Role of XBP1 in neurons

同卵双生子双相情感障碍的高符合率(约70%)提示遗传因素在该疾病中的作用。我们对双相情感障碍的两对MZ双胞胎的淋巴母细胞系进行了DNA微阵列分析。我们发现XBP1和GRP78(HSPA5)这两个在内质网应激信号中起关键作用的基因普遍下调。XBP1位于22q12，是双相情感障碍和精神分裂症的共同连锁位点。GRP78受XBP1调控，并受丙戊酸诱导。因此，我们进一步分析了XBP1和GRP78在双相情感障碍的病理生理学中的作用。双相情感障碍患者XBP-1和GRP78对内质网应激的反应较对照组小。我们在XBP1启动子上发现了一个功能多态，命名为-116C/G，丙戊酸可以改善-116G引起的功能障碍。我们发现，XBP1定位于整个神经元，并将神经再生信号从树突传递到细胞核。DNA芯片分析发现XBP1对WFS1具有调控作用，提示XBP1参与神经可塑性改变，XBP1-WFS1通路参与精神障碍的发生。

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.