Fig. 7
Schematic representation of signaling pathways that mediate the action of MCC950 in rescuing the detrimental effect of the NLRP3-dependent pathway in the presence of mutant HTT. In the current study, we demonstrated that expression of polyQ-expanded mHTT enhanced the activation of the NLRP3 inflammasome in striatal progenitor cell lines (STHdhQ7and STHdhQ109) and a transgenic mouse model of HD (R6/2 mice). Long-term treatment of HD mice with a NLRP3 inhibitor (MCC950) not only reduced the activation of the NLRP3 inflammasome but also rescued neuronal survival and reduced gliosis in a transgenic mouse model (R6/2) of HD. Importantly, oral administration of MCC950 markedly reduced disease progression in R6/2 mice. Collectively, these findings indicate that MCC950 has therapeutic potential for the treatment of HD. Further characterization of the functional role of MCC950 in HD, as proposed herein, will provide important insights that could help facilitate the development of neuroprotective strategies targeting the bioenergetic defects of HD and other aggregate-related diseases