Xu Yijiao, Liu Chunxiao, Chen Sujuan, Ye Yangjing, Guo Min, Ren Qian, Liu Lei, Zhang Hai, Xu Chong, Zhou Qian, Huang Shile, Chen Long
Jiangsu Key Laboratory for Microbes and Functional Genomics, Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, P. R. China.
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.
Cell Signal. 2014 Aug;26(8):1680-1689. doi: 10.1016/j.cellsig.2014.04.009. Epub 2014 Apr 12.
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.
帕金森病（PD）是一种以多巴胺能神经元丧失为特征的神经退行性疾病。雷帕霉素哺乳动物靶点（mTOR）的失调与PD的发病机制有关。然而，其潜在机制尚未完全阐明。在此，我们表明，帕金森病模拟物（6-羟基多巴胺、N-甲基-4-苯基吡啶或鱼藤酮）抑制了PC12细胞和原代神经元中mTOR、S6K1和4E-BP1的磷酸化，降低了细胞活力，并激活了caspase-3和PARP。在PC12细胞中过表达野生型mTOR或组成型活性S6K1，或下调4E-BP1，可部分预防因帕金森病毒素引起的细胞死亡，这表明由于帕金森病毒素导致的mTOR介导的S6K1和4E-BP1信号通路受到抑制，从而导致神经元细胞死亡。此外，我们发现，导致神经元细胞死亡的mTOR信号抑制归因于Akt的抑制和AMPK的激活。组成型活性Akt或显性负性AMPKα的异位表达，或用化合物C抑制AMPKα，部分减弱了帕金森病毒素触发的mTOR、S6K1和4E-BP1磷酸化抑制、caspase-3激活和神经元细胞死亡，这些结果支持了这一观点。结果表明，帕金森病应激激活AMPK并使Akt失活，通过抑制mTOR介导的S6K1和4E-BP1信号通路导致神经元细胞死亡。我们的研究结果表明，适当共同调控AMPK/Akt/mTOR信号可能是预防和治疗帕金森病的潜在策略。
