Role of XBP1 in neurons

双相情感障碍在同卵双胞胎（MZ）中的高一致率（约70%）表明遗传因素在这种疾病中的作用。我们在从两对双相情感障碍不一致的同卵双胞胎中获得的淋巴母细胞系中进行了DNA微阵列分析。我们发现，两个基因，XBP 1和GRP 78（HSPA 5），这两个都有一个关键的作用，内质网（ER）应激信号，通常下调。XBP 1位于22 q12，这是双相情感障碍和精神分裂症的共同连锁位点。GRP 78受XBP 1调节，并由丙戊酸盐诱导。因此，我们进一步分析了XBP 1和GRP 78在双相情感障碍的病理生理学中的作用。与对照组相比，双相情感障碍患者的XBP 1和GRP 78对ER应激的反应较小。我们发现在XBP 1的启动子区存在一个功能多态性，命名为-116C/G。丙戊酸盐可改善-116 G引起的功能障碍。我们发现XBP 1分布于整个神经元，并将神经可塑性信号从树突传递到核。通过基因芯片分析，发现XBP 1调控WFS 1。这些结果表明，XBP 1在神经可塑性变化中起作用，并且XBP 1-WFS 1通路在精神障碍中起作用。

High concordance rate of bipolar disorder in monozygotic (MZ) twins (approximately 70%) suggests the role of genetic factors in this disorder. We performed DNA microarray analysis in the lymphoblastoid cell lines obtained from two pairs of MZ twins discordant for bipolar disorder. We found that two genes, XBP1 and GRP78 (HSPA5), both of which have a pivotal role in endoplasmic reticulum (ER) stress signaling, were commonly down-regulated. XBP1 is located at 22q12, the common linkage locus for bipolar disorder and schizophrenia. GRP78 is regulated by XBP1, and induced by valproate. Thus, we further analyzed the roles of XBP1 and GRP78 in the pathophysiology of bipolar disorder. Response of XBP 1 and GRP78 to ER stress was smaller in patients with bipolar disorder compared with controls. We found a functional polymorphism in the promoter of XBP1, named -116C/G. The functional disturbance caused by -116G was improved by valproate. We found that XBP1 is located throughout the neuron and transport the neuroplastic signals from dendrite to the nucleus. By DNA microarray analysis, XBP1 was found to regulate WFS 1. These findings suggest that XBP1 plays a role in neuroplastic changes and XBP1-WFS1 pathway plays a role in mental disorders.