Fibrillar alpha-Synuclein Can Induce NLRP3-Inflammasome Activation in Parkinson Disease (PD)
Introduction. Parkinson disease (PD) is the second most common neurodegenerative disease, causing dopaminergic neuronal cell loss in the substantia nigra (SN).1,2,3 PD affects approximately 1-2% of the total population over the age of 60.3 Pathologically, PD involves misfolded aggregates of a-synuclein known as Lewy bodies.1 The decreased dopamine in the SN causes a resting tremor, rigidity, bradykinesia, and in some cases dementia.1,2,3 The exact etiology of PD is not well known, but a multitude of factors are known to be involved in its pathogenesis.1 Nod-like receptor protein 3 (NLRP3), present in microglial cells in the CNS, is involved in producing IL-1b, causing pro-inflammatory effects within the SN.4 NLRP3 requires both a priming signal which induces gene expression of pro-IL-1b and the NLRP3 components, and an activation signal, which cleaves pro-caspase-1 into caspase-1.4 Fibrillar a-synuclein, present in PD, can directly induce NLRP3-inflammasome activation, activating caspase-1, which cleaves pro-IL-1b into IL-1b.4 NLRP3 provides a potential mechanism for SN neuronal degeneration in PD patients. Methods. Mice models were injected with 6-hydroxydopamine which is used to represent PD and the mice either had intact NLRP3 function or NLRP3 knocked out (KO) .5 In addition, primary microglia from NLRP3 WT and KO mice were primed with lipopolysaccharide (LPS) and were treated with fibrillar a-synuclein.5 IL-1b levels were measured after 24 hours and compared to ATP, a potent NLRP3 activator.5 a-synuclein was also given to WT mice in the absence of LPS.5 BV2 mice microglial cell lines were treated with A53T a-synuclein to represent fibrillar a-synuclein overexpression.6 miRNA-7 were introduced into A37T and WT cells and NLRP3 components were measured.6 Results. After 24 hours, microglial cells treated with a-synuclein in the presence of LPS showed increased IL-1b, caspase 1, and ASC protein (p<0.0001).5 In the absence of LPS, IL-1b was produced but at a lower level compared to cells primed with LPS (p<0.0001).5 Introduction of miRNA-7 into BV2 cell lines resulted in decreased NLRP3, caspase-1, and IL-1b compared to control cell lines regardless of WT or A53T expression.6 Conclusion. NRLP3 has been shown to be activated by fibrillar a-synuclein, which is present in PD. Further, in both the presence and absence of the LPS priming signal, IL-1b was detected, indicating direct activation. Additionally, miRNA-7 has shown to decrease NLRP3 activation in-vitro, indicating that it may serve as a potential therapeutic option to halt PD pathogenesis.
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