Graduate Program in Genetics, The University of Iowa, Iowa City, IA, USA.
Neuroscience. 2009 Dec 1;164(2):563-72. doi: 10.1016/j.neuroscience.2009.07.068. Epub 2009 Aug 6.
DYT1, the most common inherited dystonia, is caused by a common dominant mutation in the TOR1A gene that leads to a glutamic acid deletion in the protein torsinA. Wild-type torsinA locates preferentially in the endoplasmic reticulum while the disease-linked mutant accumulates in the nuclear envelope. As a result, it has been proposed that DYT1 pathogenesis could result either from transcriptional dysregulation caused by abnormal interactions of mutant torsinA with nuclear envelope proteins, or from a loss of torsinA function in the endoplasmic reticulum that would impair specific neurobiological pathways. Aiming to determine whether one or both of these potential mechanisms are implicated in DYT1 pathogenesis, we completed unbiased transcriptional and proteomic profiling in well-characterized neural cell lines that inducibly express wild-type or mutant torsinA. These experiments demonstrated that the accumulation of mutant torsinA in the nuclear envelope is not sufficient to cause transcriptional dysregulation. However, we detected expression changes at the protein level that, together with other reports, suggest a potential implication of torsinA on energy metabolism and regulation of the redox state. Furthermore, several proteins identified in this study have been previously linked to other forms of dystonia. In conclusion, our results argue against the hypothesis of transcriptional dysregulation in DYT1 dystonia, suggesting potential alternative pathogenic pathways.
DYT1，最常见的遗传性肌张力障碍，是由 TOR1A 基因中的一个常见显性突变引起的，导致蛋白 torsinA 中的谷氨酸缺失。野生型 torsinA 优先定位于内质网，而与疾病相关的突变体则在内核膜中积累。因此，有人提出 DYT1 发病机制可能源于突变 torsinA 与核膜蛋白异常相互作用引起的转录失调，也可能源于内质网中 torsinA 功能丧失，从而损害特定的神经生物学途径。为了确定这两种潜在机制是否都与 DYT1 发病机制有关，我们在经过充分表征的神经细胞系中完成了无偏转录组和蛋白质组学分析，这些细胞系可诱导表达野生型或突变型 torsinA。这些实验表明，突变 torsinA 在核膜中的积累不足以导致转录失调。然而，我们在蛋白质水平上检测到了表达变化，这些变化连同其他报告一起，提示 torsinA 可能对能量代谢和氧化还原状态的调节有潜在影响。此外，本研究中鉴定的几种蛋白质以前与其他形式的肌张力障碍有关。总之，我们的结果反对 DYT1 肌张力障碍中存在转录失调的假说，提示存在潜在的替代发病途径。
