RNA editing blood biomarkers for predicting mood alterations in HCV patients

N Salvetat,N Salvetat,D Weissmann,D Weissmann,D Weissmann,M Doffoel,S Van Der Laan,S Cleophax,B Vire,J P Lang,J F Pujol,J P Bronowicki,B Vire,S Cleophax,M Bourlière,F Chimienti,F Chimienti,R Schwan

doi:10.1007/s13365-019-00772-9

Abstract

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.

Highlights

Catalytic deamination of adenosine (A) to inosine (I) on RNA molecules is a fundamental cellular mechanism that directly impacts expression and function of a large set of proteins
We recently identified region-specific alterations of RNA editing in phosphodiesterase 8A (PDE8A) mRNA in the brain, which could discriminate between controls and depressed suicide decedents (Chimienti et al 2019)
A small cohort of ten individuals with hepatitis C virus never treated with interferon and ribavirin and without prior records for psychiatric disorders was recruited over different medical hospitals in France

Summary

Introduction

Catalytic deamination of adenosine (A) to inosine (I) on RNA molecules is a fundamental cellular mechanism that directly impacts expression and function of a large set of proteins. Deamination is brought about by the action of specific editing enzymes, termed ADAR (adenosine deaminase acting on RNA). Adenosines that reside in the coding sequence (e.g. 5-HT2c receptor, glutamate receptor) or in non-repetitive intronic sequences (e.g. phosphodiesterase subtype 8A/PDE8A) are deaminated. While alterations in the coding sequence may lead to a change in amino acid composition and function of the translated protein (Berg et al 2001; Burns et al 1997), the editing process of the intronic sequences has been proposed to influence both RNA splicing pattern and formation of different isoforms of microRNAs, known to actively modulate gene expression (Kawahara et al 2008; Solomon et al 2013; Wulff and Nishikura 2012)

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