Neuroinflammation is a hallmark of Parkinson’s disease (PD) and is triggered by the activation of the innate immune response. Inflammasomes are key protein complexes of innate immunity that can be activated by protein aggregates such as a-synuclein (Syn). Inflammasome activation induces the release of IL-1b through the assembly of the inflammasome complex, involving ASC proteins and the recruitment of caspase-1 enzymes. Interestingly, ASC functions not only as an adaptor protein in the inflammasome but also has extracellular and prionoid activities that can propagate inflammation. This study aimed to determine the role of ASC in propagating Syn pathology and PD neurodegeneration. We initially assessed inflammasome components and ASC expression in postmortem human PD brains and serum from PD patients. We found that NLRP3 components and ASC were upregulated in the substantia nigra of PD brains, and in serum from PD patients compared to healthy controls. Next, we examined the effects of ASC deficiency in two mouse models of PD, induced through the striatal injection of Syn fibrils or the dopaminergic toxin, 6-OHDA. Strikingly, ASC-/-  mice shown a significant improvement in amphetamine-induced rotations in the 6-OHDA model, and improvements in balance-beam and wire-hang tests in Syn-injected mice compared to wild-type mice. In primary microglia, Syn induced microglial inflammasome activation inducing the extracellular release of ASC specks, in the absence of cell death (pyroptosis). Collectively, our results suggest that ASC-mediated inflammasome formation and its extracellular release could be involved in the propagation of Syn and dopaminergic neurotoxicity in PD, making it an ideal therapeutic target to mitigate disease progression