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

Adithya Gopinath; Phillip Mackie; Basil Hashimi; Anna Marie Buchanan; Aidan R Smith; Rachel Bouchard; Gerry Shaw; Martin Badov; Leila Saadatpour; Aryn Gittis; Adolfo Ramirez-Zamora; Michael S Okun; Wolfgang J Streit; Parastoo Hashemi; Habibeh Khoshbouei

doi:10.1038/s41531-022-00333-8

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

NPJ Parkinsons Dis. 2022 Jun 7;8(1):72. doi: 10.1038/s41531-022-00333-8.

Authors

Adithya Gopinath¹, Phillip Mackie², Basil Hashimi², Anna Marie Buchanan³, Aidan R Smith², Rachel Bouchard⁴, Gerry Shaw^{2

5}, Martin Badov², Leila Saadatpour^{2

6}, Aryn Gittis⁴, Adolfo Ramirez-Zamora⁷, Michael S Okun⁷, Wolfgang J Streit², Parastoo Hashemi^{3

8}, Habibeh Khoshbouei⁹

Affiliations

¹ Department of Neuroscience, University of Florida, Gainesville, FL, USA. [email protected].
² Department of Neuroscience, University of Florida, Gainesville, FL, USA.
³ University of South Carolina, Columbia, SC, USA.
⁴ Carnegie Mellon University, Pittsburgh, PA, USA.
⁵ EnCor Biotechnology, Inc, Gainesville, FL, USA.
⁶ Department of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
⁷ Department of Neurology, Norman Fixel Institute for Neurological Diseases, UF Health, Gainesville, FL, USA.
⁸ Department of Bioengineering, Imperial College, London, UK.
⁹ Department of Neuroscience, University of Florida, Gainesville, FL, USA. [email protected].

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.

Abstract

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