| Summary: | Amyotrophic lateral sclerosis (ALS) is a fatal disease in which motor neurons gradually degenerate. The mutation of the <i>C9orf72</i> gene is the main genetic cause of ALS (C9-ALS). One of its specific pathological features is the production of proline-arginine (PR) dipeptide repeat protein (DPR). In this study, we developed a PR-DPR (PR<sub>50</sub>)-expressing human HMC3 microglial cell model. We found that PR<sub>50</sub> mainly aggregates into spots in the nucleus and induces significant NLRP3 inflammasome activity. Moreover, mouse NSC-34 motor neuron cells treated with a conditional medium of PR<sub>50</sub>-expressing HMC3 cells (PR-CM) caused cell damage and apoptosis activity. However, R<sub>50</sub>-expressing HMC cells treated with MCC950 (an NLRP3 inhibitor) reversed this result. Furthermore, we identified complement component 1 q subcomponent-binding protein (C1QBP) as one of the interaction partners of PR<sub>50</sub>. The downregulation of C1QBP in HMC3 cells induces NLRP3 inflammasome activity similar to PR<sub>50</sub> expression. Finally, we found that syringin can block the interaction between PR<sub>50</sub> and C1QBP, and effectively reduce the PR<sub>50</sub>-induced NLRP3 inflammasome activity in HMC3 cells. This improves the apoptosis of NSC-34 cells caused by PR-CM. This study is the first to link PR<sub>50</sub>, C1QBP, and NLRP3 inflammasome activity in microglia and develop potential therapeutic strategies for syringin intervention in C9-ALS.
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