ER stress response plays an important role in aggregation of α-synuclein.
ER stress response plays an important role in aggregation of α-synuclein.
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DOI：
10.1186/1750-1326-5-56
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发表时间：
2010-12-13
影响因子：
15.1
通讯作者：
Yen SH
中科院分区：
文献类型：
--
作者：
Jiang P;Gan M;Ebrahim AS;Lin WL;Melrose HL;Yen SH
丝状α-突触核蛋白积聚为路易小体是帕金森病的一个标志。为了确定α-synuclein组装的机制并确定组装是否具有细胞毒性，我们建立了一个细胞模型（3D5），该模型可诱导表达野生型人α-synuclein并形成包涵体，再现路易小体的许多形态和生化特征。在本研究中，我们评估了几种组蛋白去乙酰化酶抑制剂对3D5细胞和原代神经元培养α-突触核蛋白聚集的影响。这些药物已被证明可以保护短暂过表达α-突触核蛋白的细胞免受其毒性的影响。与瞬时转染相反，药物治疗对3D5细胞和原代培养物没有好处。与未处理的菌株相比，处理后的菌株存活率较低，α-突触核蛋白低聚物、活性半胱天冬酶3和9以及内质网应激标志物含量较高。经药物处理、诱导的3d5细胞，或过表达（<2倍）α-突触核蛋白的转基因小鼠的原代培养物，比未诱导或非转基因小鼠表现出更多的α-突触核蛋白寡聚物和内质网应激标记。在内质网应激源tunicamycin处理的培养物中也显示出类似的效果。这些作用可通过与内质网应激抑制剂salubrinal共同处理而被阻断。相比之下，与泛caspase抑制剂共同处理可以保护细胞免于死亡，但不能减少α-突触核蛋白寡聚物的积累。结果表明，野生型α-突触核蛋白的增加可引起内质网应激反应，使细胞对进一步的损伤更加敏感。最重要的是，内质网应激反应的增加可以促进野生型α-synuclein的聚集。
Accumulation of filamentous α-synuclein as Lewy bodies is a hallmark of Parkinson's disease. To identify the mechanisms involved in α-synuclein assembly and determine whether the assemblies are cytotoxic, we developed a cell model (3D5) that inducibly expresses wild-type human α-synuclein and forms inclusions that reproduce many morphological and biochemical characteristics of Lewy bodies. In the present study, we evaluated the effects of several histone deacetylase inhibitors on α-synuclein aggregation in 3D5 cells and primary neuronal cultures. These drugs have been demonstrated to protect cells transiently overexpressing α-synuclein from its toxicity. Contrary to transient transfectants, the drug treatment did not benefit 3D5 cells and primary cultures. The treated were less viable and contained more α-synuclein oligomers, active caspases 3 and 9, as well as ER stress markers than non-treated counterparts. The drug-treated, induced-3D5 cells, or primary cultures from transgenic mice overexpressing (<2 fold) α-synuclein, displayed more α-synuclein oligomers and ER stress markers than non-induced or non-transgenic counterparts. Similar effects were demonstrated in cultures treated with tunicamycin, an ER stressor. These effects were blocked by co-treatment with salubrinal, an ER stress inhibitor. In comparison, co-treatment with a pan caspase inhibitor protected cells from demise but did not reduce α-synuclein oligomer accumulation. Our results indicate that an increase of wild-type α-synuclein can elicit ER stress response and sensitize cells to further insults. Most importantly, an increase of ER stress response can promote the aggregation of wild type α-synuclein.
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DOI：
10.1016/j.bbrc.2009.11.080
发表时间：
2010-01-01
影响因子：
3.1
作者：
Hillmer, Andreas S.;Putcha, Preeti;Levin, Johannes;Hoegen, Tobias;Hyman, Bradley T.;Kretzschmar, Hans;McLean, Pamela J.;Giese, Armin
通讯作者：
Giese, Armin
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
影响因子：
168.9
作者：
Ibáñez, P;Bonnet, AM;Brice, A
通讯作者：
Brice, A
影响因子：
2.9
作者：
Ito, Satoru;Nakaso, Kazuhiro;Nakashima, Kenji
通讯作者：
Nakashima, Kenji
影响因子：
4.8
作者：
Gerard, M;Debyser, Z;Engelborghs, Y
通讯作者：
Engelborghs, Y