Phosphodiesterase 8A to discriminate in blood samples depressed patients and suicide attempters from healthy controls based on A-to-I RNA editing modifications

Abstract

Mental health issues, including major depressive disorder, which can lead to suicidal behavior, are considered by the World Health Organization as a major threat to global health. Alterations in neurotransmitter signaling, e.g., serotonin and glutamate, or inflammatory response have been linked to both MDD and suicide. Phosphodiesterase 8A (PDE8A) gene expression is significantly decreased in the temporal cortex of major depressive disorder (MDD) patients. PDE8A specifically hydrolyzes adenosine 3′,5′-cyclic monophosphate (cAMP), which is a key second messenger involved in inflammation, cognition, and chronic antidepressant treatment. Moreover, alterations of RNA editing in PDE8A mRNA has been described in the brain of depressed suicide decedents. Here, we investigated PDE8A A-to-I RNA editing-related modifications in whole blood of depressed patients and suicide attempters compared to age-matched and sex-matched healthy controls. We report significant alterations of RNA editing of PDE8A in the blood of depressed patients and suicide attempters with major depression, for which the suicide attempt took place during the last month before sample collection. The reported RNA editing modifications in whole blood were similar to the changes observed in the brain of suicide decedents. Furthermore, analysis and combinations of different edited isoforms allowed us to discriminate between suicide attempters and control groups. Altogether, our results identify PDE8A as an immune response-related marker whose RNA editing modifications translate from brain to blood, suggesting that monitoring RNA editing in PDE8A in blood samples could help to evaluate depressive state and suicide risk.

RNA Editing: A New Therapeutic Target in Amyotrophic Lateral Sclerosis and Other Neurological Diseases

“…Although the influence of changes in editing efficiencies at each of the five editing sites in 5-HT2 C were inconsistent among previous reports [93][94][95][96][97][98][99], the proportion of site A-edited 5-HT2 C was higher, especially in the postmortem brains of suicide victims than in non-suicidal patients with both depression and schizophrenia [96,99]. Interestingly, editing efficiencies at sites B, C and E in phosphodiesterase 8A (PDE8A), a key modulator of signal transduction downstream of 5-HT2 C , were decreased in the brain and blood of patients with depression [100,101]. A comprehensive study on the alteration of RNA editing has demonstrated a higher overall RNA editing level and significant changes in editing efficiencies at many editing sites in the brains of patients with schizophrenia [70].…”

A game changer for bipolar disorder diagnosis using RNA editing-based biomarkers

“…Interestingly, phosphodiesterases, a key modulator of signal transduction downstream 5-HTR2c, is involved in inflammatory cell activation, memory and cognition [ 34 ]. More recently, we demonstrated the diagnostic value of PDE8A mRNA editing in depression, in the blood from HCV patients treated with interferon-α [ 35 ], and in the blood from depressed patients and suicide attempters compared to age-matched and sex-matched healthy controls [ 36 ].…”