An IBioBA research group, in collaboration with the Max Planck Institute of Psychiatry, conducted studies to evaluate the effects of antidepressants and found a molecular mechanism that contributes to explain the basis of their functioning and could be the starting point for the development of personalized drugs.
The results were published in the journal Molecular Psychiatry of the Nature group.
Under the accelerated pace at which we live, especially in big cities, the word ‘stress’ is practically something naturalized. But what does stress produce at the molecular level in our organism? How does ‘living under stress’ impact at the cellular level? A scientific publication of our Institute in the journal Molecular Psychiatry describes the mechanism by which tricyclic antidepressants act as a molecular switcher favoring the restoration of the sensitivity of the glucocorticoid receptor (GR), a protein that is affected in stress-associated diseases. This work takes on special relevance with the current incidence of stress cases resulting from confinement, care of sick patients, fears and other consequences generated by the COVID-19 pandemic.
The research group “Physiopathological impact and molecular mechanisms of inflammatory mediators”, led by Ana Liberman and Eduardo Arzt, has been working for many years on stress-related diseases, particularly in the field of psychiatric diseases such as depression, bipolar disorders, post-traumatic stress, among others. They have been pioneers in describing many of the mechanisms of action of glucocorticoids within stress circuits and, as Arzt, director of the Institute and head of the research group, points out, in their important anti-inflammatory actions.
“Stress is a normal and necessary mechanism for the body, it is a biological function that is triggered by a stressor event and activates the hypothalamic-pituitary-adrenal (HPA) axis: the stressor event is registered by our brain through the senses and this leads to stimulation of the adrenal cortex, which releases glucocorticoids into the bloodstream”, explains postdoctoral fellow Ludmila Budziñski, first author of the paper together with PhD student Clara Sokn.
Once the stimulus is generated, a shutdown occurs: the stimulus itself has a negative feedback that causes it to inhibit. That is to say that glucocorticoids act again in higher pathways (they return to the first point of the axis, the hypothalamus) to inhibit its production and end the process. “When this process is deregulated, it is as if we live our lives with a fire alarm on. You don’t sleep well, you don’t eat well, you’re not well”, Ludmila adds. Continuous stress leads to dysregulation of the HPA axis and this can lead to the onset of stress-associated diseases such as depression and numerous psychiatric disorders.
Animals do not suffer post-traumatic stress: once the zebra manages to flee from the lion, for example, it is calm in a pasture and goes back to doing what it was doing before feeling danger in the presence of its predator. Dysregulation of the system occurs in the human brain. What produces stress at the molecular level is complex, it is a chain of signals that are activated and put our organism on alert: glucocorticoids are able to act in all the cells of our body thanks to the glucocorticoid receptor, which binds to them and migrates to the cell nucleus, where it fulfills its biological function of regulating genes, which execute the ‘alert’ signal (which translates as the response to stress).
The GR, in turn, has a negative regulator: the protein FKBP51, which is responsible for inhibiting (or not allowing) its migration to the nucleus. “We studied FKBP51 in particular because it is known that high levels of this protein are associated with stress-related diseases; and these diseases, in turn, are related to glucocorticoid receptor resistance. It is as if there is a stimulus and the GR cannot respond correctly”, explains Ludmila.
“Hyperactivity of the HPA axis in patients with psychiatric disorders is related to impaired glucocorticoid receptor function and thus to a decreased ability to respond appropriately to stress. FKBP51 is an important inhibitor of the receptor activity and in fact increased expression is associated with psychiatric disorders -as described in detail in previous work of our collaborators in this report at the Max Planck Institute in Munich-, so this protein has become an important therapeutic target”, adds Ana Liberman, head of the research project.
In addition to this, FKBP51 is a target of SUMOylation (one of the various post-translational modifications, or those chemical changes that occur after the protein is synthesized by the ribosomes), “that is to say that the SUMO peptide binds to it and this is necessary for it to exert its inhibitory effect”, clarifies Ana. In turn, in order to be SUMOylated, FKBP51 needs the SUMOylation enzymatic machinery, particularly PIAS4. This enzyme is what allows FKBP51 to be specifically and effectively SUMOylated.
In this context, it was discovered some time ago that antidepressants modulate the function of the glucocorticoid receptor. Based on this knowledge, the team wondered whether antidepressants might be modulating the SUMOylation of FKBP51 and thus affecting its role as a negative regulator of GR.
The work describes that tricyclic antidepressants inhibit FKBP51 SUMOylation, and that this inhibition caused by the decreased interaction of FKBP51 with PIAS4, directly impacts on the negative regulatory functions of FKBP51 on GR (which is deregulated in stress-related diseases). Thus, the action of antidepressants as repressors of FKBP51 SUMOylation acts as a molecular switch that helps to restore glucocorticoid receptor sensitivity: “When FKBP51 fails to SUMOylate, it cannot inhibit the glucocorticoid receptor, and so we can restore its activity”, says Liberman.
“What we observed is that antidepressants, because they are preventing the interaction between FKBP51 and PIAS4, cause FKBP51 to be less SUMOylated. As it is less SUMOylated, it interacts less with the glucocorticoid receptor complex, so this receptor is able to migrate to the nucleus more freely and regulate the expression of its target genes”, Budziñski explains.
A long-standing collaboration In order to “screen” or evaluate the effects of antidepressants, the Argentine group had the collaboration of researchers at the Max Planck Institute of Psychiatry in Munich. Ludmila traveled there in two occasions -one financed by a fellowship of the Bunge and Born Foundation- to conduct experiments and measure the effect of antidepressants on SUMOylation in mice samples. “This work is part of the continuity of our historical collaboration with the Max Planck Institute of Psychiatry in Munich, of which I am an External Scientific Member and through which more than 20 thesis students and researchers from our group have visited over the years”, recalls Eduardo Arzt.
In sum, this publication provides a potential new avenue of intervention of antidepressants that contributes to explain how they favor the restoration of homeostasis -or balance- of the system, which is affected in stress-associated psychiatric diseases. Considering the growing need to find new strategies for the treatment of this type of diseases, especially in the current pandemic situation, “the study of the molecular mechanism involved in the modulation of FKBP51 activity by SUMO conjugation and the identification of possible inhibitors of its SUMOylation is of utmost importance”, says Ana Liberman.
“Much remains to be discovered about how these drugs work at the molecular level, and this paper provides information about their mechanisms of action. From our side, we seek to provide knowledge about signaling pathways that could be the basis for improving drug design or contributing to the application of more personalized therapies”, says Ludmila regarding the importance of this publication.
Having a deeper understanding of the action of these drugs could contribute in the future to the development of new antidepressant drugs with new mechanisms of action and fewer side effects; “especially in patients where the expression or activity of FKBP51 is increased, so, without a doubt, these findings contribute to understanding the importance of personalized medicine”, concludes Ana.