Characterization of FKBP51 and FKBP52 knock-out mice
Single nucleotide polymorphisms (SNPs) in the gene of FKBP5 were found to be strongly associated with the duration of depressive episodes and as well as with reduced HPA axis hyperactivity during a depressive episode in two independent samples. Interestingly, a functional correlation was also observed on the molecular level: Patients with the associated genotype responded faster to antidepressant treatment and displayed also significantly higher FKBP51 protein levels in their lymphocytes compared to other genotypes.
FKBP51 was included as a candidate gene in this genotyping study based on our previous findings that characterized this cochaperone as an important regulatory protein of GR: We demonstrated that increased levels of FKBP51 resulted in an inhibition of cortisol-dependent GR-transactivation. In contrast to FKBP51, its close homologue FKBP52 had no effect on GR in mammalian cells. Through replacing FKBP51 in the hsp90 heterocomplex, FKBP52 is able to abolish the inhibitory effect of FKBP51 on GR. Accordingly, the activity of GR appears to be determined by the ratio of FKBP51 to FKBP52 in the cell.
To evaluate the role of FKBP51 and FKBP52 on the organismic level, we are investigating FKBP51 and FKBP52 knock-out mice (kindly provided by David Smith, USA) for their HPA axis-status and -reactivity as well as for their response to antidepressant treatment. Several behavioural tests have been developed in the mouse to measure the reaction to antidepressant drugs. We are starting with two tests, namely the tail suspension and the forced swimming test. Both tests are based on the “searching-waiting strategy” which is based on the hypothesis that rodents, when faced with an inescapable threatening situation, in principle display two different kinds of behaviour, i.e. either they become active to escape the situation (searching behaviour) or they immobilize (waiting behaviour).
In addition, we plan to determine serum levels of corticosterone and ACTH under basal and stress conditions in these mice. These studies also set the stage for evaluating the FKBP51 and FKBP52 targeting drugs developed in the RG Hausch.
Research groups involved:
RG Theo Rein: Yuchen Han
RG Ulrike Schmidt: Sergej Asmus
RG Felix Hausch: Christian Kozany
Publications:
Gaali S, Kozany C, Hoogeland B, Klein M, Hausch F (in press) Facile Synthesis of a Fluorescent Cyclosporin A Analogue to study Cyclophilin 40 and Cyclophilin 18 Ligands. ACS Med. Chem. Lett.
Wochnik, G.M., J. Rüegg, J., G.A. Abel, U. Schmidt, F. Holsboer, and T. Rein (2005) FKBP51 and FKBP52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J Biol. Chem. 280:4609-4616
Binder, E.B., D. Salyakina, P. Lichtner, G.M. Wochnik, M. Ising, B. Pütz, S. Papiol, S. Seaman, S. Lucae, M.A. Kohli, T. Nickel, H.E. Künzel, B. Fuchs, M. Majer, A. Pfennig, N. Kern, J. Brunner, S. Modell, T. Baghai, T. Deiml, P. Zill, B. Bondy, R. Rupprecht, T. Messer, O. Köhnlein, H. Dabitz, T. Bruckl, N. Müller, H. Pfister, R. Lieb, J.C. Mueller, E. Lohmussaar, T.M. Strom, T. Bettecken, T. Meitinger, M. Uhr M, T. Rein, F. Holsboer, and B. Müller-Myhsok B. (2004) Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nature Genetics 36:1319-25
Wochnik, G.M., Young, J. C., Schmidt, U., Holsboer, F., Hartl, F. U., and T. Rein (2004) Inhibition of GR-Mediated Transcription by p23 Requires Interaction with Hsp90. FEBS Letters 560:35-38
Brychzy, A., Rein, T., Winklhofer, F. K., Ulrich Hartl, F. U., Young, J. C. and W. M. J. Obermann (2003) The cofactor Tpr2 combines two TPR domains and a J domain to regulate the Hsp70/Hsp90 chaperone system. EMBO J. 22: 3613-3623
Rosenhagen, M. C., Sőti, C., Schmidt, U., Wochnik, G. M., Hartl, F. U., Holsboer, F., Young, J. C., and T. Rein (2003) The Hsp90-targeting drug cisplatin selectively inhibits steroid receptor activation. Mol. Endo. 17:1991-2001
Rosenhagen, M. C., Young, J. C., Wochnik, G. M., Herr, A., Schmidt, U., Hartl, F. U., Holsboer, F., and T. Rein (2001) Synergistic inhibition of the glucocorticoid receptor by radicicol and benzoquinone ansamycins. Biological Chemistry, 382: 499-504
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