A screen for regulators of survival of motor neuron protein levels.
A screen for regulators of survival of motor neuron protein levels.
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DOI：
10.1038/nchembio.595
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发表时间：
2011-06-19
影响因子：
14.8
通讯作者：
Rubin, Lee L.
中科院分区：
文献类型：
--
作者：
Makhortova, Nina R.;Hayhurst, Monica;Cerqueira, Antonio;Sinor-Anderson, Amy D.;Zhao, Wen-Ning;Heiser, Patrick W.;Arvanites, Anthony C.;Davidow, Lance S.;Waldon, Zachary O.;Steen, Judith A.;Lam, Kelvin;Ngo, Hien D.;Rubin, Lee L.
运动神经元疾病脊髓性肌萎缩症（SMA）是由导致运动神经元生存蛋白（SMN）普遍表达水平低的突变引起的。不断增加的数据表明，提高SMN的治疗方法可能有效治疗SMA。我们对注释的化学文库进行了基于图像的筛选，发现了能够增加细胞SMN的多种化合物。其中最重要的是RTK/PI 3 K/AKT/GSK-3信号级联。GSK-3的化学抑制剂以及针对该靶点的shRNA主要通过稳定蛋白质来提高SMN水平。特别重要的是，GSK-3化学抑制剂在运动神经元中也有效，不仅可以提高SMN水平，还可以阻断SMN特异性shRNA急性减少SMN时产生的死亡。因此，我们已经建立了一个筛选能够检测药物样化合物，纠正主要的表型变化，SMA的基础。
The motor neuron disease Spinal Muscular Atrophy (SMA) results from mutations that lead to low levels of the ubiquitously expressed protein Survival of Motor Neuron (SMN). Ever-increasing data suggest that therapeutics that elevate SMN may be effective in treating SMA. We executed an image-based screen of annotated chemical libraries and discovered multiple classes of compounds that were able to increase cellular SMN. Among the most important was the RTK/PI3K/AKT/GSK-3 signaling cascade. Chemical inhibitors of GSK-3, as well as shRNAs directed against this target, elevate SMN levels primarily by stabilizing the protein. Of particular significance is that GSK-3 chemical inhibitors were also effective in motor neurons, not only in elevating SMN levels, but also in blocking the death that was produced when SMN was acutely reduced by a SMN-specific shRNA. Thus, we have established a screen capable of detecting drug-like compounds that correct the main phenotypic change that underlies SMA.
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影响因子：
64.5
作者：
LEFEBVRE, S;BURGLEN, L;MELKI, J
通讯作者：
MELKI, J
影响因子：
30.8
作者：
Lefebvre, S;Burlet, P;Melki, J
通讯作者：
Melki, J
影响因子：
4.6
作者：
Lahusen, T;De Siervi, A;Senderowicz, AM
通讯作者：
Senderowicz, AM
DOI：
10.1073/pnas.220413597
发表时间：
2000-10-24
影响因子：
11.1
作者：
Fang, XJ;Yu, SX;Mills, GB
通讯作者：
Mills, GB
影响因子：
3.2
作者：
Kunick, C;Zeng, ZH;Lemcke, T
通讯作者：
Lemcke, T