Graduate Program in Neuroscience, The University of Iowa, Iowa City, IA 52242, USA.
Neurochem Res. 2011 Mar;36(3):452-9. doi: 10.1007/s11064-010-0363-4. Epub 2010 Dec 16.
DYT1 dystonia is caused by a glutamic acid deletion (ΔE) in the endoplasmic reticulum (ER) protein torsinA. Previous studies suggest that torsinA modulates the aggregation of cytosolic misfolded proteins and ER stress responses, although the mechanisms underlying those effects remain unclear. In order to investigate the bases of these observations, we analyzed the interaction between torsinA expression, protein aggregation and ER stress in PC6.3 cells. Unexpectedly, we found that expression of torsinA(wt) or (ΔE) does not influence the inclusion formation by an expanded polyglutamine reporter protein in this cellular model. Furthermore, torsinA does not prevent the activation of ER stress induced by thapsigargin or the reducing agent DTT. Interestingly, DTT induces post-translational changes in torsinA, more prominently for torsinA(wt) than (ΔE). This work highlights the importance of model system selection for the study of torsinA function. Furthermore, it provides additional evidence suggesting that torsinA is sensitive to changes in the cellular redox potential.
DYT1 型肌张力障碍是由内质网（ER）蛋白 torsinA 中的谷氨酸缺失（ΔE）引起的。先前的研究表明，torsinA 调节细胞质错误折叠蛋白的聚集和 ER 应激反应，尽管这些影响的机制尚不清楚。为了研究这些观察结果的基础，我们分析了 PC6.3 细胞中 torsinA 表达、蛋白聚集和 ER 应激之间的相互作用。出乎意料的是，我们发现 torsinA(wt)或 (ΔE) 的表达并不影响这个细胞模型中扩增的多谷氨酰胺报告蛋白引起的包涵体形成。此外，torsinA 不能阻止 thapsigargin 或还原剂 DTT 诱导的 ER 应激的激活。有趣的是，DTT 诱导 torsinA 的翻译后变化，对于 torsinA(wt)比 (ΔE)更为明显。这项工作强调了选择模型系统对于研究 torsinA 功能的重要性。此外，它提供了额外的证据表明 torsinA 对细胞氧化还原电位的变化敏感。
