Department of Neurology, University of Ulm, Ulm, Germany.
Institute of Clinical Neurobiology, University Hospital of Wuerzburg, Wuerzburg, Germany.
J Exp Med. 2019 Feb 4;216(2):267-278. doi: 10.1084/jem.20180729. Epub 2019 Jan 11.
Heterozygous loss-of-function mutations of ( cause familial ALS, yet downstream mechanisms of mutations remained elusive. TBK1 is a pleiotropic kinase involved in the regulation of selective autophagy and inflammation. We show that heterozygous deletion alone does not lead to signs of motoneuron degeneration or disturbed autophagy in mice during a 200-d observation period. Surprisingly, however, hemizygous deletion of inversely modulates early and late disease phases in mice additionally overexpressing ALS-linked , which represents a "second hit" that induces both neuroinflammation and proteostatic dysregulation. At the early stage, heterozygous deletion impairs autophagy in motoneurons and prepones both the clinical onset and muscular denervation in mice. At the late disease stage, however, it significantly alleviates microglial neuroinflammation, decelerates disease progression, and extends survival. Our results indicate a profound effect of TBK1 on brain inflammatory cells under pro-inflammatory conditions and point to a complex, two-edged role of TBK1 in -linked ALS.
（TANK 结合激酶 1）的杂合性失活突变导致家族性肌萎缩侧索硬化症，但（TANK 结合激酶 1）突变的下游机制仍不清楚。TBK1 是一种多效激酶，参与选择性自噬和炎症的调节。我们表明，在 200 天的观察期内，单独的杂合性缺失不会导致小鼠运动神经元退化或自噬紊乱的迹象。然而，令人惊讶的是，杂合性缺失 还会反向调节在额外过表达与肌萎缩侧索硬化症相关的 的小鼠中的早发和晚发疾病阶段，这代表了一种“二次打击”，它会同时诱导神经炎症和蛋白质稳态失调。在早期阶段，杂合性缺失会损害运动神经元中的自噬，并提前引发 小鼠的临床发病和肌肉去神经支配。然而，在疾病晚期，它会显著减轻小胶质细胞的神经炎症，减缓疾病进展，并延长存活时间。我们的结果表明 TBK1 在促炎条件下对大脑炎性细胞有深远的影响，并指出 TBK1 在与肌萎缩侧索硬化症相关的疾病中具有复杂的双刃剑作用。
