The role of FKBP5 in transcriptional regulation and in shaping cellular pathways of psychopharmaca action
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vor 8 Jahren
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.
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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