Olomoucine inhibits cathepsin L nuclear translocation, activates autophagy and attenuates toxicity of 6-hydroxydopamine
Olomoucine inhibits cathepsin L nuclear translocation, activates autophagy and attenuates toxicity of 6-hydroxydopamine
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Olomoucine 抑制组织蛋白酶 L 核转位、激活自噬并减弱 6-羟基多巴胺的毒性
DOI：
10.1016/j.brainres.2009.01.057
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发表时间：
2009-04-06
期刊：
影响因子：
2.9
通讯作者：
Liang, Zhong-Qin
中科院分区：
文献类型：
--
作者：
Fei, Xi-Feng;Qin, Zheng-Hong;Liang, Zhong-Qin
组织蛋白酶L的核转位及其加工CDP/Cux转录因子的能力的发现揭示了组织蛋白酶L在控制细胞周期进程中的重要作用。由于某些细胞周期调节因子的表达与黑质神经元死亡有关，本研究旨在研究6-羟基多巴胺（6-OHDA）是否诱导DA神经元中组织蛋白酶L的核转位和某些细胞周期蛋白的表达。研究了细胞周期抑制剂olomoucine对6-OHDA诱导的黑质神经元死亡的神经保护作用。应用免疫细胞化学和实时荧光定量PCR技术，我们发现6-OHDA灌注后，部分多巴胺能神经元细胞周期蛋白D1、B1和增殖细胞核抗原（PCNA）表达异常。在黑质DA神经元中观察到组织蛋白酶L的核转位和参与自噬的蛋白LC 3的上调。细胞周期蛋白依赖性激酶（CDK）抑制剂Olomoucine可减少6-OHDA损伤引起的对侧旋转和黑质TH阳性神经元的丢失。用奥洛莫辛预处理大鼠或原代DA神经元，可部分阻断组织蛋白酶L的核转位。Olomoucine也增加了点状LC 3免疫反应性的表达，表明自噬的激活。提示奥洛莫辛可能通过抑制组织蛋白酶L核转位和激活自噬而发挥神经保护作用。(C)2009爱思唯尔有限公司版权所有。
The finding of nuclear translocation of cathepsin L and its ability to process the CDP/Cux transcription factor uncovers an important role of cathepsin L in control of cell cycle progression. As the expression of certain cell cycle regulators is associated with nigral neuronal death, the present study was sought to investigate if nuclear translocation of cathepsin L and expression of certain cyclins were induced in DA neurons by 6-hydroxydopamine (6-OHDA). The neuroprotective effects of the cell cycle inhibitor olomoucine against 6-OHDA-induced death of nigral neurons were examined. Using immunocytochemistry and real-time PCR we demonstrated that cyclin D1, cyclin B1 and proliferating cell nuclear antigen (PCNA) were aberrantly expressed in some dopaminergic neurons after 6-OHDA infusion. The nuclear translocation of cathepsin L and up-regulation of LC3, a protein involved in autophagy, were observed in nigral DA neurons. Olomoucine, a cyclin dependent kinase (CDK) inhibitor, reduced contralateral rotations and the loss of TH-positive neurons in substantia nigra induced by lesion with 6-OHDA. Pretreatment of rats or primary DA neurons with olomoucine resulted in a partial blockade of nuclear translocation of cathepsin L. Olomoucine also increased the expression of punctate LC3 immunoreactivity, indicating activation of autophagy. These findings suggest that olomoucine may exert neuroprotective effects through inhibiting cathepsin L nuclear translocation and activating autophagy. (C) 2009 Elsevier B.V. All rights reserved.