Department of Stem Cell and Regenerative Biology , Harvard University, Cambridge, Massachusetts, USA.
Nat Chem Biol. 2011 Jun 19;7(8):544-52. doi: 10.1038/nchembio.595.
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). An ever-increasing collection of data suggests that therapeutics that elevate SMN may be effective in treating SMA. We executed an image-based screen of annotated chemical libraries and discovered several 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 glycogen synthase kinase 3 (GSK-3) and short hairpin RNAs (shRNAs) directed against this target elevated SMN levels primarily by stabilizing the protein. It was particularly notable 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 an SMN-specific shRNA. Thus, we have established a screen capable of detecting drug-like compounds that correct the main phenotypic change underlying SMA.
运动神经元疾病脊髓性肌萎缩症（SMA）是由导致广泛表达的运动神经元存活蛋白（SMN）水平降低的突变引起的。越来越多的数据表明，提高 SMN 的治疗方法可能对治疗 SMA 有效。我们进行了基于图像的注释化学文库筛选，发现了几类能够增加细胞 SMN 的化合物。其中最重要的是 RTK-PI3K-AKT-GSK-3 信号级联。糖原合酶激酶 3（GSK-3）的化学抑制剂和针对该靶点的短发夹 RNA（shRNA）能够通过稳定蛋白质来提高 SMN 水平。特别值得注意的是，GSK-3 化学抑制剂在运动神经元中也很有效，不仅能提高 SMN 水平，还能阻止因 SMN 特异性 shRNA 急性减少而导致的死亡。因此，我们建立了一个能够检测到类似药物的化合物的筛选方法，这些化合物可以纠正 SMA 主要表型变化的基础。
