Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
J Neurosci. 2010 Jan 20;30(3):1166-75. doi: 10.1523/JNEUROSCI.3944-09.2010.
We report that rapamycin, an allosteric inhibitor of certain but not all actions of the key cellular kinase mammalian target of rapamycin (mTOR), protects neurons from death in both cellular and animal toxin models of Parkinson's disease (PD). This protective action appears to be attributable to blocked translation of RTP801/REDD1/Ddit4, a protein that is induced in cell and animal models of PD and in affected neurons of PD patients and that causes neuron death by leading to dephosphorylation of the survival kinase Akt. In support of this mechanism, in PD models, rapamycin spares phosphorylation of Akt at a site critical for maintenance of its survival-promoting activity. The capacity of rapamycin to provide neuroprotection in PD models appears to arise from its selective suppression of some but not all actions of mTOR, as indicated by the contrasting finding that Torin1, a full catalytic mTOR inhibitor, is not protective and induces Akt dephosphorylation and neuron death.
我们报告称，雷帕霉素是一种别构抑制剂，可阻断关键细胞激酶哺乳动物雷帕霉素靶蛋白（mTOR）的某些但不是所有作用，它可保护神经元免受帕金森病（PD）的细胞和动物毒素模型中神经元的死亡。这种保护作用似乎归因于 RTP801/REDD1/Ddit4 的翻译阻断，RTP801/REDD1/Ddit4 是 PD 细胞和动物模型以及 PD 患者受影响神经元中诱导的一种蛋白，通过导致生存激酶 Akt 的去磷酸化而导致神经元死亡。支持这一机制，在 PD 模型中，雷帕霉素可避免 Akt 在其生存促进活性的维持中至关重要的位点的磷酸化。雷帕霉素在 PD 模型中提供神经保护的能力似乎源于其对 mTOR 的某些但不是所有作用的选择性抑制，这一点与 Torin1（一种完全的催化 mTOR 抑制剂）的对比发现一致，Torin1 没有保护作用，并诱导 Akt 去磷酸化和神经元死亡。
