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Abstract:
Background: FK506 binding protein 51 (FKBP51) is an Hsp90 co-chaperone
and regulator of the glucocorticoid receptor, and consequently of stress
physiology. Clinical studies suggest a genetic link between FKBP51 and
antidepressant response in mood disorders; however, the underlying
mechanisms remain elusive. The objective of this study was to elucidate
the role of FKBP51 in the actions of antidepressants, with a particular
focus on pathways of autophagy.
Methods and Findings: Established cell lines, primary neural cells,
human blood cells of healthy individuals and patients with depression,
and mice were treated with antidepressants. Mice were tested for several
neuroendocrine and behavioral parameters. Protein interactions and
autophagic pathway activity were mainly evaluated by
co-immunoprecipitation and Western blots. We first show that the effects
of acute antidepressant treatment on behavior are abolished in FKBP51
knockout (51KO) mice. Autophagic markers, such as the autophagy
initiator Beclin1, were increased following acute antidepressant
treatment in brains from wild-type, but not 51KO, animals. FKBP51 binds
to Beclin1, changes decisive protein interactions and phosphorylation of
Beclin1, and triggers autophagic pathways. Antidepressants and FKBP51
exhibited synergistic effects on these pathways. Using chronic social
defeat as a depression-relevant stress model in combination with chronic
paroxetine (PAR) treatment revealed that the stress response, as well as
the effects of antidepressants on behavior and autophagic markers,
depends on FKBP51. In human blood cells of healthy individuals, FKBP51
levels correlated with the potential of antidepressants to induce
autophagic pathways. Importantly, the clinical antidepressant response
of patients with depression (n = 51) could be predicted by the
antidepressant response of autophagic markers in patient-derived
peripheral blood lymphocytes cultivated and treated ex vivo
(Beclin1/amitriptyline: r = 0.572, p = 0.003; Beclin1/PAR: r = 0.569, p
= 0.004; Beclin1/fluoxetine: r = 0.454, p = 0.026; pAkt/amitriptyline: r
= -0.416, p = 0.006; pAkt/PAR: r = -0.355, p = 0.021; LC3B-II/PAR: r =
0.453, p = 0.02), as well as by the lymphocytic expression levels of
FKBP51 (r = 0.631, p < 0.0001), pAkt (r = -0.515, p = 0.003), and
Beclin1 (r = 0.521, p = 0.002) at admission. Limitations of the study
include the use of male mice only and the relatively low number of
patients for protein analyses.
Conclusions: To our knowledge, these findings provide the first evidence
for the molecular mechanism of FKBP51 in priming autophagic pathways;
this process is linked to the potency of at least some antidepressants.
These newly discovered functions of FKBP51 also provide novel predictive
markers for treatment outcome, consistent with physiological and
potential clinical relevance.
