Targeting the microglial NLRP3 inflammasome and its role in Parkinson's disease

Abstract

Excessive activation of microglia and subsequent release of proinflammatory cytokines play a crucial role in neuroinflammation and neurodegeneration in Parkinson's disease (PD). Components of the nucleotide-binding oligomerization domain and leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome complex, leucine-rich-repeat- and pyrin-domain-containing 3, caspase-1, and apoptosis-associated speck-like protein containing a CARD, are highly expressed in activated microglia in PD patient brains. Findings suggest that neurotoxins, aggregation of α-synuclein, mitochondrial reactive oxygen species, and disrupted mitophagy are the key regulators of microglial leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome activation and release of interleukin-1β and interleukin-18 caspase-1-mediated pyroptotic cell death in the substantia nigra of the brain. Although this evidence suggests the leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome may be a potential drug target for treatment of PD, the exact mechanism of how the microglia sense these stimuli and initiate leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome signaling is unknown. Here, the molecular mechanism and regulation of microglial leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome activation and its role in the pathogenesis of PD are discussed. Moreover, the potential of both endogenous and synthetic leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome modulators, long noncoding RNA, microRNA to develop novel therapeutics to treat PD is presented. Overall, we recommend that the microglial leucine-rich-repeat- and pyrin-domain-containing 3 inflammasome can be a potential target for PD treatment. © 2019 International Parkinson and Movement Disorder Society.