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

Abstract

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.

P2X7 receptor/NLRP3 inflammasome complex and a-synuclein/parkin balance in neo-diagnosed, treatment-naïve Parkinson disease: a prospective study

“…This potentiated system does not translate, in our study, in different level of systemic in ammation, as shown by the similar IL-1β and IL-18 levels in PD and CTL, even in the presence of a trend for IL-18. This resonates with the recent publication by White and colleagues [32], even in a stimulated setting, and could be due to the short duration of the disease of our patients, the very good matching of our controls (same age and biochemical pro le), or to the relatively small number of studied subjects. Matter of fact that a weak but signi cant correlation between IL-18 and P2 × 7R was found.…”

Mitochondrial Dysfunction, Oxidative Stress, and Neuroinflammation: Intertwined Roads to Neurodegeneration

“…Sporadic forms of PD recapitulate all major hallmarks of aging, thus making PD a prototypical geroscience condition [4,129]. The co-occurrence of mitochondrial dysfunction and neuroinflammation are alleged pathogenic mechanisms of neuronal degeneration [24,136,137]. In particular, defective MQC and DAMPs generation are proposed to be major contributing factors [52].…”

Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

“…PD has a multifaceted pathophysiology that recapitulates all major hallmarks of aging and has therefore been proposed as a prototypical geroscience condition [4,129,151]. In this complex scenario, mitochondrial dysfunction in neurons and systemic inflammation are invoked as major pathogenic mechanisms in PD [152,153]. Although the molecular events linking these two processes are yet to be disentangled, failing MQC and the release of mitochondrial DAMPs within small EVs (sEVs) have recently been associated with a specific inflammatory profile in older adults with PD [71].…”