The role of FKBP5 in transcriptional regulation and in shaping cellular pathways of psychopharmaca action

Episode von Fakultät für Chemie und Pharmazie - Digitale Hochschulschriften der LMU - Teil 06/06 von Ludwig-Maximilians-Universität München · 10. März 2016

FK506 binding protein 5 (FKBP5) has been linked to stress related diseases and treatment response in depression (Binder et al., 2004). The corresponding protein FKBP51 was first identified as co-chaperone of HSP90 in a complex with steroid hormone receptors, where it diminishes hormone affinity and nuclear translocation efficiency of the receptors (Pratt and Toft, 1997; Wochnik et al., 2005). With FKBP5 transcription being induced by glucocorticoid signalling, an ultra-short feedback loop is provided for regulation and termination of GR activity. Dysregulation of this ultra-short feedback loop interferes with the stress hormone regulation and likely contributes to the association of FKBP5 with stress-related psychiatric disorders. Recently, important actions of FKBP51 beyond glucocorticoid signalling have been characterised in shaping the posttranslational regulation of certain molecular pathways in response to treatment with particular psychopharmaca (Gassen et al., 2014, 2015).

As a contribution to elucidating the role of FKBP5 in stress related diseases, a two-sided approach was taken in this study by analysing the role of FKBP5 in regulation of transcription and in calibrating the responsiveness of these pathways to psychopharmacological treatment.

To elucidate the transcriptional effects of FKBP5 in an unbiased approach, the expression profile of mice with deleted FKBP5 and their litter mates with functional FKBP5 were compared. A marked difference in glyoxalase-1 (GLO1) transcription was observed with higher GLO1 transcription in mice with deleted FKBP5, which was reflected by about two-fold more GLO1 protein in these mice. The efforts in deciphering the role of FKBP5 in elevation of GLO1 expression led to the identification of a duplication of the GLO1 gene inherent to mice with deleted FKBP5; this likely explains the enhanced GLO1 expression in these mice. This observation exemplifies the flanking gene problem and is a note of caution for interpreting data from conventionally generated knock-out mice. Overall, deletion of FKBP5 did not markedly change gene expression.

In the second part of this thesis, the molecular effects of psychopharmacologic drugs were profiled for their dependency on FKBP51 function to modulate intracellular pathways relevant for treatment outcome in a cellular FKBP5 knockout model. For this purpose, psychopharmaca from the classes of SSRIs, SSNRIs, TCAs, atypical antidepressants, mood stabilisers, and NMDA receptor antagonists were analysed. In addition to GSK3β and AKT, which were reported to interact with and be targeted by FKBP51 recently (Gassen et al., 2015; Pei et al., 2009), ERK was identified as a novel kinase interacting with and being targeted by FKBP51 in this work. With GSK3β, AKT, and ERK, three major kinases were observed to be regulated by psychopharmaca. The effects were not homogeneous across all psychopharmaca and only loosely followed drug classes. Moreover, regulation of these kinases as well as their downstream targets was non-uniformly influenced by FKBP51. With FKBP51 being a stress induced gene, this transcriptional mechanism efficiently links the stress response to the regulation of the targets analysed in this work. Moreover, markers of autophagy, a cellular degradation process which has been linked to neurotransmission, were detected to be regulated by valproic acid (VPA), a mood stabiliser with HDAC inhibitory activity. VPA, as well as a second HDAC inhibitor butyric acid (BUT) enhanced the transcription of late and delayed autophagy markers controlled by FOXO3 signalling.

Considering the versatile action of FKBP51 on targets analysed in this work, the list of proteins modulated by FKBP5 seems by far not complete. The diversity of effects evoked by different psychopharmaca hints to superimposed molecular effects underlying treatment outcome. Better understanding of pathway responsiveness could yield molecular markers for personalised medication that could be utilised to improve treatment outcome in stress related psychiatric diseases.

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