The Peripheral Inflammatory Response to Alpha-Synuclein and Endotoxin in Parkinson's Disease.

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White, Alice J 
Wijeyekoon, Ruwani S 
Scott, Kirsten M 
Gunawardana, Nushan P 
Hayat, Shaista 

The immune system is activated in Parkinson's Disease (PD), as evidenced by neuroinflammatory changes within the brain as well as elevated immune markers in peripheral blood. Furthermore, inflammatory cytokine levels in the blood are associated with disease severity and rate of progression. However, the factors driving this immune response in PD are not well established. We investigated cell-extrinsic factors in systemic immune activation by using α-synuclein monomers and fibrils, as well as bacterial toxins, to stimulate peripheral blood mononuclear cells (PBMCs) derived from 31 patients and age/gender-matched controls. α-synuclein monomers or fibrils resulted in a robust cytokine response (as measured by supernatant cytokine concentrations and mRNA expression in cultured cells) in both PD and control PBMCs, similar to that induced by bacterial LPS. We found no PD vs. control differences in cytokine production, nor in mRNA expression. Levels of endotoxin within the recombinant α-synuclein used in these experiments were very low (0.2-1.3EU/mL), but nonetheless we found that comparable levels were sufficient to potentially confound our cytokine concentration measurements for a number of cytokines. However, α-synuclein monomers increased production of IL-1β and IL-18 to levels significantly in excess of those induced by low-level endotoxin. In conclusion, this study: (i) highlights the importance of accounting for low-level endotoxin in antigen-PBMC stimulation experiments; (ii) indicates that cell-extrinsic factors may be a major contributor to immune activation in PD; and (iii) suggests that α-synuclein may play a role in inflammasome-related cytokine production in the periphery.

Parkinson's disease, alpha-synuclein, cytokines, endotoxin, immune system
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Front Neurol
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Frontiers Media SA
Academy of Medical Sciences (unknown)
Addenbrooke's Charitable Trust (ACT) (PF15/CWG)
Stevenage Bioscience Catalyst (unknown)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)
Medical Research Council (MR/R007446/1)
Grant funding from the Academy of Medical Sciences UK, the Rosetrees Trust, the Stevenage Biosciences Catalyst and Addenbrooke’s Charitable Trust contributed to this work. The research was also supported by the NIHR Cambridge Biomedical Research Centre (Cambridge University Hospitals NHS Trust/University of Cambridge). C H Williams-Gray is supported by a fellowship from the Medical Research Council. A J White was funded by Homerton College. R S Wijeyekoon was supported by a fellowship from Addenbrooke’s Charitable Trust. K M Scott is supported by a fellowship from the Wellcome Trust. R A Barker is supported by the Wellcome-MRC Cambridge Stem Cell Institute and is an NIHR Senior Investigator.