State Key Laboratory of Virology, Department of Medical Microbiology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
Hubei Province Key Laboratory of Allergy & Immunology, Wuhan University, Wuhan 430071, China.
Viruses. 2023 May 31;15(6):1298. doi: 10.3390/v15061298.
Schizophrenia, a mental disorder, afflicts 1% of the worldwide population. The dysregulation of homeostasis in the endoplasmic reticulum (ER) has been implicated in schizophrenia. Moreover, recent studies indicate that ER stress and the unfolded protein response (UPR) are linked to this mental disorder. Our previous research has verified that endogenous retrovirus group W member 1 envelope (ERVW-1), a risk factor for schizophrenia, is elevated in individuals with schizophrenia. Nevertheless, no literature is available regarding the underlying relationship between ER stress and ERVW-1 in schizophrenia. The aim of our research was to investigate the molecular mechanism connecting ER stress and ERVW-1 in schizophrenia. Here, we employed Gene Differential Expression Analysis to predict differentially expressed genes (DEGs) in the human prefrontal cortex of schizophrenic patients and identified aberrant expression of UPR-related genes. Subsequent research indicated that the UPR gene called had a positive correlation with , and in individuals with schizophrenia using Spearman correlation analysis. Furthermore, results from the enzyme-linked immunosorbent assay (ELISA) suggested increased serum protein levels of ATF6 and XBP1 in schizophrenic patients compared with healthy controls, exhibiting a strong correlation with ERVW-1 using median analysis and Mann-Whitney U analysis. However, serum GANAB levels were decreased in schizophrenic patients compared with controls and showed a significant negative correlation with ERVW-1, ATF6, and XBP1 in schizophrenic patients. Interestingly, in vitro experiments verified that ERVW-1 indeed increased ATF6 and XBP1 expression while decreasing GANAB expression. Additionally, the confocal microscope experiment suggested that ERVW-1 could impact the shape of the ER, leading to ER stress. GANAB was found to participate in ER stress regulated by ERVW-1. In conclusion, ERVW-1 induced ER stress by suppressing GANAB expression, thereby upregulating the expression of ATF6 and XBP1 and ultimately contributing to the development of schizophrenia.
精神分裂症是一种影响全球 1%人口的精神疾病。内质网（ER）的内稳态失调与精神分裂症有关。此外，最近的研究表明，内质网应激和未折叠蛋白反应（UPR）与这种精神疾病有关。我们之前的研究已经证实，精神分裂症的风险因素内源性逆转录病毒组 W 成员 1 包膜（ERVW-1）在精神分裂症患者中升高。然而，目前尚无文献报道内质网应激与 ERVW-1 在精神分裂症中的潜在关系。我们的研究旨在探讨内质网应激与 ERVW-1 在精神分裂症中的分子机制。在这里，我们采用基因差异表达分析预测精神分裂症患者人类前额叶皮层的差异表达基因（DEGs），并鉴定出 UPR 相关基因的异常表达。随后的研究表明，使用 Spearman 相关分析，UPR 基因 与精神分裂症患者中的 、 和 呈正相关。此外，酶联免疫吸附试验（ELISA）的结果表明，与健康对照组相比，精神分裂症患者的血清 ATF6 和 XBP1 蛋白水平升高，采用中位数分析和 Mann-Whitney U 分析显示与 ERVW-1 呈强相关。然而，与对照组相比，精神分裂症患者的血清 GANAB 水平降低，与精神分裂症患者中的 ERVW-1、ATF6 和 XBP1 呈显著负相关。有趣的是，体外实验证实 ERVW-1 确实增加了 ATF6 和 XBP1 的表达，同时降低了 GANAB 的表达。此外，共聚焦显微镜实验表明，ERVW-1 可以影响 ER 的形状，导致内质网应激。发现 GANAB 参与了由 ERVW-1 调节的内质网应激。总之，ERVW-1 通过抑制 GANAB 的表达诱导内质网应激，从而上调 ATF6 和 XBP1 的表达，最终导致精神分裂症的发生。
