Lithium protects dopaminergic cells from rotenone toxicity via autophagy enhancement.
Lithium protects dopaminergic cells from rotenone toxicity via autophagy enhancement.
复制标题
锂通过增强自噬保护多巴胺能细胞免受鱼藤酮毒性
DOI：
10.1186/s12868-015-0222-y
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发表时间：
2015-11-25
期刊：
影响因子：
2.4
通讯作者：
Wang T
中科院分区：
文献类型：
--
作者：
Hou L;Xiong N;Liu L;Huang J;Han C;Zhang G;Li J;Xu X;Lin Z;Wang T
先前的研究表明，自噬溶酶体途径的增强可能对帕金森病（PD）有益，其中聚集/错误折叠蛋白的异常积累和线粒体功能障碍被认为是重要的发病机制。近年来，许多研究表明，锂在包括帕金森病在内的几种神经退行性疾病模型中具有神经保护作用。然而，这种神经保护的确切机制尚不清楚。在我们的研究中，我们使用鱼藤酮暴露的SH-SY5Y细胞作为体外帕金森模型来评估锂对自噬的增强作用，并进一步研究其潜在机制。与常用的自噬增强剂雷帕霉素（Rap, 0.2 μM）类似，锂离子（LiCl, 10 mM）可显著恢复SH-SY5Y细胞的收缩，减轻鱼tenon诱导的细胞凋亡、线粒体膜电位降低和活性氧积累。此外，自噬抑制剂如3-甲基腺嘌呤（3-MA, 10 mM）或氯喹（CHL, 10 μM）共处理可部分阻断LiCl诱导的保护作用。此外，在免疫印迹实验中，3-MA或Chl抑制licl诱导的自噬。此外，我们还观察到LC3和线粒体的共定位以及在licl处理的细胞中线粒体功能的保存，证实了受损的线粒体通过自噬（mitophagy）被清除。这些结果表明，锂对鱼藤酮引起的神经损伤的保护作用部分是通过自噬途径实现的。从药理学上讲，锂作为一种疾病调节剂诱导自噬可能是一种新的治疗策略。
Previous studies have indicated that enhancement of autophagy lysosome pathway may be beneficial for Parkinson’s disease (PD), in which aberrant accumulation of aggregated/misfolded proteins and mitochondrial dysfunction are considered as crucial pathogenesis. Recently, a number of studies have suggested the neuroprotective effects of lithium in models of several neurodegenerative diseases including PD. However, the exact mechanisms underlying this neuroprotection remain unclear. In our study, rotenone-exposed SH-SY5Y cells were used as an in vitro parkinsonian model to assess the autophagy-enhancing effect of lithium and the underlying mechanisms were further investigated. Similar to the common used autophagy enhancer rapamycin (Rap, 0.2 μM), lithium (LiCl, 10 mM) significantly recovered the shrinkage of SH-SY5Y cells, and alleviated rotenone-induced cell apoptosis, mitochondrial membrane potential reduction and reactive oxygen species accumulation. Furthermore, the protective effects induced by LiCl were partially blocked by the co-treatment of autophagy inhibitors such as 3-methyladenine (3-MA, 10 mM) or chloroquine (CHL, 10 μM). Moreover, 3-MA or Chl suppressed LiCl-induced autophagy in the immunoblot assay. In addition, the co-localization of LC3 and mitochondria and the preservation of mitochondrial function within LiCl-treated cells were observed, confirming that the damaged mitochondria were cleared through autophagy (mitophagy). These findings suggested that lithium exerted neuroprotection against rotenone-induced injuries partially through the autophagy pathway. Pharmacologically induction of autophagy by lithium may represent a novel therapeutic strategy as a disease-modifier in PD.