抑制 NF-κB 诱导激酶可改善 ALS 动物模型的运动功能。

Inhibiting NF-κB inducing kinase improved the motor performance of ALS animal model.

机构信息

Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China.

Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou, Jiangsu, China; Jiangsu Provincial Key Laboratory of Central Nervous System Drugs, Xuzhou, Jiangsu, China.

出版信息

Brain Res. 2024 Nov 15;1843:149124. doi: 10.1016/j.brainres.2024.149124. Epub 2024 Jul 15.

DOI:10.1016/j.brainres.2024.149124

PMID:39019135

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.

CONCLUSION

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）通路的激活与 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（一种 NIK 抑制剂）处理年龄匹配的 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 小鼠杂交建立了一种新的小鼠模型，以进一步评估 NIK 与 ALS 动物模型中疾病进展之间的相互关系。