Brain region-specific alterations of RNA editing in PDE8A mRNA in suicide decedents

Fabrice Chimienti,Mark D Underwood,Jean-François Pujol,Nicolas Salvetat,Dinah Weissmann,Victoria Arango,Laurent Cavarec,J John Mann,Laurent Vincent

doi:10.1038/s41398-018-0331-3

Abstract

Phosphodiesterases (PDE) are key modulators of signal transduction and are involved in inflammatory cell activation, memory and cognition. There is a two-fold decrease in the expression of phosphodiesterase 8A (PDE8A) in the temporal cortex of major depressive disorder (MDD) patients. Here, we studied PDE8A mRNA-editing profile in two architectonically distinct neocortical regions in a clinically well-characterized cohort of age- and sex-matched non-psychiatric drug-free controls and depressed suicide decedents. By using capillary electrophoresis single-stranded conformational polymorphism (CE-SSCP), a previously validated technique to identify A-to-I RNA modifications, we report the full editing profile of PDE8A in the brain, including identification of two novel editing sites. Editing of PDE8A mRNA displayed clear regional difference when comparing dorsolateral prefrontal cortex (BA9) and anterior cingulate cortex (BA24). Furthermore, we report significant intra-regional differences between non-psychiatric control individuals and depressed suicide decedents, which could discriminate the two populations. Taken together, our results (i) highlight the importance of immune/inflammatory markers in major depressive disorder and suicide and (ii) establish a direct relationship between A-to-I RNA modifications of peripheral markers and A-to-I RNA editing-related modifications in brain. This work provides the first immune response-related brain marker for suicide and could pave the way for the identification of a blood-based biomarker that predicts suicidal behavior.

Highlights

Suicide and suicidal behavior are a major public health concern
Epigenetics studies indicate a broad reprogramming of promoter DNA methylation patterns in the hippocampus of suicide decedents, including genes involved in cognitive processes[4]
Raw data of the complete phosphodiesterase 8A (PDE8A) RNA-editing profiles are shown in Supplementary Tables S1 and S2

Summary

Introduction

Suicide and suicidal behavior are a major public health concern. Suicide ranks among the three leading causes of death worldwide with an estimated 1 million deaths every year[1]. Multifactorial outcome whose biological basis remain poorly understood. Genome-wide association studies have contributed to a better understanding of the genetic basis of suicidal behavior. No single gene/SNP has been identified with genome-wide significance, though there is much evidence for an association between lower serotonergic function and suicidal behavior[2]. Recent studies have shown an association between gene alterations by epigenetic mechanisms and suicidal behavior[3]. Epigenetics studies indicate a broad reprogramming of promoter DNA methylation patterns in the hippocampus of suicide decedents, including genes involved in cognitive processes[4]

Methods

Results

Conclusion