Monomeric ASC inhibits α-synuclein aggregation through its CARD domain

Abstract Synucleinopathies, including Parkinson disease, are characterized by the pathological aggregation of α-synuclein (α-syn) in the brain, which promotes neurodegeneration and inflammation. While inflammasome activation is implicated in disease progression, the direct role of the inflammasome adaptor protein ASC in α-syn aggregation remains unclear. Here we demonstrate that ASC monomers directly bind α-syn fibrils via their CARD domain, inhibiting α-syn aggregation both in vitro and in cultured cells. This interaction reduces seeded α-syn fibrillization without altering fibril structure, suggesting a protective mechanism by steric hindrance. Moreover, ASC overexpression decreases intracellular α-syn aggregation, indicating functional relevance in cells. These findings suggest that maintaining monomeric ASC, potentially through inflammasome inhibition, may mitigate α-syn pathology and associated neurodegeneration. Thus, targeting ASC dynamics offers a promising avenue for therapeutic intervention in synucleinopathies.