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

Authors

Jonathan J. Sabbagh, University of South Florida
Ricardo A. Cordova, University of South FloridaFollow
Dali Zheng, University of South Florida
Marangelie Criado-Marrero, University of South FloridaFollow
Andrea Lemus, University of South FloridaFollow
Pengfei Liang, University of South FloridaFollow
Jeremy D. Baker, University of South Florida
Bryce A. Nordhues, University of South Florida
April L. Darling, University of South FloridaFollow
Carlos Martinez-Licha, University of South Florida
Daniel A. Rutz, University of South Florida
Shreya Patel, University of South FloridaFollow
Johannes Buchner, University of South Florida
James W. Leahy, University of South FloridaFollow
John Koren III, University of South FloridaFollow
Chad Anthony Dickey, University of South Florida
Laura J. Blair, University of South FloridaFollow

Document Type

Article

Publication Date

8-2018

Digital Object Identifier (DOI)

https://doi.org/10.1021/acschembio.8b00454

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.

Was this content written or created while at USF?

Yes

Citation / Publisher Attribution

ACS Chemical Biology, v. 13, issue 8, p. 2288-2299

Scholar Commons Citation

Sabbagh, Jonathan J.; Cordova, Ricardo A.; Zheng, Dali; Criado-Marrero, Marangelie; Lemus, Andrea; Liang, Pengfei; Baker, Jeremy D.; Nordhues, Bryce A.; Darling, April L.; Martinez-Licha, Carlos; Rutz, Daniel A.; Patel, Shreya; Buchner, Johannes; Leahy, James W.; Koren, John III; Dickey, Chad Anthony; and Blair, Laura J., "Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD" (2018). Chemistry Faculty Publications. 62.
https://digitalcommons.usf.edu/chm_facpub/62