Targeting Microglial α-Synuclein/TLRs/NF-kappaB/NLRP3 Inflammasome Axis in Parkinson's Disease

Abstract

According to emerging studies, the excessive activation of microglia and the subsequent release of pro-inflammatory cytokines play important roles in the pathogenesis and progression of Parkinson's disease (PD). However, the exact mechanisms governing chronic neuroinflammation remain elusive. Findings demonstrate an elevated level of NLRP3 inflammasome in activated microglia in the substantia nigra of PD patients. Activated NLRP3 inflammasome aggravates the pathology and accelerates the progression of neurodegenerative diseases. Abnormal protein aggregation of α-synuclein (α-syn), a pathologically relevant protein of PD, were reported to activate the NLRP3 inflammasome of microglia through interaction with toll-like receptors (TLRs). This eventually releases pro-inflammatory cytokines through the translocation of nuclear factor kappa-B (NF-κB) and causes an impairment of mitochondria, thus damaging the dopaminergic neurons. Currently, therapeutic drugs for PD are primarily aimed at providing relief from its clinical symptoms, and there are no well-established strategies to halt or reverse this disease. In this review, we aimed to update existing knowledge on the role of the α-syn/TLRs/NF-κB/NLRP3 inflammasome axis and microglial activation in PD. In addition, this review summarizes recent progress on the α-syn/TLRs/NF-κB/NLRP3 inflammasome axis of microglia as a potential target for PD treatment by inhibiting microglial activation.

Keywords: NLRP3 inflammasome; Parkinson’s disease; microglia; neuroinflammation; α-synuclein.

Figure 1

NLRP3 inflammasome activation evoked by α-syn aggregates. In Parkinson’s disease, the imbalance between the α-syn synthesis and clearance contributes to the aggregation and accumulation of α-syn in the neurons. Neurons release α-syn in distinct ways, including passive and active mechanisms; the type of release depends on the different forms of α-syn. Exosomes are also involved in the release of aggregated α-syn. The α-syn aggregates released into the extracellular space provide the priming signal for the activation of NLRP3 through binding to TLR2, triggering NF-κB-dependent upregulation of NLRP3 and production of pro-inflammatory cytokine. In addition, α-syn aggregates impair mitochondrial function following the internalization of α-syn fibrils by microglia, thereby inducing the generation of mtDNA and mtROS. Several molecular mechanisms have been proposed for mitochondrial dysfunction, including the reduction of SIRT3 via the AMPKα-CREB signaling pathway, the blockage of TOM20 and the engagement of CD11b. The aforementioned process provides the second “activation” signal for the activation of the NLRP3 inflammasome, which induces activated caspase-1-mediated release of mature IL-1β and IL-18. The inflammatory cytokines are capable of augmenting cytotoxicity and α-syn accumulation. Several therapeutic approaches exert a neuroprotection effect by targeting the α-syn/TLRs/NF-κB/NLRP3 process, including immune antibodies, molecular compounds, the repurpose of pre-existing drugs and natural extracts. NLRP3, leucine-rich repeat- and pyrin domain-containing 3; TLRs, toll like receptors; IL-1β, interleukin-1β; IL-18, interleukin-18; NF-κB, nuclear factor kappa light chain enhancer of activated B cells; TOM20, the translocase of the outer membrane receptors; CD11b, the α chain of a non-covalently associated heterodimeric transmembrane receptor integrin αMβ2; ASC, apoptosis-associated speck-like protein; SIRT3, nicotinamide adenine dinucleotide-dependent deacetylase.