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.
Highlights
Parkinson’s disease (PD) is a chronic progressive neurodegenerative disease associated with aging
Aggregated a-syn-and microglia-mediated neuroinflammation play a core role in the onset and progression of PD, respectively
Pathological a-syn is closely related to microgliainduced neuroinflammation
Summary
Parkinson’s disease (PD) is a chronic progressive neurodegenerative disease associated with aging. NLRP3 inflammasome is a multiprotein inflammatory signaling complex, activated by a variety of microbial or damage-associated molecular patterns [8]. Pathogenic protein aggregates, such as a-syn fibrils, another hallmark of PD pathology and the primary component of Lewy bodies, were reported to activate NLRP3 inflammasome in microglia through an interaction with toll-like receptors (TLRs) and the activation of nuclear factor kappa-B(NF-kB) [9, 10]. Pathological a-syn exerts deleterious effects on synaptic function and mitochondrial homeostasis, in addition to inducing excessive microglial activation [11] This possibly contributes to neuroinflammation and neuronal death [12]. We intended to introduce various pharmacological agents or molecular compounds targeting the a-syn/TLRs/NF-kB/NLRP3 inflammasome axis, which might be a promising target for PD treatment
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