ER Stress-Induced eIF2-alpha Phosphorylation Underlies Sensitivity of Striatal Neurons to Pathogenic Huntingtin

A hallmark of Huntington’s disease is the pronounced sensitivity of striatal neurons to polyglutamine-expanded huntingtin expression. Here we show that cultured striatal cells and murine brain striatum have remarkably low levels of phosphorylation of translation initiation factor eIF2α, a stress-induced process that interferes with general protein synthesis and also induces differential translation of pro-apoptotic factors. EIF2α phosphorylation was elevated in a striatal cell line stably expressing pathogenic huntingtin, as well as in brain sections of Huntington’s disease model mice. Pathogenic huntingtin caused endoplasmic reticulum (ER) stress and increased eIF2α phosphorylation by increasing the activity of PKR-like ER-localized eIF2α kinase (PERK). Importantly, striatal neurons exhibited special sensitivity to ER stress-inducing agents, which was potentiated by pathogenic huntingtin. We could strongly reduce huntingtin toxicity by inhibiting PERK. Therefore, alteration of protein homeostasis and eIF2α phosphorylation status by pathogenic huntingtin appears to be an important cause of striatal cell death. A dephosphorylated state of eIF2α has been linked to cognition, which suggests that the effect of pathogenic huntingtin might also be a source of the early cognitive impairment seen in patients.

亨廷顿病（Huntington’s disease）的典型特征，是纹状体神经元（striatal neurons）对聚谷氨酰胺扩增型亨廷顿蛋白（polyglutamine-expanded huntingtin）表达的显著敏感性。本研究发现，体外培养的纹状体细胞与小鼠脑纹状体组织中，翻译起始因子eIF2α（translation initiation factor eIF2α）的磷酸化水平极低；该应激诱导过程可抑制整体蛋白质合成，并介导促凋亡因子（pro-apoptotic factors）的差异化翻译。在稳定表达致病性亨廷顿蛋白的纹状体细胞系，以及亨廷顿病模型小鼠的脑切片中，eIF2α磷酸化水平均显著升高。致病性亨廷顿蛋白可通过增强类似PKR的内质网（ER）定位eIF2α激酶（PKR-like ER-localized eIF2α kinase, PERK）的活性，诱发内质网应激并提升eIF2α磷酸化水平。尤为关键的是，纹状体神经元对内质网应激诱导剂表现出特异性敏感，且该敏感性可被致病性亨廷顿蛋白进一步强化。通过抑制PERK，可显著降低亨廷顿蛋白介导的毒性。由此可见，致病性亨廷顿蛋白所引发的蛋白质稳态失衡与eIF2α磷酸化状态改变，或是纹状体细胞死亡的重要诱因。eIF2α的去磷酸化状态与认知功能密切相关，这提示致病性亨廷顿蛋白的作用机制，或许也是患者早期出现认知障碍的潜在成因之一。