Mitigation of ALS Pathology by Neuron-Specific Inhibition of Nuclear Factor Kappa B Signaling
Mitigation of ALS Pathology by Neuron-Specific Inhibition of Nuclear Factor Kappa B Signaling
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DOI：
10.1523/jneurosci.0536-20.2020
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发表时间：
2020-06-24
影响因子：
5.3
通讯作者：
Julien, Jean-Pierre
中科院分区：
文献类型：
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作者：
Dutta, Kallol;Thammisetty, Sai Sampath;Julien, Jean-Pierre
为了探讨神经细胞核因子-kappa B活性在肌萎缩侧索硬化症(ALS)发病机制中的作用，我们建立了神经元特异性表达核因子-kappa B抑制物(I-kappa Bα-SR)的转基因小鼠，然后与不同性别的小鼠杂交，表达与ALS相关的TAR DNA结合蛋白(TDP-43)和超氧化物歧化酶1(SOD1)基因突变体。值得注意的是，在表达TDP-43(A315T)或TDP-43(G348C)的小鼠中，转I kappa Bα-SR基因的小鼠的神经元表达导致人TDP-43的胞质与核的比例下降。Ikappa Bα-SR对TDP-43神经病理的缓解可能是由于自噬的诱导，与认知和运动障碍的改善以及运动神经元丢失和胶质细胞增生的减少有关。抑制SOD1(G93A)小鼠神经元中的核因子-kappaB活性也能减少错误折叠的SOD1水平，显著延长寿命，从而起到神经保护作用。结果提示，神经性核因子-kappaB信号通路是治疗ALS疾病和TDP-43蛋白病相关疾病的新靶点。
To investigate the role of neuronal NF-kappa B activity in pathogenesis of amyotrophic lateral sclerosis (ALS), we generated transgenic mice with neuron-specific expression of a super-repressor form of the NF-kappa B inhibitor (I kappa B alpha-SR), which were then crossed with mice of both sexes, expressing ALS-linked gene mutants for TAR DNA-binding protein (TDP-43) and superoxide dismutase 1 (SOD1). Remarkably, neuronal expression of I kappa B alpha-SR transgene in mice expressing TDP-43(A315T) or TDP-43(G348C) mice led to a decrease in cytoplasmic to nuclear ratio of human TDP-43. The mitigation of TDP-43 neuropathology by I kappa B alpha-SR, which is likely due to an induction of autophagy, was associated with amelioration of cognitive and motor deficits as well as reduction of motor neuron loss and gliosis. Neuronal suppression of NF-kappa B activity in SOD1(G93A) mice also resulted in neuroprotection with reduction of misfolded SOD1 levels and significant extension of life span. The results suggest that neuronal NF-kappa B signaling constitutes a novel therapeutic target for ALS disease and related disorders with TDP-43 proteinopathy.