Reductions of the components of the calreticulin/calnexin quality-control system by proteasome inhibitors and their relevance in a rodent model of Parkinson's disease.
Reductions of the components of the calreticulin/calnexin quality-control system by proteasome inhibitors and their relevance in a rodent model of Parkinson's disease.
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蛋白酶体抑制剂对钙网蛋白/钙连接蛋白质量控制系统成分的减少及其在帕金森病啮齿动物模型中的相关性
DOI：
10.1002/jnr.23413
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发表时间：
2014-10
影响因子：
4.2
通讯作者：
Wu, Shengzhou
中科院分区：
文献类型：
--
作者：
Kuang, Xiu-Li;Liu, Fang;Chen, Huifang;Li, Yiping;Liu, Yimei;Xiao, Jian;Shan, Ge;Li, Mingjie;Snider, B. Joy;Qu, Jia;Barger, Steven W.;Wu, Shengzhou
关键词：
有证据表明，泛素-蛋白酶体系统和内质网（ER）质量控制系统协同工作，以确保蛋白质在ER中正确折叠，错误折叠的蛋白质被逆转运到胞质溶胶中，由蛋白酶体降解。任何一个系统的功能障碍都会导致动物的发育异常甚至死亡。本研究探讨蛋白酶体抑制是否以及如何影响钙网蛋白（CRT）/钙连接蛋白（CNX）糖蛋白折叠机制，一个典型的ER蛋白质质量控制系统的组件，在早期神经元损伤的背景下。在这里，我们报告说，蛋白酶体抑制剂治疗，在非致死水平，降低CRT和ERp 57的蛋白水平，但不CNX。这些处理增加了培养基中CRT的蛋白质水平，这种作用被布雷菲德菌素A（一种蛋白质运输抑制剂）阻断;相反，在培养基中未检测到ERp 57。单独敲低CRT水平增加了神经元细胞系SH-SY 5 Y对6-羟基多巴胺（6-OHDA）毒性的脆弱性。在帕金森病大鼠模型中，纹状体内6-OHDA损伤导致中脑CRT和ERp 57水平降低。这些发现表明，CRT/CNX糖蛋白质量控制系统组分的减少可能在帕金森病和其他与遍在蛋白-蛋白酶体系统功能障碍相关的神经退行性疾病的神经元损伤中发挥作用。
Evidence indicates that the ubiquitin-proteasome system and the endoplasmic retculum (ER) quality-control system work in concert to ensure that proteins are correctly folded in the ER and that misfolded proteins are retrotransported to the cytosol for degradation by proteasomes. Dysfunction of either system results in developmental abnormalities and even death in animals. This study investigates whether and how proteasome inhibition impacts the components of the calreticulin (CRT)/calnexin (CNX) glycoprotein folding machinery, a typical ER protein quality-control system, in the context of early neuronal injury. Here we report that proteasome inhibitor treatments, at nonlethal levels, reduced protein levels of CRT and ERp57 but not of CNX. These treatments increased protein levels of CRT in culture media, an effect blocked by brefeldin A, an inhibitor of protein trafficking; by contrast, ERp57 was not detected in culture media. Knockdown of CRT levels alone increased the vulnerability of SH-SY5Y, a neuronal cell line, to 6-hydroxydopamine (6-OHDA) toxicity. In a rat model of Parkinson’s disease, intrastriatal 6-OHDA lesions resulted in decreased levels of CRT and ERp57 in the midbrain. These findings suggest that reduction of the components of CRT/CNX glycoprotein quality-control system may play a role in neuronal injury in Parkinson’s disease and other neurodegenerative disorders associated with dysfunction of the ubiquitin-proteasome system.
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钙网蛋白结构域的功能专业化。
影响因子：
7.8
作者：
Nakamura, K;Zuppini, A;Arnaudeau, S;Lynch, J;Ahsan, I;Krause, R;Papp, S;De Smedt, H;Parys, J B;Muller-Esterl, W;Lew, D P;Krause, K H;Demaurex, N;Opas, M;Michalak, M
通讯作者：
Michalak, M
影响因子：
4.7
作者：
Keller, JN;Hanni, KB;Markesbery, WR
通讯作者：
Markesbery, WR
影响因子：
64.8
作者：
BURNS, K;DUGGAN, B;MICHALAK, M
通讯作者：
MICHALAK, M
影响因子：
5.3
作者：
Denzel, A;Molinari, M;Owen, MJ
通讯作者：
Owen, MJ
影响因子：
7.8
作者：
Mesaeli, N;Nakamura, K;Zvaritch, E;Dickie, P;Dziak, E;Krause, K H;Opas, M;MacLennan, D H;Michalak, M
通讯作者：
Michalak, M