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Targeted disruption of dual leucine zipper kinase and leucine zipper kinase promotes neuronal survival in a model of diffuse traumatic brain injury.
Molecular Neurodegeneration ( IF 15.1 ) Pub Date : 2019-11-27 , DOI: 10.1186/s13024-019-0345-1
Derek S Welsbie 1, 2 , Nikolaos K Ziogas 3 , Leyan Xu 3 , Byung-Jin Kim 4 , Yusong Ge 3 , Amit K Patel 1 , Jiwon Ryu 3 , Mohamed Lehar 5 , Athanasios S Alexandris 3 , Nicholas Stewart 3 , Donald J Zack 4, 6, 7, 8 , Vassilis E Koliatsos 2, 3, 9
Affiliation  

BACKGROUND Traumatic brain injury (TBI) is a major cause of CNS neurodegeneration and has no disease-altering therapies. It is commonly associated with a specific type of biomechanical disruption of the axon called traumatic axonal injury (TAI), which often leads to axonal and sometimes perikaryal degeneration of CNS neurons. We have previously used genome-scale, arrayed RNA interference-based screens in primary mouse retinal ganglion cells (RGCs) to identify a pair of related kinases, dual leucine zipper kinase (DLK) and leucine zipper kinase (LZK) that are key mediators of cell death in response to simple axotomy. Moreover, we showed that DLK and LZK are the major upstream triggers for JUN N-terminal kinase (JNK) signaling following total axonal transection. However, the degree to which DLK/LZK are involved in TAI/TBI is unknown. METHODS Here we used the impact acceleration (IA) model of diffuse TBI, which produces TAI in the visual system, and complementary genetic and pharmacologic approaches to disrupt DLK and LZK, and explored whether DLK and LZK play a role in RGC perikaryal and axonal degeneration in response to TAI. RESULTS Our findings show that the IA model activates DLK/JNK/JUN signaling but, in contrast to axotomy, many RGCs are able to recover from the injury and terminate the activation of the pathway. Moreover, while DLK disruption is sufficient to suppress JUN phosphorylation, combined DLK and LZK inhibition is required to prevent RGC cell death. Finally, we show that the FDA-approved protein kinase inhibitor, sunitinib, which has activity against DLK and LZK, is able to produce similar increases in RGC survival. CONCLUSION The mitogen-activated kinase kinase kinases (MAP3Ks), DLK and LZK, participate in cell death signaling of CNS neurons in response to TBI. Moreover, sustained pharmacologic inhibition of DLK is neuroprotective, an effect creating an opportunity to potentially translate these findings to patients with TBI.

中文翻译:

双亮氨酸拉链激酶和亮氨酸拉链激酶的靶向破坏促进弥漫性创伤性脑损伤模型中的神经元存活。

背景创伤性脑损伤 (TBI) 是 CNS 神经变性的主要原因,并且没有改变疾病的疗法。它通常与轴突的特定类型的生物力学破坏有关,称为外伤性轴突损伤 (TAI),这通常会导致中枢神经系统神经元的轴突退化,有时还会导致核周退化。我们之前曾在原代小鼠视网膜神经节细胞 (RGC) 中使用基于基因组规模的阵列 RNA 干扰筛选来鉴定一对相关激酶,即双亮氨酸拉链激酶 (DLK) 和亮氨酸拉链激酶 (LZK),它们是响应简单轴突切断术的细胞死亡。此外,我们发现 DLK 和 LZK 是全轴突横断后 JUN N 端激酶 (JNK) 信号传导的主要上游触发因素。然而,DLK/LZK 参与 TAI/TBI 的程度尚不清楚。方法 在这里,我们使用在视觉系统中产生 TAI 的弥漫性 TBI 的冲击加速 (IA) 模型,以及干扰 DLK 和 LZK 的互补遗传和药理学方法,并探讨了 DLK 和 LZK 是否在 RGC 核周和轴突变性中发挥作用回应TAI。结果 我们的研究结果表明 IA 模型激活 DLK/JNK/JUN 信号传导,但与轴突切断术相比,许多 RGC 能够从损伤中恢复并终止该通路的激活。此外,虽然 DLK 破坏足以抑制 JUN 磷酸化,但需要联合抑制 DLK 和 LZK 以防止 RGC 细胞死亡。最后,我们表明 FDA 批准的蛋白激酶抑制剂舒尼替尼对 DLK 和 LZK 具有活性,能够产生类似的 RGC 存活率增加。结论 丝裂原活化激酶激酶激酶 (MAP3Ks)、DLK 和 LZK 参与响应 TBI 的 CNS 神经元的细胞死亡信号。此外,DLK 的持续药理学抑制具有神经保护作用,这种作用创造了将这些发现转化为 TBI 患者的机会。
更新日期:2020-04-22
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