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首页> 外文期刊>The Canadian Journal of Neurological Sciences: le Journal Canadien des Sciences Neurologiques >Proteasome inhibitor lactacystin induces cholinergic degeneration.
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Proteasome inhibitor lactacystin induces cholinergic degeneration.

机译：蛋白酶体抑制剂lacacycystin诱导胆碱能变性。

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OBJECTIVE: Ubiquitin proteasome system dysfunction is believed to play an important role in the development of Parkinson's disease (PD), and almost all studies till now have mainly focused on the susceptibility of dopaminergic neurons to proteasome inhibition. However, in fact, there are many other types of neurons such as cholinergic ones involved in PD. In our present study, we attempt to figure out what effect the failure of ubiquitin proteasome function would execute on cholinergic cells in culture. METHODS: We treated cholinergic cells in culture with various doses of lactacystin. Then MTT assay was used to evaluate the cellular viability and the AnnexinV-PI method was used to detect apoptosis. Both cellular soluble and insoluble polyubiquitinated proteins were detected by western blot. Furthermore, the mitochondrial membrane potential was analyzed using JC-1 and the intracellular production of reactive oxygen species (ROS) was determined using the fluorescent probe CM-H2DCFDA. RESULTS: We found that low doses of lactacystin were enough to induce significant apoptotic cell death, disturb the mitochondrial membrane potential, and cause oxidative stress. We also found that the amounts of polyubiquitinated proteins dramatically increased with high doses, although the loss of cells did not increase accordingly. CONCLUSIONS: Our results suggest that cholinergic cells are sensitive to ubiquitin proteasome system dysfunction, which exerts its toxic effect by causing mitochondrial dysfunction and subsequent oxidative stress, not through polyubiquitinated proteins accumulation.
机译：目的：泛素蛋白酶体系统功能异常被认为在帕金森氏病（PD）的发展中起着重要作用，到目前为止，几乎所有研究都集中在多巴胺能神经元对蛋白酶体抑制的敏感性上。但是，实际上，PD还涉及许多其他类型的神经元，例如胆碱能神经元。在我们目前的研究中，我们试图找出泛素蛋白酶体功能衰竭对培养的胆碱能细胞产生何种影响。方法：我们用不同剂量的乳酸菌素处理了培养物中的胆碱能细胞。 MTT法检测细胞活力，AnnexinV-PI法检测细胞凋亡。通过蛋白质印迹检测到细胞可溶性和不溶性多泛素化蛋白。此外，使用JC-1分析线粒体膜电位，并使用荧光探针CM-H2DCFDA确定细胞内活性氧（ROS）的产生。结果：我们发现低剂量的乳酸菌足以引起明显的凋亡细胞死亡，扰乱线粒体膜电位，并引起氧化应激。我们还发现，尽管细胞损失并没有相应增加，但大剂量的泛素化蛋白的数量却急剧增加。结论：我们的结果表明胆碱能细胞对泛素蛋白酶体系统功能失调敏感，这是通过引起线粒体功能失调和随后的氧化应激而不是通过多泛素化蛋白积累来发挥其毒性作用。

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