ALCEDIAG, Sys2Diag / CNRS UMR9005, Parc Euromédecine Cap Delta, 1682 Rue de la Valsière, 34184, Montpellier Cedex 4, France.
Biocortech, rue de la Croix Jarry, 75013, Paris, France.
J Neurovirol. 2019 Dec;25(6):825-836. doi: 10.1007/s13365-019-00772-9. Epub 2019 Jul 22.
Treatment-emergent depression is a common complication in patients with chronic hepatitis C virus (HCV) infection undergoing antiviral combination therapy with IFN-α and ribavirin. It has recently been shown that changes in A-to-I RNA editing rates are associated with various pathologies such as inflammatory disorders, depression and suicide. Interestingly, IFN-α induces gene expression of the RNA editing enzyme ADAR1-1 (ADAR1a-p150) and alters overall RNA editing activity. In this study, we took advantage of the high prevalence of pharmacologically induced depression in patients treated with IFN-α and ribavirin to test the interest of RNA editing-related biomarkers in white blood cells of patients. In this 16-week longitudinal study, a small cohort of patients was clinically evaluated using standard assessment methods prior to and during antiviral therapy and blood samples were collected to analyse RNA editing modifications. A-I RNA editing activity on the phosphodiesterase 8A (PDE8A) gene, a previously identified RNA editing hotspot in the context of lupus erythematosus, was quantified by using an ultra-deep next-generation sequencing approach. We also monitored gene expression levels of the ADAR enzymes and the PDE8A gene during treatment by qPCR. As expected, psychiatric evaluation could track treatment-emergent depression, which occurred in 30% of HCV patients. We show that PDE8A RNA editing is increased in all patients following interferon treatment, but differently in 30% of patients. This effect was mimicked in a cellular model using SHSY-5Y neuroblastoma cells. By combining the data of A-I RNA editing and gene expression, we generated an algorithm that allowed discrimination between the group of patients who developed a treatment-emergent depression and those who did not. The current model of drug-induced depression identified A-I RNA editing biomarkers as useful tools for the identification of individuals at risk of developing depression in an objective, quantifiable biological blood test.
治疗中出现的抑郁症是慢性丙型肝炎病毒 (HCV) 感染患者接受 IFN-α和利巴韦林抗病毒联合治疗的常见并发症。最近的研究表明，A-to-I RNA 编辑率的变化与各种病理有关，如炎症性疾病、抑郁症和自杀。有趣的是，IFN-α诱导 RNA 编辑酶 ADAR1-1（ADAR1a-p150）的基因表达，并改变整体 RNA 编辑活性。在这项研究中，我们利用 IFN-α和利巴韦林治疗患者中普遍存在的药物引起的抑郁症，来测试白细胞 RNA 编辑相关生物标志物在患者中的应用价值。在这项 16 周的纵向研究中，通过标准评估方法在抗病毒治疗前和治疗期间对一小部分患者进行临床评估，并采集血液样本分析 RNA 编辑修饰。通过超深度下一代测序方法，对磷酸二酯酶 8A（PDE8A）基因的 A-I RNA 编辑活性进行了定量，该基因是红斑狼疮背景下先前确定的 RNA 编辑热点。我们还通过 qPCR 监测 ADAR 酶和 PDE8A 基因在治疗过程中的表达水平。正如预期的那样，精神科评估可以跟踪治疗中出现的抑郁症，在 HCV 患者中，有 30%出现了这种情况。我们表明，干扰素治疗后所有患者的 PDE8A RNA 编辑都会增加，但有 30%的患者情况不同。在使用 SHSY-5Y 神经母细胞瘤细胞的细胞模型中，也可以模拟这种效应。通过将 A-I RNA 编辑和基因表达的数据相结合，我们生成了一个算法，可以区分发生治疗中出现的抑郁症和未发生的患者。这种药物引起的抑郁症模型将 A-I RNA 编辑生物标志物确定为一种有用的工具，可用于在客观、可量化的生物血液测试中识别有发生抑郁症风险的个体。
