Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD

Abstract

Genetic and epigenetic alterations in FK506-binding protein 5 ( FKBP5) have been associated with increased risk for psychiatric disorders, including post-traumatic stress disorder (PTSD). Some of these common variants can increase the expression of FKBP5, the gene that encodes FKBP51. Excess FKBP51 promotes hypothalamic-pituitary-adrenal (HPA) axis dysregulation through altered glucocorticoid receptor (GR) signaling. Thus, we hypothesized that GR activity could be restored by perturbing FKBP51. Here, we screened 1280 pharmacologically active compounds and identified three compounds that rescued FKBP51-mediated suppression of GR activity without directly activating GR. One of the three compounds, benztropine mesylate, disrupted the association of FKBP51 with the GR/Hsp90 complex in vitro. Moreover, we show that removal of FKBP51 from this complex by benztropine restored GR localization in ex vivo brain slices and primary neurons from mice. In conclusion, we have identified a novel disruptor of the FKBP51/GR/Hsp90 complex. Targeting this complex may be a viable approach to developing treatments for disorders related to aberrant FKBP51 expression.

Structure, Function, and Regulation of the Hsp90 Machinery

“…Intriguingly, treatment of human cells led to a selective destabilization of SHRs, making it an interesting candidate for diseases caused by misregulated GR activity (Patwardhan et al 2013). Most recently, a substance specifically disrupting the Hsp90:GR: FKBP51 complex was found, which did not impede the binding of FKPB52 to Hsp90 (Sabbagh et al 2018). This is of significant interest, given the described association of FKBP51 with mood affective disorders.…”

Hippocampal Neurogenesis Is Enhanced in Adult Tau Deficient Mice

“…10% charcoal-stripped FBS was used throughout (Life Technologies, Carlsbad, CA, USA). Cells were lysed and subjected to Dual-Luciferase reporter assay kit (Promega, Madison, WI, USA) as previously described [32,33]. A parallel experiment was lysed in MPER and 30 µg of lysate was evaluated by Western blotting, as we have done previously [32], using Tau 12 (kind gift from Nicholas Kanaan) and Actin (Sigma Aldrich, St. Louis, MO, USA) antibodies.…”

<p>Sleep, a Governor of Morbidity in PTSD: A Systematic Review of Biological Markers in PTSD-Related Sleep Disturbances</p>

“…Central regulation of this process is facilitated by the HPA-axis, functional alterations to which have been linked to psychiatric conditions such as depression, anxiety and PTSD. 38,39 Following exposure to a stressor, neurons of the paraventricular nucleus (PVN) in the hypothalamus respond by releasing corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) into hypophysial portal blood, causing the pituitary gland to release adrenocorticotrophic hormone (ACTH) into the general circulation. 40 ATCH acts on the adrenal glands to stimulate the synthesis and release of glucocorticoids, of which cortisol is the primary in humans.…”

“…46 Despite controversy over the exact functional response of the HPA-axis in PTSD, inhibitors of FKPB51, the functional protein produced in response to FKBP5 expression, are being developed with the aim to use as novel therapies in the treatment of psychiatric conditions such as PTSD and depression. 39 Further understanding of the HPA-axis, GRs and associated molecular partners, in psychiatric disorders, is required before any therapeutic potential of such FKBP51 antagonists can be discussed. However, by inhibiting the activity of FBKP51 without activating GRs themselves, such antagonists may prove useful experimental tools to aid in this endeavour.…”

“…However, by inhibiting the activity of FBKP51 without activating GRs themselves, such antagonists may prove useful experimental tools to aid in this endeavour. 39…”