Functional characterization of the biogenic amine transporter system on human macrophages

Mackie, Phillip; Gopinath, Adithya; Montas, Dominic; Nielsen, Anne Kathrine; Nolan, Rachel; Runner, Kaitlyn; Matt, Stephanie; McNamee, John; Ricklan, Joshua; Adachi, Kengo; Doty, Andria; Ramirez‐Zamora, Adolfo; Long, Yan; Gaskill, Peter J.; Streit, Wolfgang J.; Okun, Michael S.; Khoshbouei, Habibeh

doi:10.1101/2021.09.08.459459

Cited by 2 publications

(1 citation statement)

References 89 publications

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“…Materials and equipment are listed in Tables 1, 2 and 3. As previously published 29–32 , whole blood was collected in K2EDTA vacutainer blood collection tubes (BD, 366643) and kept at room temperature for up to 2 hours prior to PBMC isolation. Briefly, blood from healthy volunteers and PD patients was overlaid in Leucosep tubes for PBMC isolation, centrifuged for 20 minutes at 400g with brakes turned off and acceleration set to minimum.…”

Section: Methodsmentioning

confidence: 99%

Longitudinal immunophenotyping to track motor progression in Parkinson’s Associated with a TH mutation

Gopinath,

Ramirez-Zamora,

Franks

et al. 2024

Preprint

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Background and Objectives: PD is the second most common neurodegenerative disorder and the fastest growing. Genetic factors account for ∼15% of cases. Despite some consistency in symptoms across idiopathic and genetic PD cases, tracking progression and treatment response remains an important challenge especially in the development of new therapies. There have been many traditional approaches to tracking including DaTscan imaging, cardiac 123I-MIBG scintigraphy, MRI, CSF analysis, and following clinical symptom progression. Methods: Our previous work showed that peripheral blood mononuclear cells (PBMCs) expressing dopamine transporter (DAT) and tyrosine hydroxylase (TH) in PD patients may correlate with disease progression and with the response to treatment with levodopa. We describe a single case longitudinal follow up of a 40-45-year-old woman with PD who carried a heterozygous TH mutation. We assessed her clinical features over 18 months with DaT scans and immunophenotyping of her PBMCs. Her data were compared with idiopathic PD (n=130 subjects, both sexes) and healthy controls (n=80, age/sex matched). Results: The results revealed a rise in DAT+ immune cells which occurred coincident to documented worsening of her UPDRS-III motor scores. Unlike idiopathic PD patients, following levodopa therapy, the TH+ immune cell levels remained elevated, despite UPDRS-III score improvement. Discussion: The longitudinal immunophenotyping in this PD patient with a TH mutation suggested that DAT+ and TH+ PBMCs could be candidate biomarkers for PD progression and possibly treatment effectiveness. This study provides proof of concept to explore this approach to investigate immunophenotyping in PD progression.

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Section: Methodsmentioning

confidence: 99%

Longitudinal immunophenotyping to track motor progression in Parkinson’s Associated with a TH mutation

Gopinath,

Ramirez-Zamora,

Franks

et al. 2024

Preprint

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

Gopinath

Mackie

Hashimi

et al. 2022

npj Parkinsons Dis.

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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.

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Functional characterization of the biogenic amine transporter system on human macrophages

Cited by 2 publications

References 89 publications

Longitudinal immunophenotyping to track motor progression in Parkinson’s Associated with a TH mutation

Longitudinal immunophenotyping to track motor progression in Parkinson’s Associated with a TH mutation

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

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