Abstract：
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a typical neurodegenerative disorder typically characterized by inflammation activation. However, the relationship between non-canonical NF-κB (ncNF-κB) pathway activation and ALS progression is not clear.
METHODS: We tested the ncNF-κB pathway in the ALS animal model including hSOD1-G93A transgenic mice and TBK1 deletion mice.We treated age-matched SOD1-G93A mice with B022 (a NIK inhibitor) to investigate the role of NIK in the ALS animal model. We also established a new mice model by crossing SOD1-G93A mice with NIK+/- mice to further evaluate the interrelationship between the NIK and the disease progression in ALS animal model.
RESULTS: In this study, we found the ncNF-κB pathway was activated in SOD1-G93A animal model and TBK1 deletion model. Inhibition of NIK activity by small molecule B022 significantly improved the motor performance of the ALS animal model. However, NIK deletion enhanced the mutant SOD1 toxicity by inflammatory infiltration.
CONCLUSIONS: TBK1 deletion and mutant SOD1 shared the common pathological feature possibly via effects on NIK activation and inhibitor of NIK could be a novel strategy for treating ALS.
METHODS: We tested the ncNF-κB pathway in the ALS animal model including hSOD1-G93A transgenic mice and TBK1 deletion mice.We treated age-matched SOD1-G93A mice with B022 (a NIK inhibitor) to investigate the role of NIK in the ALS animal model. We also established a new mice model by crossing SOD1-G93A mice with NIK+/- mice to further evaluate the interrelationship between the NIK and the disease progression in ALS animal model.
RESULTS: In this study, we found the ncNF-κB pathway was activated in SOD1-G93A animal model and TBK1 deletion model. Inhibition of NIK activity by small molecule B022 significantly improved the motor performance of the ALS animal model. However, NIK deletion enhanced the mutant SOD1 toxicity by inflammatory infiltration.
CONCLUSIONS: TBK1 deletion and mutant SOD1 shared the common pathological feature possibly via effects on NIK activation and inhibitor of NIK could be a novel strategy for treating ALS.
摘要：
背景：肌萎缩侧索硬化症（ALS）是一种典型的神经退行性疾病，通常以炎症激活为特征。然而,非经典NF-κB（ncNF-κB）通路激活与ALS进展之间的关系尚不清楚。
方法：我们在包括hSOD1-G93A转基因小鼠和TBK1缺失小鼠在内的ALS动物模型中测试了ncNF-κB通路。我们用B022(NIK抑制剂)治疗年龄匹配的SOD1-G93A小鼠以研究NIK在ALS动物模型中的作用。我们还通过将SOD1-G93A小鼠与NIK+/-小鼠杂交建立了新的小鼠模型，以进一步评估ALS动物模型中NIK与疾病进展之间的相互关系。
结果：在这项研究中，我们发现在SOD1-G93A动物模型和TBK1缺失模型中ncNF-κB通路被激活。小分子B022对NIK活性的抑制显著改善了ALS动物模型的运动性能。然而,NIK缺失通过炎性浸润增强了突变体SOD1的毒性。
结论：BK1缺失和突变型SOD1具有共同的病理特征，可能通过影响NIK的激活，NIK抑制剂可能是治疗ALS的新策略。
方法：我们在包括hSOD1-G93A转基因小鼠和TBK1缺失小鼠在内的ALS动物模型中测试了ncNF-κB通路。我们用B022(NIK抑制剂)治疗年龄匹配的SOD1-G93A小鼠以研究NIK在ALS动物模型中的作用。我们还通过将SOD1-G93A小鼠与NIK+/-小鼠杂交建立了新的小鼠模型，以进一步评估ALS动物模型中NIK与疾病进展之间的相互关系。
结果：在这项研究中，我们发现在SOD1-G93A动物模型和TBK1缺失模型中ncNF-κB通路被激活。小分子B022对NIK活性的抑制显著改善了ALS动物模型的运动性能。然而,NIK缺失通过炎性浸润增强了突变体SOD1的毒性。
结论：BK1缺失和突变型SOD1具有共同的病理特征，可能通过影响NIK的激活，NIK抑制剂可能是治疗ALS的新策略。
