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

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.

Deficits of Hippocampal RNA Editing and Social Interaction Resulting from Prenatal Stress are Mitigated by Clozapine

“…GluA2 RNA editing may be a target for the development of drugs to ameliorate the long-term effects of stress on behavior. These data also indicate that reduced RNA editing is likely to contribute to the hippocampal deficits observed in psychiatric disorders associated with impaired SI, such as schizophrenia 8,39,40,105,106 , autism 19,38 , mood disorders 92,[107][108][109][110][111] and Alzheimer's disease 8,10,112,113 .…”

The Role of PDE8 in T Cell Recruitment and Function in Inflammation

“…Recently, there have been numerous studies on PDE8A and PDE8B, a family of cAMP specific PDEs (Fisher et al, 1998a;Hayashi et al, 1998;Soderling et al, 1998a;Glavas et al, 2001;Kobayashi et al, 2003;Dong et al, 2006Dong et al, , 2010Dong et al, , 2015Chen et al, 2009;Vang et al, 2010Vang et al, , 2016DeNinno et al, 2011;Tsai and Beavo, 2012;Brown et al, 2013;Demirbas et al, 2013;Maurice, 2013;Shimizu-Albergine et al, 2016;Basole et al, 2017;Johnstone et al, 2017;Kelly, 2018). PDE8A and B are expressed widely in human tissue (Wang et al, 2008) with functions identified in testosterone and corticosteroid production (Tsai et al, 2010;Demirbas et al, 2013), myocyte contraction (Patrucco et al, 2010), lymphocyte adhesion and chemotaxis (Dong et al, 2006(Dong et al, , 2015Vang et al, 2010Vang et al, , 2013Basole et al, 2017), memory and coordination , human airway smooth muscle regulation (Johnstone et al, 2017), strong association with immune protection against intracellular pathogens (Blanco et al, 2017), brain disorders associated with inflammation (Chimienti et al, 2019) and T cells in systemic lupus erythematosus (SLE) (Orlowski et al, 2008). In a recent study, single nucleotide polymorphisms in the PDE8 region were found to be associated with Sjögren's Syndrome (Taylor et al, 2017).…”

RNA Editing and Modifications in Mood Disorders

“…Specifically, a robust increase in editing on 5-HT2c-R was seen in the anterior cingulate cortex of suicide victims, linking the editing reaction in this cortical area to suicide risk [46]. Intriguing, phosphodiesterases (PDE), a key modulator of signal transduction downstream 5-HT2c-R, involved in inflammatory cell activation, memory and cognition, was differently edited between depressed suicide decedents and controls [47]. As already noted [48], Table 1 clearly indicates that literature data is not always consistent, which could be due to different factors such as the number of samples analyzed, inconsistency in the precise brain regions analyzed, the techniques used to measure editing levels, technical artefact associated to post-mortem brain etc.…”

“…Specifically, a robust increase in editing on 5-HT2c-R was seen in the anterior cingulate cortex of suicide victims, linking the editing reaction in this cortical area to suicide risk [ 46 ]. Intriguing, phosphodiesterases (PDE), a key modulator of signal transduction downstream 5-HT2c-R, involved in inflammatory cell activation, memory and cognition, was differently edited between depressed suicide decedents and controls [ 47 ].…”