, but not granulocytic MDSCs are increased, suggesting a targeted immune response to PD. Because in peripheral immune cells DAT activity underlies an immune suppressive mechanism, we investigated whether expression levels of DAT and TH in the peripheral immune cells marks PD. We found drug naïve PD patients exhibit differential DAT+/TH+ expression in peripheral blood mononuclear cells (PBMCs) compared to aged/sex matched healthy subjects. While total PBMCs are not different between the groups, the percentage of DAT+/TH+ PBMCs was significantly higher in drug naïve PD patients compared to healthy controls irrespective of age, gender, disease duration, disease severity or treatment type. Importantly, treatment for PD negatively modulates DAT+/TH+ expressing PBMCs. Neither total nor the percentage of DAT+/TH+ PBMCs were altered in the Alzheimer’s disease cohort. The mechanistic underpinning of this discovery in human PD was revealed when these findings were recapitulated in animal models of PD. The reverse translational experimental strategy revealed that alterations in dopaminergic markers in peripheral immune cells are due to the disease associated changes in the CNS. Our study demonstrates that the dopaminergic machinery on peripheral immune cells displays an association with human PD, with exciting implications in facilitating diagnosis and investigation of human PD pathophysiology.

The Interface between Inflammatory Bowel Disease, Neuroinflammation, and Neurological Disorders

“…We demonstrated that peripheral immune cells display an association with human PD. 124 The role of neuroinflammation in the pathogenesis of PD is clear, with elevated levels of proinflammatory mediators in the basal ganglia and cerebrospinal fluid of PD patients. Furthermore, reducing inflammation (a major therapeutic target of IBD therapy) may reduce the risk of developing PD, suggesting a different biological effect.…”

Dopaminergic regulation of inflammation and immunity in Parkinson's disease: friend or foe?

“…101 Interestingly, same as TH expression in monocytes, 130 DAT expression in PBMCs from PD patients was also found to be increased. 131 Experimental evidence shows DA can modulate inflammation through redox pathways and the generation of reactive oxygen metabolites, such as DA quinone (DAQ). 98,153,154 For example, DA can reduce NO and iNOS production, TNF-a, IL-1b and IL-6 expression in the presence of tyrosinase, which catalyses the oxidation of DA to DAQ in both murine primary and microglial BV-2 cell line 98,153 (Table 1).…”

“…131 The treatments also affect the expression patterns of DAT and TH as L-dopa/benserazide treatment in mice restored baseline levels of both DAT and TH, whereas L-dopa alone only restored TH expression on PBMC. 131 Besides their effects on immune regulation in the periphery, L-dopa also contributes to glial neuroinflammatory responses and long-term therapy side-effects, including LID. 188,189 The exact mechanism that causes LID and other motor complications has yet to be defined but increasing preclinical evidence suggests that glial cells are potential contributors.…”

“…It has also been found that DA signalling can occur through Dopamine transporter (DAT) and other transporters, such as the plasma membrane monoamine transporter (PMAT) 101 . Interestingly, same as TH expression in monocytes, 130 DAT expression in PBMCs from PD patients was also found to be increased 131 . Experimental evidence shows DA can modulate inflammation through redox pathways and the generation of reactive oxygen metabolites, such as DA quinone (DAQ) 98,153,154 .…”

Search for Molecular Biomarkers of Parkinson’s Disease. New Tissues and Methods

“…Despite this fact, the utilisation of TH as a biomarker of PD was investigated in a few studies several decades ago. Recent studies unexpectedly revealed that monocytes isolated from blood of PD patients express significantly higher levels of TH in comparison to age-matched healthy controls (38). It was suggested that the dopaminergic machinery on peripheral immune cells displays an association with human PD, with some implications in facilitating diagnosis.…”