Post-traumatic stress disorder (PTSD) can develop after exposure to severe psychological trauma, leaving patients with debilitating anxiety, nightmares, and flashbacks. In this study, scientists discovered new proteins associated with PTSD and how they function and interact in neurons. This has led to new target molecules and pathways for potential new drugs.
Post-traumatic stress disorder (PTSD) was initially identified in soldiers exposed to war trauma, but the concept of psychological trauma has evolved to encompass any life-threatening event or physical integrity, in both military and civilian settings.
PTSD is characterized by symptoms such as flashbacks, nightmares, avoidance of situations that resemble the trauma, hypervigilance, and insomnia. Approximately 20% of war veterans and victims of physical assault are affected, and about 2% of U.S. military personnel have PTSD symptoms. In Canada, it is estimated that 9% of the general population will experience the disorder at some point in their lives.
Standard treatment includes cognitive-behavioral psychotherapy (CBT), which focuses on desensitizing patients to traumatic memories through gradual, repeated exposure.
Although medications such as sertraline and paroxetine, both antidepressants, are FDA-approved for PTSD, they are less effective than therapy, and full recovery is rare.
What distinguishes PTSD from other psychiatric disorders is that it is triggered by a specific event, followed by an interval before symptoms appear. This interval creates a unique opportunity for preventive interventions.
However, the molecular mechanisms underlying PTSD are not yet fully understood. One promising pathway involves the protein FKBP5, which downregulates the glucocorticoid receptor (GR). When FKBP5 levels are high, it reduces the effectiveness of GRs, promoting glucocorticoid resistance, which affects the stress response.
Previous studies have hypothesized that FKBP51, a variant of FKBP5, binds to the GR, preventing it from functioning properly. Recently, researchers from the University of Toronto provided further evidence of this interaction in a study published in The Journal of Clinical Investigation.
They proposed that the GR-FKBP51 protein complex would be more present in PTSD patients and mice exposed to trauma. A total of 22 human patients with PTSD were recruited from specialized clinics and hospitals, while another 22 healthy controls came from public advertisements. This is common in clinical studies that seek a comparison between people affected by a condition and healthy individuals.
To assess PTSD, the PCL-C checklist, which is a self-report questionnaire based on DSM-IV criteria, was used, in addition to a structured clinical interview called MINI. Excluding people with other physical or psychiatric illnesses is intended to ensure that the symptoms assessed are related to PTSD and not to other conditions.
Next, they collected blood from the participants. The blood sample allows the collection of lymphocytes, which are immune cells used for molecular and genetic analysis. The use of the Ficoll-Paque method to isolate lymphocytes is a standard technique that separates these cells from the blood for further analysis, such as the detection of genetic or molecular markers relevant to PTSD.
The mice used in the study are C57BL/6 mice, a very common model in biomedical research due to their well-characterized genetics and similarities with human biological processes.
The surgery to implant cannulas in areas of the mice's brains, such as the amygdala and motor cortex, serves to manipulate these regions, making detailed studies on how these areas influence behaviors associated with fear and stress, important in the study of PTSD. The blood and brains of these animals were also analyzed.
With the analysis of the results, the hypothesis was tested and validated: mice and humans with PTSD showed elevated levels of the protein complex GR-FKBP51.
Summary of molecular pathways within the neuron in the presence of TAT-GRpep. (A) TAT-GRpep can pass the blood-brain barrier and enter the neuron due to the TAT sequence. (B) Once TAT-GRpep enters the cell, it competes with GR for binding to FKBP51. (C) More GR is phosphorylated and (D) consequently, more GR can bind to FKBP52. (E) Both events are responsible for the translocation of GR to the nucleus, where it binds to specific DNA sequences and promotes transcription.
To test for the reversal of this effect, the researchers created a peptide that disrupts the interaction between GR and FKBP51. In tests with traumatized mice, the peptide not only decreased fearful behavior (such as freezing in the face of threatening stimuli) but also restored normal GR function.
This allowed GR to return to the cell nucleus, where it regulates genes essential for the stress response, such as the 14-3-3ε gene.
These findings indicate that the interaction between GR and FKBP51 may be a crucial factor in the development of PTSD, suggesting that this protein complex could be used as a biomarker to diagnose the disorder and as a therapeutic target for new treatments.
The study opens new possibilities for preventive therapies and treatments that can reverse the changes caused by trauma, improving the brain's response to stress.
READ MORE:
The glucocorticoid receptor–FKBP51 complex contributes to fear conditioning and posttraumatic stress disorder
Haiyin Li, et al.
J Clin Invest. 2020; 130(2) : 877–889. https://doi.org/10.1172/JCI130363.
Abstract:
Posttraumatic stress disorder (PTSD) can develop after exposure to severe psychological trauma, leaving patients with disabling anxiety, nightmares, and flashbacks. Current treatments are only partially effective, and the development of better treatments is hampered by limited knowledge of molecular mechanisms underlying PTSD. We have discovered that the glucocorticoid receptor (GR) and FK506 binding protein 51 (FKBP51) form a protein complex that is elevated in PTSD patients compared with unaffected control subjects, subjects exposed to trauma without PTSD, and patients with major depressive disorder (MDD). The GR-FKBP51 complex is also elevated in fear-conditioned mice, an aversive learning paradigm that models some aspects of PTSD. Both PTSD patients and fear-conditioned mice had decreased GR phosphorylation, decreased nuclear GR, and lower expression of 14-3-3ε, a gene regulated by GR. We created a peptide that disrupts GR-FKBP51 binding and reverses behavioral and molecular changes induced by fear conditioning. This peptide reduces freezing time and increases GR phosphorylation, GR-FKBP52 binding, GR nuclear translocation, and 14-3-3ε expression in fear-conditioned mice. These experiments demonstrate a molecular mechanism contributing to PTSD and suggest that the GR-FKBP51 complex may be a diagnostic biomarker and a potential therapeutic target for preventing or treating PTSD.
Commentaires