<EM >IN VITRO</EM> ANALYSIS OF NEURONAL INFLAMMATORY RESPONSE AND NLRP3 INFLAMMASOME INHIBITION IN A HUNTINGTON’S DISEASE MODEL

Huntington’s disease (HD) is an inherited neurodegenerative disorder marked by progressive motor, cognitive, and psychiatric decline caused by mutant huntingtin (mHTT). Beyond classical mechanisms of neurodegeneration, chronic neuronal inflammation plays a crucial role in disease progression. The NLRP3 inflammasome has emerged as a potential therapeutic target, although its neuronal function remains unclear. In this study, we investigated the effects of pharmacological NLRP3 inhibition with MCC950 in mouse striatal progenitor cell models (STHdh) expressing either wild-type or mutant huntingtin. Pro-inflammatory stimulation activated the NLRP3 pathway, increasing caspase‑1 activation and gasdermin D expression, particularly in mutant cells, indicating susceptibility to pyroptotic cell death. MCC950 treatment reduced caspase‑1 activation and gasdermin D levels, demonstrating effective inhibition of NLRP3‑dependent pyroptosis in mHTT cells. Moreover, preliminary results suggest that MCC950 partially restores mitochondrial function under inflammatory stress, improving oxidative metabolism, ATP production, and mitochondrial integrity. However, despite these protective actions, MCC950 did not rescue overall cell viability, implying the involvement of additional death pathways. Elevated caspase‑3/7 activity in mutant cells indicates the activation of apoptosis, supporting the hypothesis that PANoptosis, a coordinated process integrating pyroptosis, apoptosis, and necroptosis, may occur in inflamed neurons. Data from differentiated neuronal models further revealed partial restoration of caspase‑1 activation and viability upon MCC950 treatment under inflammatory conditions. Overall, our findings identify MCC950 as an effective modulator of neuronal inflammasome activation in HD and highlight the complexity of inflammation‑driven neuronal cell death, emphasizing the need for combined therapeutic strategies targeting multiple pathways.