Systemic activation of NLRP3 inflammasome and plasma α-synuclein levels are correlated with motor severity and progression in Parkinson’s disease

Abstract

Background: Emerging evidence indicates that inflammasome-induced inflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Several proteins including α-synuclein trigger the activation of NLRP3 inflammasome. However, few studies examined whether inflammasomes are activated in the periphery of PD patients and their possible value in the diagnosis or tracking of the progress of PD. The aim of this study was to determine the association between inflammasome-induced inflammation and clinical features in PD. Methods: There were a total of 67 participants, including 43 patients with PD and 24 controls, in the study. Participants received a complete evaluation of motor and non-motor symptoms, including Hoehn and Yahr (H-Y) staging scale. Blood samples were collected from all participants. The protein and mRNA expression levels of inflammasomes subtypes and components in peripheral blood mononuclear cells (PBMCs) were determined using western blotting and RT-qPCR. We applied Meso Scale Discovery (MSD) immunoassay to measure the plasma levels of IL-1β and α-synuclein. Results: We observed increased gene expression of NLRP3, ASC, and caspase-1 in PBMCs, and increased protein levels of NLRP3, caspase-1, and IL-1β in PD patients. Plasma levels of IL-1β were significantly higher in patients with PD compared with controls and have a positive correlation with H-Y stage and UPDRS part III scores. Furthermore, plasma α-synuclein levels were also increased in PD patients and have a positive correlation with both UPDRS part III scores and plasma IL-1β levels. Conclusions: Our data demonstrated that the NLRP3 inflammasome is activated in the PBMCs from PD patients. The related inflammatory cytokine IL-1β and total α-synuclein in plasma were increased in PD patients than controls, and both of them presented a positive correlation with motor severity in patients with PD. Furthermore, plasma α-synuclein levels have a positive correlation with IL-1β levels in PD patients. All these findings suggested that the NLRP3 inflammasome activation-related cytokine IL-1β and α-synuclein could serve as non-invasive biomarkers to monitor the severity and progression of PD in regard to motor function.

Neurovascular Inflammaging in Health and Disease

“…Furthermore, the hepatic inhibition of NLRP3 was also shown to attenuate dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, outlining the role of systemic activation of NLRP3 in PD. This is further supported by reports of elevated NLRP3, caspase-1 and IL-1β in the blood serum of PD patients and its correlation with α-synuclein [104,105].…”

A modern view on potential biomarkers of Parkinson’s disease (review)

“…Chun-Wei Chang et al revealed that the serum α-synuclein level showed a significant correlation with patients in Hoehn-Yahr stages 1-3, implying that the serum α-synuclein level may be a potential marker of motor symptom severity in patients with early PD [34]. Zheng Fan with co-authors also found the correlation between elevated plasma total α-synuclein level in PD patients and the severity of their motor symptoms [35]. However, there is now a tendency for scientists to study the α-synuclein level not just in blood plasma, but in its neuronal exosomes.…”

Proteostasis Disturbances and Inflammation in Neurodegenerative Diseases

“…NLRP3, caspase-1, and IL-1β were increased in PD patients’ PBMCs and plasma when compared to age-matched healthy controls [ 115 , 116 , 117 ]. In addition, increased levels of IL-1b and IL-18 levels have been detected in the cerebrospinal fluid of PD patients [ 118 ].…”

“…Several studies have now linked the α-SYN and NLRP3 inflammasome activation in PD. Increased plasma levels of α-SYN and IL-1β in PD patients have been shown to correlate with the motor severity in PD patients [ 115 ]. Moreover, the fibrillar form of α-SYN induced NLRP3–caspase-1 complex activation and the release of IL-1β in PBMCs, monocytes, microglia, and astrocytes [ 117 , 121 ].…”