Association of FKBP51 with priming of autophagy pathways and mediation of antidepressant treatment response: evidence in cells, mice, and humans.
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.


RESULTS
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. Please see later in the article for the Editors' Summary.
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
Nils C
NC
Gassen
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Jakob
J
Hartmann
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
Jürgen
J
Zschocke
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Jens
J
Stepan
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
Kathrin
K
Hafner
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
Andreas
A
Zellner
Department of Clinical Research, Max Planck Institute of Psychiatry, Munich, Germany.
Thomas
T
Kirmeier
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
Lorenz
L
Kollmannsberger
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Klaus V
KV
Wagner
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Nina
N
Dedic
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Georgia
G
Balsevich
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Jan M
JM
Deussing
Department of Clinical Research, Max Planck Institute of Psychiatry, Munich, Germany.
Stefan
S
Kloiber
Department of Clinical Research, Max Planck Institute of Psychiatry, Munich, Germany.
Susanne
S
Lucae
Department of Clinical Research, Max Planck Institute of Psychiatry, Munich, Germany.
Florian
F
Holsboer
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Matthias
M
Eder
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
Manfred
M
Uhr
Department of Clinical Research, Max Planck Institute of Psychiatry, Munich, Germany.
Marcus
M
Ising
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
Mathias V
MV
Schmidt
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany.
Theo
T
Rein
D000328:Adult; D000639:Amitriptyline / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics*; D000071186:Beclin-1; D001773:Blood Cells / Q000378:metabolism; D003863:Depression / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D017374:Paroxetine / Q000494:pharmacology / Q000627:therapeutic use; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D022021:Tacrolimus Binding Proteins / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
D000928:Antidepressive Agents; D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D000639:Amitriptyline; D017374:Paroxetine; D022021:Tacrolimus Binding Proteins