Stress, generally defined as mental or emotional strain, primarily involves the hypothalamic-pituitary-adrenal (HPA) axis. In this process, hypothalmic neurons release corticotropin-releasing hormone, which indirectly leads to the secretin of glucocorticoids, such as cortisol, into the bloodstream. Circulating glucocorticoids act on receptors throughout the body, including the intracellular glucocorticoid receptor (GR). The GR participates in a negative feedback loop with FK506 binding protein 51, or FKBPS, a co-chaperone protein that inhibits GR signalling in response to stress. This has significant implications for health and disease.
FKBP5-mediated pathway of stress
FKBP5 regulates GR sensitivity by binding to co-chaperone proteins of the receptor, lowering GR glucocorticoid-binding affinity and attenuating GR transcriptional activity. Upon glucocorticoid binding, FKBP5 is replaced by FK506-binding protein 52 (FKBP52/FKBP4), a co-chaperone protein with opposing functions.
The GR controls FKBP5 gene transcription by 1) forming a homodimer that binds to glucocorticoid response element (GRE) sequences in introns of the FKBP5 gene, and 2) interacting as a monomer with other transcription factors. Thus, glucocorticoid release promotes FKBP5 expression, initiating the negative feedback loop and enabling cortisol self-regulation.
Upstream factors of FKBP5
Chronic stress leads to elevated glucocorticoid levels. Gene-interaction studies have demonstrated that alleles associated with higher FKBP5 expression induce prolonged cortisol response and increase the risk of stress-related psychiatric disorders following trauma. This has implicated FKBP5 disinhibition in impaired cognitive processing. FKBP5 polymorphisms disrupt HPA axis activity and thus the glucocorticoid negative feedback loop, causing variable susceptibility to major depressive disorder (MDD), bipolar disorder, post-traumatic stress disorder (PTSD), and suicide risk. A large cross-sectional study observed associations between four single nucleotide polymorphisms (SNPs) within the FKBP5 gene and the severity of child abuse as a predictor of adult PTSD symptoms. One of the most commonly described polymorphisms is rs1360780 in intron 2 of FKBP5. In particular, the rs1360780 T allele upregulates FKBP5 mRNA expression and inducing excessive GR activation, causing GR resistance and an extended cortisol response to stressors in healthy carriers. The variable effects of these polymorphisms reconciles the broad spectrum in the magnitude of HPA axis disruption in patients suffering from disorders such as MDD and PTSD.
Additionally, epigenetic modifications regulate the glucocorticoid regulation pathway through the GR and FKBP5 genes. In particular, considered a protective influence on stressors and their appraisal, maternal behaviour tested in rodents has been found to influence hippocampal GR expression in the offspring. Specifically, nurturing maternal behaviour induces long-lasting epigenetic alterations, such as decreased methylation upstream of the gene encoding the GR, reducing stress reactivity. Conversely, evidence has shown that DNA methylation of the FKBP5 gene increases stress susceptibility. In rs1360780 T allele carriers, demethylation in intron 7 of the functional GRE is associated with enhanced FKBP5 transcription and subsequent GR resistance. This leads to further disinhibition of FKBP5 transcriptional regulation.
The pathological relevance of FKBP5 disinhibition to the development of psychiatric disease in humans presents a potent therapeutic target. Through the use of FKBP5 gene knockouts (FKBP5 KO) in animal studies, scientists have elucidated that relative to wild-type controls, FKBP5 KO demonstrated increased resilience due to improved stress hormone signalling and stress-coping behaviours. These findings have propelled the discovery of efficacious pharmacological agents targeting FKBP5 activity. Previously, most FKBP5 ligands were unselective, with significant off-target interaction with the similar binding sites of homologous FKBP4. Recently, scientists have elucidated a class of potent and selective FKBP5 inhibitors known as SAFits, which have been found to promote HPA axis regulation and stress-coping behaviours. This evidence may potentially inform mechanistically new therapeutics for stress-related psychiatric diseases.
Though the etiology of psychiatric diseases remains unclear, existing literature supports the role of gene-environment interactions in causing FKBP5 disinhibition and increased vulnerability to neurological illnesses. Excessive stress has long-term consequences for health and disease, particularly in a genetically vulnerable population, presenting FKBP5 and glucocorticoid dysregulation as a pertinent therapeutic target.
Written by Takhliq Amir, Owen Luo
References may be found in the journal.