Activation of AMPK and inactivation of Akt result in suppression of mTOR-mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson's disease.
Activation of AMPK and inactivation of Akt result in suppression of mTOR-mediated S6K1 and 4E-BP1 pathways leading to neuronal cell death in in vitro models of Parkinson's disease.
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DOI：
10.1016/j.cellsig.2014.04.009
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发表时间：
2014-08
影响因子：
4.8
通讯作者：
Chen L
中科院分区：
文献类型：
--
作者：
Xu Y;Liu C;Chen S;Ye Y;Guo M;Ren Q;Liu L;Zhang H;Xu C;Zhou Q;Huang S;Chen L
帕金森病（PD）是一种以多巴胺能神经元缺失为特征的神经退行性疾病。哺乳动物雷帕霉素靶蛋白（mTOR）的失调与PD的发病机制有关。然而，其内在机制尚未完全阐明。在这里，我们发现PD模拟物（6-羟基多巴胺，N-甲基-4-苯基吡啶或鱼藤酮）抑制mTOR，S6 K1和4 E-BP 1的磷酸化，降低细胞活力，并激活caspase-3和PARP在PC 12细胞和原代神经元。野生型mTOR或组成型活性S6 K1的过表达或PC 12细胞中4 E-BP 1的下调部分地阻止了响应于PD毒素的细胞死亡，揭示了由于PD毒素而导致的mTOR介导的S6 K1和4 E-BP 1途径被抑制，导致神经元细胞死亡。此外，我们发现，mTOR信号的抑制有助于神经元细胞死亡归因于Akt的抑制和AMPK的激活。这得到以下发现的支持：组成型活性Akt或显性阴性AMPKα的异位表达，或用化合物C抑制AMPKα，部分减弱了对mTOR、S6 K1和4 E-BP 1磷酸化的抑制，半胱天冬酶-3的活化，以及由PD毒素触发的神经元细胞死亡。结果表明，PD应激激活AMPK和AMPK Akt，通过抑制mTOR介导的S6 K1和4 E-BP 1通路引起神经元细胞死亡。我们的研究结果表明，适当共同操纵AMPK/Akt/mTOR信号可能是预防和治疗PD的潜在策略。
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons. Dysregulation of mammalian target of rapamycin (mTOR) has been implicated in the pathogenesis of PD. However, the underlying mechanism is incompletely elucidated. Here, we show that PD mimetics (6-hydroxydopamine, N-methyl-4-phenylpyridine or rotenone) suppressed phosphorylation of mTOR, S6K1 and 4E-BP1, reduced cell viability, and activated caspase-3 and PARP in PC12 cells and primary neurons. Overexpression of wild-type mTOR or constitutively active S6K1, or downregulation of 4E-BP1 in PC12 cells partially prevented cell death in response to the PD toxins, revealing that mTOR-mediated S6K1 and 4E-BP1 pathways due to the PD toxins were inhibited, leading to neuronal cell death. Furthermore, we found that the inhibition of mTOR signaling contributing to neuronal cell death was attributed to suppression of Akt and activation of AMPK. This is supported by the findings that ectopic expression of constitutively active Akt or dominant negative AMPKα, or inhibition of AMPKα with compound C partially attenuated inhibition of phosphorylation of mTOR, S6K1 and 4E-BP1, activation of caspase-3, and neuronal cell death triggered by the PD toxins. The results indicate that PD stresses activate AMPK and inactivate Akt, causing neuronal cell death via inhibiting mTOR-mediated S6K1 and 4E-BP1 pathways. Our findings suggest that proper co-manipulation of AMPK/Akt/mTOR signaling may be a potential strategy for prevention and treatment of PD.
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