RNA editing blood biomarkers for predicting mood alterations in HCV patients

• Published in: Journal of neurovirology 2019-12, Vol.25 (6), p.825-836
• Main Authors: Salvetat, N., Van der Laan, S., Vire, B., Chimienti, F., Cleophax, S., Bronowicki, J. P., Doffoel, M., Bourlière, M., Schwan, R., Lang, J. P., Pujol, J. F., Weissmann, D.
• Format: Article
• Language: English
• Subjects: Biochemistry, Molecular Biology; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Computer Science; Human health and pathology; Immunology; Infectious Diseases; Life Sciences; Medication; Molecular biology; Neurology; Neurosciences; Pharmaceutical sciences; Psychiatrics and mental health; Statistics; Virology
• ISSN: 1355-0284; 1538-2443
• DOI: 10.1007/s13365-019-00772-9

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.