Academic Neurology Unit, Department of Neuroscience, School of Medicine and Biomedical Sciences, University of Sheffield, Sheffield S10 2RX, UK.
Hum Mol Genet. 2010 Aug 15;19(16):3159-68. doi: 10.1093/hmg/ddq226. Epub 2010 Jun 4.
Phosphatase and tensin homolog (PTEN), a negative regulator of the mammalian target of rapamycin (mTOR) pathway, is widely involved in the regulation of protein synthesis. Here we show that the PTEN protein is enriched in cell bodies and axon terminals of purified motor neurons. We explored the role of the PTEN pathway by manipulating PTEN expression in healthy and diseased motor neurons. PTEN depletion led to an increase in growth cone size, promotion of axonal elongation and increased survival of these cells. These changes were associated with alterations of downstream signaling pathways for local protein synthesis as revealed by an increase in pAKT and p70S6. Most notably, this treatment also restores beta-actin protein levels in axonal growth cones of SMN-deficient motor neurons. Furthermore, we report here that a single injection of adeno-associated virus serotype 6 (AAV6) expressing siPTEN into hind limb muscles at postnatal day 1 in SMNDelta7 mice leads to a significant PTEN depletion and robust improvement in motor neuron survival. Taken together, these data indicate that PTEN-mediated regulation of protein synthesis in motor neurons could represent a target for therapy in spinal muscular atrophy.
磷酸酶和张力蛋白同源物（PTEN）是哺乳动物雷帕霉素靶蛋白（mTOR）通路的负调节剂，广泛参与蛋白质合成的调节。在这里，我们显示 PTEN 蛋白在纯化的运动神经元的细胞体和轴突末端富集。我们通过在健康和患病的运动神经元中操纵 PTEN 表达来探索 PTEN 通路的作用。PTEN 耗竭导致生长锥增大，促进轴突伸长，并增加这些细胞的存活。这些变化与局部蛋白质合成的下游信号通路的改变有关，如 pAKT 和 p70S6 的增加所揭示的那样。最值得注意的是，这种治疗方法还可以恢复 SMN 缺陷运动神经元轴突生长锥中的β-肌动蛋白蛋白水平。此外，我们在这里报告，在 SMNDelta7 小鼠出生后第 1 天通过单次注射表达 siPTEN 的腺相关病毒血清型 6（AAV6）到后肢肌肉中，导致明显的 PTEN 耗竭，并显著改善运动神经元的存活。总之，这些数据表明，运动神经元中 PTEN 介导的蛋白质合成调节可能成为脊髓性肌萎缩症治疗的靶点。
