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.

中文翻译：

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针对FKBP51 / GR / Hsp90复合物，以识别抑郁症和PTSD的功能相关治疗

FK506结合蛋白5（FKBP5）的遗传和表观遗传学改变与精神疾病（包括创伤后应激障碍（PTSD））的风险增加相关。这些常见变体中的一些可以增加FKBP5的表达，FKBP5是编码FKBP51的基因。过量的FKBP51通过改变糖皮质激素受体（GR）信号传导促进下丘脑-垂体-肾上腺（HPA）轴失调。因此，我们假设可以通过扰动FKBP51恢复GR活性。在这里，我们筛选了1280种药理活性化合物，并鉴定了3种在不直接激活GR的情况下挽救了FKBP51介导的GR活性抑制作用的化合物。三种化合物之一甲磺酸苄索平破坏了FKBP51与GR / Hsp90复合物的缔合体外。此外，我们表明苯甲曲平从该复合物中去除FKBP51可以恢复离体脑切片和小鼠原代神经元中的GR定位。总之，我们已经确定了FKBP51 / GR / Hsp90复合物的新型破坏者。靶向这种复合物可能是开发治疗与FKBP51异常表达有关的疾病的可行方法。