Altered Functional Protein Networks in the Prefrontal Cortex and Amygdala of Victims of Suicide

Katalin Adrienna Kékesi,Péter Gulyássy,Botond Penke,Attila Simor,Miklós Palkovits,András Czurkó,Katalin F Medzihradszky,Gábor Juhász,Éva Hunyadi-Gulyás,Zsuzsanna Darula,Éva Mónika Szegő

doi:10.1371/journal.pone.0050532

Abstract

Probing molecular brain mechanisms related to increased suicide risk is an important issue in biological psychiatry research. Gene expression studies on post mortem brains indicate extensive changes prior to a successful suicide attempt; however, proteomic studies are scarce. Thus, we performed a DIGE proteomic analysis of post mortem tissue samples from the prefrontal cortex and amygdala of suicide victims to identify protein changes and biomarker candidates of suicide. Among our matched spots we found 46 and 16 significant differences in the prefrontal cortex and amygdala, respectively; by using the industry standard t test and 1.3 fold change as cut off for significance. Because of the risk of false discoveries (FDR) in these data, we also made FDR adjustment by calculating the q-values for all the t tests performed and by using 0.06 and 0.4 as alpha thresholds we reduced the number of significant spots to 27 and 9 respectively. From these we identified 59 proteins in the cortex and 11 proteins in the amygdala. These proteins are related to biological functions and structures such as metabolism, the redox system, the cytoskeleton, synaptic function, and proteolysis. Thirteen of these proteins (CBR1, DPYSL2, EFHD2, FKBP4, GFAP, GLUL, HSPA8, NEFL, NEFM, PGAM1, PRDX6, SELENBP1 and VIM,) have already been suggested to be biomarkers of psychiatric disorders at protein or genome level. We also pointed out 9 proteins that changed in both the amygdala and the cortex, and from these, GFAP, INA, NEFL, NEFM and TUBA1 are interacting cytoskeletal proteins that have a functional connection to glutamate, GABA, and serotonin receptors. Moreover, ACTB, CTSD and GFAP displayed opposite changes in the two examined brain structures that might be a suitable characteristic for brain imaging studies. The opposite changes of ACTB, CTSD and GFAP in the two brain structures were validated by western blot analysis.

Highlights

Suicide is a human attribute without a proper equivalent in animals; some behavioural traits, such as aggression, hopelessness, and impulsivity, are correlated with suicide and can be reproduced in animals [1]
We used DIGE proteomics technology to investigate the differences in the protein expression pattern of suicide compared to control brain samples
From these matched spots with the t test and 1.3 fold change as cut off we found 46 significant differences between the control and suicide prefrontal cortex samples from which we could identify 84 proteins

Summary

Introduction

Suicide is a human attribute without a proper equivalent in animals; some behavioural traits, such as aggression, hopelessness, and impulsivity, are correlated with suicide and can be reproduced in animals [1]. Suicidal behaviour often occurs in conjunction with different psychiatric diseases, such as major depression or schizophrenia [2]. Suicide is linked with the downregulation of serotonin (5HT) release and/or uptake [6] together with 5-HT1A receptor dysfunction. These dysfunctions are thought to be major factors in several mental disorders, including major depression [7]; the current gene expression data suggest that suicide is possibly correlated with extensive changes in the brain and is not restricted to only one neurotransmitter system [8,9,10]. Understanding the molecular brain mechanisms involved in suicide is important for the development of both psychoactive drugs and predictive diagnostic tools

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