Department of Neurobiology of First Affiliated Hospital, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310020, China.
School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou 310058, China; MOE Frontier Science Center for Brain Research and Brain-Machine Integration, Zhejiang University, Hangzhou 310058, China.
Cell Rep. 2023 Feb 28;42(2):112133. doi: 10.1016/j.celrep.2023.112133. Epub 2023 Feb 16.
Expansion of the hexanucleotide repeat GGGGCC in the C9orf72 gene is the most common genetic factor in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Poly-Gly-Ala (poly-GA), one form of dipeptide repeat proteins (DPRs) produced from GGGGCC repeats, tends to form neurotoxic protein aggregates. The C9orf72 GGGGCC repeats and microglial receptor TREM2 are both associated with risk for ALS/FTD. The role and regulation of TREM2 in C9orf72-ALS/FTD remain unclear. Here, we found that poly-GA proteins activate the microglial NLRP3 inflammasome to produce interleukin-1β (IL-1β), which promotes ADAM10-mediated TREM2 cleavage and inhibits phagocytosis of poly-GA. The inhibitor of the NLRP3 inflammasome, MCC950, reduces the TREM2 cleavage and poly-GA aggregates, resulting in the alleviation of motor deficits in poly-GA mice. Our study identifies a crosstalk between NLRP3 and TREM2 signaling, suggesting that targeting the NLRP3 inflammasome to sustain TREM2 is an approach to treat C9orf72-ALS/FTD.
GGGCC 六核苷酸重复扩展是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）最常见的遗传因素。GGGCC 重复产生的二肽重复蛋白（DPRs）之一的聚甘氨酸-丙氨酸（poly-GA），往往会形成神经毒性蛋白聚集体。C9orf72 GGGGCC 重复和小胶质细胞受体 TREM2 都与 ALS/FTD 的风险相关。TREM2 在 C9orf72-ALS/FTD 中的作用和调节尚不清楚。在这里，我们发现 poly-GA 蛋白激活小胶质细胞 NLRP3 炎性体产生白细胞介素-1β（IL-1β），促进 ADAM10 介导的 TREM2 裂解，并抑制 poly-GA 的吞噬作用。NLRP3 炎性体的抑制剂 MCC950 减少了 TREM2 的裂解和 poly-GA 聚集体，从而减轻了 poly-GA 小鼠的运动功能障碍。我们的研究确定了 NLRP3 和 TREM2 信号之间的串扰，表明靶向 NLRP3 炎性体以维持 TREM2 是治疗 C9orf72-ALS/FTD 的一种方法。
