Alpha-Synuclein Aggregates Activate the Nlrp3 Inflammasome Following Vesicle Rupture

Parkinson\u27s disease (PD) and related synucleinopathies are progressive neurodegenerative disorders that feature the accumulation of intracellular inclusions known as Lewy bodies (LBs) in the brain. The presynaptic protein α-synuclein is the primary constituent of LBs and has been documented to play a major role in the pathogenesis of synucleinopathies. Recently, aggregated α-synuclein has been implicated in prompting microglia-mediated inflammation, a process associated with the progression of neuronal death in neurodegenerative disorders. Although the mechanisms surrounding the induction of neuroinflammation are not well understood, the recently discovered inflammasome-forming NLR proteins have emerged as regulators of inflammation. In this study, we sought to understand the involvement of the inflammasome in response to aggregated α-synuclein in microglia-like cells. We report that aggregated α-synuclein induces vesicle rupture in THP-1 cells that is sensed as a `danger signal\u27 resulting in the assembly of the NLRP3 inflammasome, activation of caspase-1, and the release of proinflammatory cytokines