NLRP3 inflammasome inhibitor(Exscientia/University of Oxford)

Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons and the pathological aggregation of α-synuclein, which drives neurodegeneration. The NLRP3 inflammasome inhibitor MCC950 has shown neuroprotective effects in various PD models, but its direct impact on α-synuclein aggregation remains unclear. Here, we investigated the effects of MCC950 in an α-synuclein-overexpressing MN9D dopaminergic neuronal model. MCC950 significantly alleviated α-synuclein-induced neuronal damage, as evidenced by improved cell viability, reduced apoptosis, and downregulated tumor necrosis factor-alpha (TNF-α) expression. Proteomic analysis revealed that MCC950 modulates protein processing in the endoplasmic reticulum (ER), potentially alleviating stress-induced protein misfolding. Molecular docking and biochemical assays demonstrated that MCC950 directly binds to the C-terminal region of α-synuclein, inhibiting its aggregation. Additionally, MCC950 upregulated heat shock protein 70 (HSP70), a molecular chaperone that suppresses α-synuclein oligomerization. Notably, the neuroprotective effects of MCC950 were independent of autophagy modulation or NLRP3 inflammasome inhibition in this model. These findings highlight MCC950 as a multi-target therapeutic agent that directly inhibits α-synuclein aggregation, offering a promising strategy for treating PD and related α-synucleinopathies.