Proteomic profiling of postmortem prefrontal cortex identifies molecular signatures of borderline personality disorder

Borderline personality disorder (BPD) is characterized by a severe pattern of symptoms including emotional instability, impulsivity, and unstable interpersonal relationships. A complex interplay between genetics and environmental factors has been hypothesized to be associated with the development of BPD. While neuroimaging studies have identified structural and functional changes in the brain, and genome-wide association studies described some first genetic risk loci, the neurobiological underpinnings of BPD remain poorly described. To better understand disease processes in BPD, we performed a molecular characterization of the prefrontal cortex (PFC), an important brain region for emotion and impulsivity regulation in BPD. Label-free brain proteomics was performed in postmortem human brain tissue in a sample of n=79, with a case group of n=36 individuals with BPD and a control group of n=43 individuals without BPD. Differential protein expression analysis suggested protein-level dysregulation of mitochondrial, immunological, and neuroplasticity pathways. Network analyses identified a BPD-associated co-expression module enriched for protein secretory and synaptic processes that is druggable with selective serotonin reuptake inhibitors. Additional druggability analyses on protein-protein interaction networks and drug-repositioning analysis suggested VEGF signaling as a potential pharmacologic target in BPD. When we integrated BPD proteomic signatures with genomic and proteomic datasets of common comorbidities such as posttraumatic stress disorder and major depressive disorder, we observed a strong convergent overlap across disorders, with STX7 and RTN4 identified as conserved, differentially expressed proteins. Our study provides first insights into proteomic signatures of BPD in the brain, suggests potential pharmacological targets, and provides evidence for convergent protein signatures across BPD and common comorbidites.