miR-7 and miR-153 protect neurons against MPP(+)-induced cell death via upregulation of mTOR pathway.
miR-7 and miR-153 protect neurons against MPP(+)-induced cell death via upregulation of mTOR pathway.
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DOI：
10.3389/fncel.2014.00182
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发表时间：
2014
影响因子：
5.3
通讯作者：
Doxakis E
中科院分区：
文献类型：
--
作者：
Fragkouli A;Doxakis E
microRNAs（miRs）在神经退行性疾病患者脑中的差异表达表明它们可能在这些疾病的发展中具有关键的调节作用。最近已经显示两种这样的miR，miR-7和miR-153靶向α-突触核蛋白，α-突触核蛋白是一种关键参与帕金森病病理过程的蛋白质。通过使用神经毒素1-甲基-4-苯基-吡啶鎓（MPP+）的良好建立的培养帕金森病模型，我们检查了miR-7和miR-153是否显示神经保护特性。在此，我们证明了MPP+处理皮质神经元诱导了具有凋亡特征的剂量依赖性细胞死亡。这反映在改变的细胞内信号传导中，其特征在于活化的激酶p38 MAPK和ERK 1/2的水平增加以及活化的AKT、p70 S6 K和SAPK/JNK的水平降低。通过腺病毒转导过表达miR-7或miR-153保护皮质神经元免受MPP+诱导的毒性，恢复神经元活力和抗凋亡BCL-2蛋白水平，同时减弱caspase-3的活化。此外，miR-7和miR-153都以部分重叠的方式干扰MPP+诱导的细胞内信号通路的改变;具体地说，它们在MPP+处理的神经元中保留了mTOR和SAPK/JNK信号通路的激活，而miR-153也减弱了MPP+诱导的p38 MAPK激活。在研究的其余信号级联或蛋白质中未观察到重大影响。此外，当MPP+与雷帕霉素共同施用时，miR-7和miR-153的神经保护作用减轻。总之，我们的结果表明，miR-7和miR-153通过干扰MPP+诱导的mTOR信号转导下调来保护神经元免于细胞死亡。
Differential expression of microRNAs (miRs) in the brain of patients with neurodegenerative diseases suggests that they may have key regulatory roles in the development of these disorders. Two such miRs, miR-7, and miR-153 have recently been shown to target α-synuclein, a protein critically involved in the pathological process of Parkinson's disease. By using a well-established in culture Parkinson's disease model that of neurotoxin 1-Methyl-4-Phenyl-Pyridinium (MPP+), we examined whether miR-7 and miR-153 display neuroprotective properties. Herein, we demonstrate that treatment of cortical neurons with MPP+ induced a dose-dependent cell death with apoptotic characteristics. This was reflected in altered intracellular signaling characterized by increased levels of activated kinases p38MAPK and ERK1/2 and reduced levels of activated AKT, p70S6K, and SAPK/JNK. Overexpression of miR-7 or miR-153 by adenoviral transduction protected cortical neurons from MPP+-induced toxicity, restored neuronal viability and anti-apoptotic BCL-2 protein levels while attenuated activation of caspase-3. Moreover, both miR-7 and miR-153 interfered with MPP+-induced alterations in intracellular signaling pathways in a partially overlapping manner; specifically, they preserved activation of mTOR and SAPK/JNK signaling pathways in the MPP+-treated neurons, while miR-153 also attenuated MPP+-induced activation of p38MAPK. No major effects were observed in the rest of signaling cascades or proteins investigated. Furthermore, the neuroprotective effect of miR-7 and miR-153 was alleviated when MPP+ was co-administered with rapamycin. Taken together, our results suggest that miR-7 and miR-153 protect neurons from cell death by interfering with the MPP+-induced downregulation of mTOR signaling.
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影响因子：
5.3
作者：
Björkblom, B;Östman, N;Coffey, ET
通讯作者：
Coffey, ET
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