Abstract
Background
Suicide is one of the top 20 causes of death worldwide, but few interventions consistently reduce suicidal thoughts and behaviors. Our limited understanding of the neurobiology of suicide hinders development of efficacious and safe interventions. Kinases fine-tune signaling in complex biological networks. Kinase gene and protein expression levels are reduced in depressed subjects who die by suicide. Measuring individual kinase expression alone is not sufficient to understand the kinome, the complex network of kinase interactions which represents the intrinsic state of kinases. The kinome has not been studied in subjects who died by suicide.
Methods
We investigated changes in serine/threonine kinase activity in the frontal cortex of depressed subjects who died by suicide and comparison subjects (n=20 per group) using a kinome peptide array-based system (PamGene12).
Results
We demonstrate large scale abnormalities in activity (fold change >1.15 or <0.85) of kinases in depressed subjects who die by suicide, including p53 related protein kinase (PRPK), AMP-activated protein kinase (AMPK), and protein kinase C (PKCd). The kinase data undergo connectivity mapping using the Library of Integrated Network-based Cellular Signatures (LINCS) database. Connectivity mapping links changes in patterns of gene expression induced by altered kinase network activity in depressed-suicide subjects, with chemical perturbagens that induce similar and opposing patterns of change in gene expression.
Conclusions
Kinases have the potential to modulate complex behaviors like suicide but are yet to be exploited therapeutically. Studying the kinome will increase our understanding of the neurobiology of suicide and may lead to the development of novel interventions for suicide.
Suicide is one of the top 20 causes of death worldwide, but few interventions consistently reduce suicidal thoughts and behaviors. Our limited understanding of the neurobiology of suicide hinders development of efficacious and safe interventions. Kinases fine-tune signaling in complex biological networks. Kinase gene and protein expression levels are reduced in depressed subjects who die by suicide. Measuring individual kinase expression alone is not sufficient to understand the kinome, the complex network of kinase interactions which represents the intrinsic state of kinases. The kinome has not been studied in subjects who died by suicide.
Methods
We investigated changes in serine/threonine kinase activity in the frontal cortex of depressed subjects who died by suicide and comparison subjects (n=20 per group) using a kinome peptide array-based system (PamGene12).
Results
We demonstrate large scale abnormalities in activity (fold change >1.15 or <0.85) of kinases in depressed subjects who die by suicide, including p53 related protein kinase (PRPK), AMP-activated protein kinase (AMPK), and protein kinase C (PKCd). The kinase data undergo connectivity mapping using the Library of Integrated Network-based Cellular Signatures (LINCS) database. Connectivity mapping links changes in patterns of gene expression induced by altered kinase network activity in depressed-suicide subjects, with chemical perturbagens that induce similar and opposing patterns of change in gene expression.
Conclusions
Kinases have the potential to modulate complex behaviors like suicide but are yet to be exploited therapeutically. Studying the kinome will increase our understanding of the neurobiology of suicide and may lead to the development of novel interventions for suicide.
Original language | English (Ireland) |
---|---|
Journal | Biological Psychiatry |
Volume | 85 |
Issue number | 10_S161 |
Publication status | Published - 15 May 2019 |