SMN regulates axonal local translation via miR-183/mTOR pathway
SMN regulates axonal local translation via miR-183/mTOR pathway
复制标题
DOI：
10.1093/hmg/ddu350
复制
发表时间：
2014-12-01
影响因子：
3.5
通讯作者：
Sahin, Mustafa
中科院分区：
文献类型：
--
作者：
Kye, Min Jeong;Niederst, Emily D.;Sahin, Mustafa
SMN蛋白表达减少导致脊髓性肌萎缩症（SMA），这是一种导致运动神经元功能障碍和丧失的神经退行性疾病。然而，SMN调节神经元功能障碍的分子机制尚未完全了解。在这里，我们报告了SMN蛋白水平降低会改变神经元中miRNA的表达和分布。特别是，miR-183水平在SMN缺陷神经元的神经突中增加。我们证明了miR-183通过直接结合其3 'UTR来调节mTor的翻译。有趣的是，在SMN缺陷的神经元中，mTor的局部轴突翻译减少，并且这可以通过miR-183抑制来恢复。最后，在SMA小鼠模型的脊髓中抑制miR-183表达可降低存活率并改善Smn突变小鼠的运动功能。总之，这些观察结果表明，轴突miRNA和mTOR通路是先前未鉴定的有助于SMA病理学的分子机制。
Reduced expression of SMN protein causes spinal muscular atrophy (SMA), a neurodegenerative disorder leading to motor neuron dysfunction and loss. However, the molecular mechanisms by which SMN regulates neuronal dysfunction are not fully understood. Here, we report that reduced SMN protein level alters miRNA expression and distribution in neurons. In particular, miR-183 levels are increased in neurites of SMN-deficient neurons. We demonstrate that miR-183 regulates translation of mTor via direct binding to its 3' UTR. Interestingly, local axonal translation of mTor is reduced in SMN-deficient neurons, and this can be recovered by miR-183 inhibition. Finally, inhibition of miR-183 expression in the spinal cord of an SMA mouse model prolongs survival and improves motor function of Smn-mutant mice. Together, these observations suggest that axonal miRNAs and the mTOR pathway are previously unidentified molecular mechanisms contributing to SMA pathology.