Association of FKBP51 with Priming of Autophagy Pathways and Mediation of Antidepressant Treatment Response: Evidence in Cells, Mice, and Humans

Gassen, Nils C.; Hartmann, Jakob; Zschocke, Jürgen; Stĕpán, J; Hafner, Kathrin; Zellner, Andreas; Kirmeier, Thomas; Kollmannsberger, Lorenz K.; Wagner, Klaus V.; Dedic, Nina; Balsevich, Georgia; Deussing, Jan M.; Kloiber, Stefan; Lucae, Susanne; Holsboer, Florian; Eder, Matthias; Uhr, Manfred; Ising, Marcus; Schmidt, Mathias V.; Rein, Theo

doi:10.1371/journal.pmed.1001755

Cited by 143 publications

(174 citation statements)

References 75 publications

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“…However, antidepressant activity of rapamycin (an mTOR inhibitor) has also been reported in an animal model [63] . Moreover, autophagic markers, such as beclin1, are increased following antidepressant treatment in mouse brain [64] . Autophagy might be a double-edged sword in MDD, which may be the reason why some MDD patients remain resistant to certain antidepressant medications.…”

Section: Antidepressants and Autophagymentioning

confidence: 99%

Molecular network of neuronal autophagy in the pathophysiology and treatment of depression

Jia

Le²

2015

Neurosci. Bull.

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Major depressive disorder (MDD) is a complicated multifactorial induced disease, characterized by depressed mood, anhedonia, fatigue, and altered cognitive function. Recently, many studies have shown that antidepressants regulate autophagy. In fact, autophagy, a conserved lysosomal degradation pathway, is essential for the central nervous system. Dysregulation of autophagic pathways, such as the mammalian target of rapamycin (mTOR) signaling pathway and the beclin pathway, has been studied in neurodegenerative diseases. However, autophagy in MDD has not been fully studied. Here, we discuss whether the dysregulation of autophagy contributes to the pathophysiology and treatment of MDD and summarize the current evidence that shows the involvement of autophagy in MDD.

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Section: Antidepressants and Autophagymentioning

confidence: 99%

Molecular network of neuronal autophagy in the pathophysiology and treatment of depression

Jia

Le²

2015

Neurosci. Bull.

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“…A related target is the FK506 binding protein 51 (FKBP51), which is a regulator of the GR via its action on the chaperone Hsp90. Knockouts for FKBP51 have been generated that do display resistance both to the behavioural and physiological effects of chronic paroxetine while if anything being less sensitive to stress (Gassen et al 2014). …”

Section: Genetic Factorsmentioning

confidence: 99%

Treatment-resistant depression: are animal models of depression fit for purpose?

2015

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“…6 HEK293T cells were transfected with Lipofectamine 2000 (Life Technologies/ Thermo Fisher Scientific, Carlsbad, CA, USA) following the manufacturer's instruction, and were electroporated for in vitro hormone binding, as previously described. 46 FKBP51 − / − MEFs were electroporated as previously described. 46 HT22 and Neuro-2a cells were transfected with Lipofectamine and PLUS reagent (Life Technologies/Thermo Fisher Scientific) following the manufacturer's instructions.…”

Section: Discussionmentioning

confidence: 99%

“…46 FKBP51 − / − MEFs were electroporated as previously described. 46 HT22 and Neuro-2a cells were transfected with Lipofectamine and PLUS reagent (Life Technologies/Thermo Fisher Scientific) following the manufacturer's instructions. Lipofectamine 2000 was used in siRNA experiments.…”

Section: Discussionmentioning

confidence: 99%

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

et al. 2016

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FK506-binding protein 51 (FKBP51) regulates the activity of the glucocorticoid receptor (GR), and is therefore a key mediator of the biological actions of glucocorticoids. However, the understanding of the molecular mechanisms that govern its activity remains limited. Here, we uncover a novel regulatory switch for GR activity by the post-translational modification of FKBP51 with small ubiquitin-like modifier (SUMO). The major SUMO-attachment site, lysine 422, is required for FKBP51-mediated inhibition of GR activity in hippocampal neuronal cells. Importantly, impairment of SUMO conjugation to FKBP51 impacts on GR-dependent neuronal signaling and differentiation. We demonstrate that SUMO conjugation to FKBP51 is enhanced by the E3 ligase PIAS4 and by environmental stresses such as heat shock, which impact on GR-dependent transcription. SUMO conjugation to FKBP51 regulates GR hormone-binding affinity and nuclear translocation by promoting FKBP51 interaction within the GR complex. SUMOylation-deficient FKBP51 fails to interact with Hsp90 and GR thus facilitating the recruitment of the closely related protein, FKBP52, which enhances GR transcriptional activity. Moreover, we show that the modification of FKBP51 with SUMO modulates its binding to Hsp90. Our data establish SUMO conjugation as a novel regulatory mechanism in the Hsp90 cochaperone activity of FKBP51 with a functional impact on GR signaling in a neuronal context.

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Association of FKBP51 with Priming of Autophagy Pathways and Mediation of Antidepressant Treatment Response: Evidence in Cells, Mice, and Humans

Abstract: Theo Rein and colleagues examine the role of FKBP51 in the actions of antidepressants, with a particular focus on pathways of autophagy. Please see later in the article for the Editors' Summary

Cited by 143 publications

References 75 publications

Molecular network of neuronal autophagy in the pathophysiology and treatment of depression

Molecular network of neuronal autophagy in the pathophysiology and treatment of depression

Treatment-resistant depression: are animal models of depression fit for purpose?

The activity of the glucocorticoid receptor is regulated by SUMO conjugation to FKBP51

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