Upregulation of the E3 ligase NEDD4-1 by oxidative stress degrades IGF-1 receptor protein in neurodegeneration.
Upregulation of the E3 ligase NEDD4-1 by oxidative stress degrades IGF-1 receptor protein in neurodegeneration.
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DOI：
10.1523/jneurosci.1836-12.2012
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发表时间：
2012-08-08
期刊：
影响因子：
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通讯作者：
Liao FF
中科院分区：
文献类型：
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作者：
Kwak YD;Wang B;Li JJ;Wang R;Deng Q;Diao S;Chen Y;Xu R;Masliah E;Xu H;Sung JJ;Liao FF
泛素E3连接酶在神经退行性变中的重要性越来越被认识到。NEDD 4 -1（神经前体细胞表达的发育下调基因4）在神经发育中的关键作用是众所周知的;然而，它在神经退行性变中的作用仍然未被探索。在此，我们报告了NEDD 4 -1在几种主要神经退行性疾病的退行性组织中的表达增加。此外，其表达在培养的神经元中上调，以响应各种神经毒素，包括锌和过氧化氢，通过转录激活可能介导的ROS响应FOXM 1B。观察到胰岛素样生长因子受体（IGF-1 R β）的蛋白水平降低，这是通过泛素-蛋白酶体系统（UPS）上调NEDD 4 -1的结果。在神经母细胞瘤细胞中过表达SOD-1的家族性突变形式（G93 A）导致IGF-1 R β蛋白的类似减少。在症状前年龄的突变型（G93 A）SOD-1转基因小鼠的皮质和脊髓中也观察到了NEDD 4 -1和IGF-1 R β之间的这种负相关性，这在WT C57 BL/6小鼠中也是通过体内给予锌诱导的。此外，组织化学显示在脊髓腰前角的变性/变性运动神经元中NEDD 4 -1免疫反应性显著增加，表明NEDD 4 -1在神经变性中的直接致病作用。事实上，通过shRNA下调NEDD 4 -1或过表达催化失活形式拯救了锌诱导的细胞死亡的神经元。类似地，具有NEDD 4 -1单倍型的神经元对凋亡更有抵抗力，这主要是由于IGF-1 R β表达水平较高。总之，我们的工作确定了神经退行性疾病中ROS上调NEDD 4 -1和随后降低IGF-1 R β信号传导的新分子机制。
The importance of ubiquitin E3 ligases in neurodegeneration is being increasingly recognized. The crucial role of NEDD4-1 (neural precursor cell-expressed developmentally down-regulated gene 4) in neural development is well-appreciated; however, its role in neurodegeneration remains unexplored. Herein, we report increased NEDD4-1 expression in the degenerated tissues of several major neurodegenerative diseases. Moreover, its expression is upregulated in cultured neurons in response to various neurotoxins, including zinc and hydrogen superoxide, via transcriptional activation likely mediated by the ROS-responsive FOXM1B. Reduced protein levels of the insulin-like growth factor receptor (IGF-1Rβ) were observed as a consequence of upregulated NEDD4-1 via the ubiquitin-proteasome system (UPS). Overexpression of a familial mutant form of SOD-1 (G93A) in neuroblastoma cells resulted in a similar reduction of IGF-1Rβ protein. This inverse correlation between NEDD4-1 and IGF-1Rβ was also observed in the cortex and spinal cords of mutant (G93A) SOD-1 transgenic mice at a pre-symptomatic age, which was similarly induced by in vivo administered zinc in WT C57BL/6 mice. Furthermore, histochemistry reveals markedly increased NEDD4-1 immunoreactivity in the degenerating/degenerated motor neurons in the lumbar anterior horn of the spinal cord, suggesting a direct causative role for NEDD4-1 in neurodegeneration. Indeed, downregulation of NEDD4-1 by shRNA or overexpression of a catalytically inactive form rescued neurons from zinc-induced cell death. Similarly, neurons with a NEDD4-1 haplotype are more resistant to apoptosis, largely due to expression of higher levels of IGF-1Rβ. Taken together, our work identifies a novel molecular mechanism for ROS-upregulated NEDD4-1 and the subsequently reduced IGF-1Rβ signaling in neurodegeneration.