Abstract
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms and loss of dopaminergic neurons of the substantia nigra. Inflammation and cell death are recognized aspects of PD suggesting that strategies to monitor and modify these processes may improve the management of the disease. Inflammasomes are pro-inflammatory intracellular pattern recognition complexes that couple these processes. The NLRP3 inflammasome responds to sterile triggers to initiate pro-inflammatory processes characterized by maturation of inflammatory cytokines, cytoplasmic membrane pore formation, vesicular shedding, and if unresolved, pyroptotic cell death. Histologic analysis of tissues from PD patients and individuals with nigral cell loss but no diagnosis of PD identified elevated expression of inflammasome-related proteins and activation-related “speck” formation in degenerating mesencephalic tissues compared with controls. Based on previous reports of circulating inflammasome proteins in patients suffering from heritable syndromes caused by hyper-activation of the NLRP3 inflammasome, we evaluated PD patient plasma for evidence of inflammasome activity. Multiple circulating inflammasome proteins were detected almost exclusively in extracellular vesicles indicative of ongoing inflammasome activation and pyroptosis. Analysis of plasma obtained from a multi-center cohort identified elevated plasma-borne NLRP3 associated with PD status. Our findings are consistent with others indicating inflammasome activity in neurodegenerative disorders. Findings suggest mesencephalic inflammasome protein expression as a histopathologic marker of early-stage nigral degeneration and suggest plasma-borne inflammasome-related proteins as a potentially useful class of biomarkers for patient stratification and the detection and monitoring of inflammation in PD.
Highlights
Parkinson’s disease (PD) is a complex age-related neurodegenerative disease impacting multiple systems and characterized clinically by a host of motor and non-motor symptomologies[1,2].Diagnostic tests and neuroprotective strategies have been slow to emerge in part because the molecular mechanisms of disease initiation and progression are not completely defined[3,4]
Our studies build on a growing body of evidence indicating a role for NLRP3 in cell, animal, and human studies of neurodegenerative disease[17,27,31,63]
We have considered the secretory aspects of inflammasome activity and explored the potential that the release of cytosolic proteins observed during these pro-inflammatory processes[36,37,64,65] may result in the detection of pyroptosisrelated proteins in biofluids
Summary
Parkinson’s disease (PD) is a complex age-related neurodegenerative disease impacting multiple systems and characterized clinically by a host of motor and non-motor symptomologies[1,2]. The inflammasome components including Nlrp[3], Pycard, Casp[1], as well number of pigmented neurons in the nigral cell loss patients was as direct targets and elicitors of inflammatory pyroptosis, Gsdmd intermediate compared with healthy controls and confirmed PD and IL-1b, in the aged mouse brain (Supplemental Fig. 2c). Significant numbers of monocytes (MNC) and macrophages (MAC) present in aged mouse brain tissues expressed the core components of the NLRP3 inflammasome In light of these findings, we confirmed previous reports[52,53] characterizing the release of pyroptosis-related proteins from. The detectable concentration of NLRP3 was significantly higher in the EV fraction compared to its respective plasma sample (P = 0.0411) (Supplemental Fig. 6) These data suggest that future studies designed to isolate and further evaluate inflammasome-related EVs may provide an inroad towards PD stratification and the discovery of plasma-borne biomarkers of inflammation
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