IC100 blocks inflammasome activation induced by α-synuclein aggregates and ASC specks

Parkinson's disease (PD) is associated with chronic sterile inflammation and persistent inflammasome activation involving α-synuclein and ASC protein aggregates, but the underlying mechanisms of the neuroinflammatory response remain unclear. Here, we used midbrain postmortem samples from donors with and without α-synucleinopathies to assess the expression of inflammasome proteins in patients with Parkinsonism. We show that dopaminergic neurons exhibit increased expression of ASC, NOD-like receptor protein (NLRP) 1, and modification of α-synuclein phosphorylation at serine129 (pS129) within the Lewy body inclusions, whereas NLRP3 was identified mainly in microglial. Moreover, treatment of LRRK2 cells with ASC specks from PD and Lewy body dementia patients induced inflammasome activation and cytotoxicity that was blocked by IC100. Administration of preformed α-synuclein aggregates to microglia resulted in a significant elevation in pS129, and this effect was also blocked by IC100. Thus, IC100 may be a promising therapeutic strategy for inflammatory disease modification in synucleinopathies and other diseases.