P307. Dysregulated Kinase Networks in Major Depressive Disorder

Background
Major depressive disorder (MDD) is a chronic debilitating disorder with an unknown etiology. MDD is associated with the altered expression and activity of protein kinases, which regulate signaling in complex biological networks. Abnormalities in kinase signaling are involved in the pathophysiology of MDD. However, of the hundreds of kinases expressed in human brain, only a small number have been studied in MDD.
Methods
To address this gap in our knowledge, we assayed the activity of the serine/threonine subfamily of protein kinases in postmortem tissue from the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) using an array-based platform (Pamgene12). Relative changes in kinase activity were assessed in MDD subjects, MDD subjects who died by suicide and non-psychiatrically ill controls (pooled samples, male n= 2-9/grp; female n= 3-9/grp). Kinome data was analyzed using multiple bioinformatic pipelines (UKA, KRSA) to identify kinases with significantly altered activity (peptide signal intensity threshold: log 2-fold change ±0.2).
Results
Significant kinases like PKA (Z-score=2.42) and AKT (Z-score=2.31), which were previously implicated in MDD, were also identified in our study. We also identified novel kinases including FRAY (Z-score=2.14), whose role in MDD has yet to be elucidated. In the DLPFC, global kinase activity was downregulated in MDD compared to controls. Conversely, in the ACC global kinase activity was increased in MDD, suggesting that region-specific differences in kinase activity in MDD.
Conclusions
Studying the activity of protein kinases, which are essential for cellular signal transduction, provides valuable insight dysregulated biological processes that are implicated in the neurobiology of MDD disorder.