Felix Hausch

Max Planck Institute of Neurobiology, München, Bavaria, Germany

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Publications (57)312.66 Total impact

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    ABSTRACT: Early-life stress is a key risk factor for the development of neuropsychiatric disorders later in life. Neuronal cell adhesion molecules have been strongly implicated in the pathophysiology of psychiatric disorders and in modulating social behaviors associated with these diseases. Neuroligin-2 is a synaptic cell adhesion molecule, located at the postsynaptic membrane of inhibitory GABAergic synapses, and is involved in synaptic stabilization and maturation. Alterations in neuroligin-2 expression have previously been associated with changes in social behavior linked to psychiatric disorders, including schizophrenia and autism. In this study, we show that early-life stress, induced by limited nesting and bedding material, leads to impaired social recognition and increased aggression in adult mice, accompanied by increased expression levels of hippocampal neuroligin-2. Viral overexpression of hippocampal neuroligin-2 in adulthood mimics early-life stress-induced alterations in social behavior and social cognition. Moreover, viral knockdown of neuroligin-2 in the adult hippocampus attenuates the early-life stress-induced behavioral changes. Our results highlight the importance of neuroligin-2 in mediating early-life stress effects on social behavior and social cognition and its promising role as a novel therapeutic target for neuropsychiatric disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Psychoneuroendocrinology 02/2015; 55:128-143. DOI:10.1016/j.psyneuen.2015.02.016 · 5.59 Impact Factor
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    ABSTRACT: One function of the glucocorticoid receptor (GR) in corticotroph cells is to suppress the transcription of the gene encoding proopiomelanocortin (POMC), the precursor of the stress hormone adrenocorticotropin (ACTH). Cushing disease is a neuroendocrine condition caused by partially glucocorticoid-resistant corticotroph adenomas that excessively secrete ACTH, which leads to hypercortisolism. Mutations that impair GR function explain glucocorticoid resistance only in sporadic cases. However, the proper folding of GR depends on direct interactions with the chaperone heat shock protein 90 (HSP90, refs. 7,8). We show here that corticotroph adenomas overexpress HSP90 compared to the normal pituitary. N- and C-terminal HSP90 inhibitors act at different steps of the HSP90 catalytic cycle to regulate corticotroph cell proliferation and GR transcriptional activity. C-terminal inhibitors cause the release of mature GR from HSP90, which promotes its exit from the chaperone cycle and potentiates its transcriptional activity in a corticotroph cell line and in primary cultures of human corticotroph adenomas. In an allograft mouse model, the C-terminal HSP90 inhibitor silibinin showed anti-tumorigenic effects, partially reverted hormonal alterations, and alleviated symptoms of Cushing disease. These results suggest that the pathogenesis of Cushing disease caused by overexpression of heat shock proteins and consequently misregulated GR sensitivity may be overcome pharmacologically with an appropriate HSP90 inhibitor.
    Nature Medicine 02/2015; DOI:10.1038/nm.3776 · 28.05 Impact Factor
  • Felix Hausch
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    ABSTRACT: Ligands for FK506-binding proteins, also referred to as neuroimmunophilin ligands, have repeatedly been described as neuritotrophic, neuroprotective or neuroregenerative agents. However, the precise molecular mechanism of action underlying the observed effects have remained elusive, which eventually led to a reduced interest in FKBP ligand development. A survey is presented on the pharmacology of neuroimmunophilin ligands, of the current understanding of individual FKBP homologs in neuronal processes and an assessment of their potential as drug targets for CNS disorders. FKBP51 is the relevant target accounting for the neuritotrophic effect of neuroimmunophilin ligands. Selectivity against the homolog FKBP52 is essential for optimal neuritotrophic efficacy. Selectivity within the FKBP family, in particular selective inhibition of FKBP12 or FKBP51, is possible. FKBP51 is a pharmacologically tractable target for stress-related disorders. The role of FKBPs in neurodegeneration remains to be clarified. This article is part of a Special Issue entitled Redox regulation of differentiation and de-differentiation. Copyright © 2015. Published by Elsevier B.V.
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    ABSTRACT: Um höchst effiziente Inhibitoren für FK506-bindende Proteine zu erzielen, wurde eine neue asymmetrische Synthese für pro-(S)-C5-verzweigte [4.3.1]-Aza-Amid-Bicyclen entwickelt. Der entscheidende Syntheseschritt war dabei eine HF-vermittelte N-Acyliminium-Cyclisierung. Die Funktionalisierung des C5-Restes führte zu neuen Proteinkontakten mit dem psychiatrischen Risikofaktor FKBP51, was eine mehr als 280-fache Steigerung der Affinität ermöglichte. Die besten Liganden verstärkten potent die Differenzierung von N2a-Neuroblastomazellen.
    Angewandte Chemie 01/2015; 127(1). DOI:10.1002/ange.201408776
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    ABSTRACT: To create highly efficient inhibitors for FK506-binding proteins, a new asymmetric synthesis for pro-(S)-C5-branched [4.3.1] aza-amide bicycles was developed. The key step of the synthesis is an HF-driven N-acyliminium cyclization. Functionalization of the C5 moiety resulted in novel protein contacts with the psychiatric risk factor FKBP51, which led to a more than 280-fold enhancement in affinity. The most potent ligands facilitated the differentiation of N2a neuroblastoma cells with low nanomolar potency.
    Angewandte Chemie International Edition 01/2015; 54(1). DOI:10.1002/anie.201408776 · 11.34 Impact Factor
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    ABSTRACT: The FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is an established risk factor for stress-related psychiatric disorders such as major depression. Drug discovery for FKBP51 has been hampered by the inability to pharmacologically differentiate against the structurally similar but functional opposing homolog FKBP52, and all known FKBP ligands are unselective. Here, we report the discovery of the potent and highly selective inhibitors of FKBP51, SAFit1 and SAFit2. This new class of ligands achieves selectivity for FKBP51 by an induced-fit mechanism that is much less favorable for FKBP52. By using these ligands, we demonstrate that selective inhibition of FKBP51 enhances neurite elongation in neuronal cultures and improves neuroendocrine feedback and stress-coping behavior in mice. Our findings provide the structural and functional basis for the development of mechanistically new antidepressants.
    Nature Chemical Biology 12/2014; 11(1). DOI:10.1038/nchembio.1699 · 13.22 Impact Factor
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    ABSTRACT: B0AT2, encoded by the SLC6A15 gene, is a transporter for neutral amino acids that has recently been implicated in mood and metabolic disorders. It is predominantly expressed in the brain but little is otherwise known about its function. In order to identify inhibitors for this transporter we screened a library of different 3133 bioactive compounds. Loratadine, a clinically used histamine H1 receptor antagonist, was identified as a selective inhibitor of B0AT2 with an IC50 of 4 µM while being less active or inactive against several other members of the SLC6 family. Reversible inhibition of B0AT2 was confirmed by electrophysiology. A series of loratadine analogs was synthesized to get insight into the structure-activity relationships. Our studies provide the first chemical tool for B0AT2.
    Journal of Medicinal Chemistry 10/2014; 57(22):9473–9479. DOI:10.1021/jm501086v · 5.48 Impact Factor
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    ABSTRACT: A stereoselective synthesis of a derivatized bicyclic [4.3.1]decane scaffold based on an acyclic precursor is described. The key steps involve a Pd-catalyzed sp(3)-sp(2) Negishi-coupling, an asymmetric Shi epoxidation, and an intramolecular epoxide opening. Representative derivatives of this novel scaffold were synthesized and found to be potent inhibitors of the psychiatric risk factor FKBP51, which bound to FKBP51 with the intended molecular binding mode.
    Organic Letters 10/2014; 16(20). DOI:10.1021/ol5023195 · 6.32 Impact Factor
  • Serena Cuboni, Felix Hausch
    Angewandte Chemie 05/2014; 126(20). DOI:10.1002/ange.201310567
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    ABSTRACT: Chronic stress is a risk factor for psychiatric disorders but does not necessarily lead to uniform long-term effects on mental health, suggesting modulating factors such as genetic predispositions. Here we address the question whether natural genetic variations in the mouse corticotropin releasing hormone receptor 1 (Crhr1) locus modulate the effects of adolescent chronic social stress (ACSS) on long-term stress hormone dysregulation in outbred CD1 mice, which allows a better understanding of the currently reported GxE interactions of early trauma and CRHR1 in humans. We identified two main haplotype variants in the mouse Crhr1 locus that modulate the long-term effects of ACSS on basal hypothalamic-pituitary-adrenal axis activity. This effect is likely mediated by higher levels of CRHR1, as Crhr1 mRNA expression and CRHR1 binding was enhanced in risk haplotype carriers. Furthermore, a CRHR1 receptor antagonist normalized these long-term effects. Deep-sequencing of the Crhr1 locus in CD1 mice revealed a large number of linked single nucleotide polymorphisms with some located in important regulatory regions, similar to the location of human CRHR1 variants implicated in modulating GxE interactions. Our data support that the described gene x stress exposure interaction in this animal model is based on naturally occurring genetic variations in the Crhr1 gene associated with enhanced CRHR1 mediated signaling. Our results suggest that patients with a specific genetic predisposition in the CRHR1 gene together with an exposure to chronic stress may benefit from a treatment selectively antagonizing CRHR1 hyperactivity.
    Endocrinology 04/2014; 155(7):en20131986. DOI:10.1210/en.2013-1986 · 4.64 Impact Factor
  • Serena Cuboni, Felix Hausch
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    ABSTRACT: In the sweet spot: Cocrystal structures of engineered neurotransmitter transporters reveal the binding mode of commonly prescribed antidepressants, providing a basis for a rational drug design for this class of proteins. The picture shows the structure of the dopamine transporter of Drosophila melanogaster in complex with the antidepressant nortriptyline.
    Angewandte Chemie International Edition 04/2014; 53(20). DOI:10.1002/anie.201310567 · 11.34 Impact Factor
  • Experimental and Clinical Endocrinology & Diabetes 03/2014; 122(03). DOI:10.1055/s-0034-1372049 · 1.76 Impact Factor
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    ABSTRACT: FK506-binding protein 51 (FKBP51) is a co-chaperone of the glucocorticoid receptor, functionally linked to its activity via an ultra-short negative feedback loop. Thus, FKBP51 plays an important regulatory role in the hypothalamic-pituitary-adrenocortical (HPA) axis necessary for stress adaptation and recovery. Previous investigations illustrated that HPA functionality is influenced by polymorphisms in the gene encoding FKBP51, which are associated with both increased protein levels and depressive episodes. Because FKBP51 is a key molecule in stress responses, we hypothesized that its deletion impacts sleep. To study FKBP51-involved changes in sleep, polysomnograms of FKBP51 knockout (KO) mice and wild-type (WT) littermates were compared at baseline and in the recovery phase after 6-h sleep deprivation (SD) and 1-h restraint stress (RS). Using another set of animals, the 24-h profiles of hippocampal free corticosterone levels were also determined. The most dominant effect of FKBP51 deletion appeared as increased nocturnal wake, where the bout length was significantly extended while non-rapid eye movement sleep (NREMS) and rapid eye movement sleep were rather suppressed. After both SD and RS, FKBP51KO mice exhibited less recovery or rebound sleep than WTs, although slow-wave activity during NREMS was higher in KOs, particularly after SD. Sleep compositions of KOs were nearly opposite to sleep profiles observed in human depression. This might result from lower levels of free corticosterone in FKBP51KO mice, confirming reduced HPA reactivity. The results indicate that an FKBP51 deletion yields a pro-resilience sleep phenotype. FKBP51 could therefore be a therapeutic target for stress-induced mood and sleep disorders.
    Journal of Sleep Research 12/2013; 23(2). DOI:10.1111/jsr.12112 · 2.95 Impact Factor
  • Felix Hausch
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    ABSTRACT: Neue Mitglieder im GPCR‐Familienalbum! Erste Kristallstrukturen der G‐Protein‐gekoppelten Rezeptoren (GPCRs) der Peptidhormon‐erkennenden Klasse B sind gelöst (siehe Bild; blau: Rezeptor für den Corticotropin‐freisetzenden Faktor, grün: allosterisch gebundener, nicht‐peptidischer Antagonist). Sie liefern die Grundlage für ein rationelles Design von besseren Arzneimitteln zur Behandlung von Diabetes, Osteoporose, Migräne oder Depression.
    Angewandte Chemie 12/2013; 125(49). DOI:10.1002/ange.201307542
  • Felix Hausch
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    ABSTRACT: New members in the GPCR photo gallery! Crystal structures of class B G protein-coupled receptors, which bind peptide hormones, have been solved [see picture of the corticotropin-releasing factor receptor 1 (blue) and a bound allosteric nonpeptide antagonist (green)]. The structures provide a basis for a rational design of better drugs for diabetes, osteoporosis, migraine, or depression.
    Angewandte Chemie International Edition 12/2013; 52(49). DOI:10.1002/anie.201307542 · 11.34 Impact Factor
  • Experimental and Clinical Endocrinology & Diabetes 11/2013; 121(10). DOI:10.1055/s-0033-1359453 · 1.76 Impact Factor
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    ABSTRACT: The human Hsp90 co-chaperone FKBP52 belongs to the family of FK506-binding proteins, which act as peptidyl-prolyl isomerases. FKBP52 specifically enhances the signalling of steroid hormone receptors, modulates ion channels and regulates neuronal outgrowth dynamics. In turn, small molecule ligands of FKBP52 have been suggested as potential neurotrophic or anti-prostate cancer agents. The usefulness of available ligands is however limited by a lack of selectivity. The immunophilin FKBP52 is composed of three domains, a FK506-binding domain with peptidyl-prolyl isomerase activity, a FKBP-like domain of unknown function and a TPR-clamp domain, which recognizes the C-terminal peptide of Hsp90 with high affinity. The herein reported crystal structures of FKBP52 reveal that the short linker connecting the FK506-binding domain and the FKBP-like domain acts as a flexible hinge. This enhanced flexibility and its modulation by phosphorylation might explain some of the functional antagonism between the closely related homologs FKBP51 and FKBP52. We further present two co-crystal structures of FKBP52 in complex with the prototypic ligand FK506 and a synthetic analogue thereof. These structures revealed the molecular interactions in great detail, which enabled in-depth comparison with the corresponding complexes of FKBP51 and FKBP12, which coexist with FKBP52 in human cytosol. The observed subtle differences provide crucial insights for the rational design of ligands with improved selectivity for FKBP52.
    Journal of Molecular Biology 08/2013; 18. DOI:10.1016/j.jmb.2013.07.041 · 3.96 Impact Factor
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    ABSTRACT: SLC6A15 is a neuron-specific neutral amino acid transporter that belongs to the solute carrier 6 gene family. This gene family is responsible for presynaptic re-uptake of the majority of neurotransmitters. Convergent data from human studies, animal models and pharmacological investigations suggest a possible role of SLC6A15 in major depressive disorder. In this work, we explored potential functional variants in this gene that could influence the activity of the amino acid transporter and thus downstream neuronal function and possibly the risk for stress-related psychiatric disorders. DNA from 400 depressed patients and 400 controls was screened for genetic variants using a pooled targeted re-sequencing approach. Results were verified by individual re-genotyping and validated non-synonymous coding variants were tested in an independent sample (N = 1934). Nine variants altering the amino acid sequence were then assessed for their functional effects by measuring SLC6A15 transporter activity in a cellular uptake assay. In total, we identified 405 genetic variants, including twelve non-synonymous variants. While none of the non-synonymous coding variants showed significant differences in case-control associations, two rare non-synonymous variants were associated with a significantly increased maximal (3)H proline uptake as compared to the wildtype sequence. Our data suggest that genetic variants in the SLC6A15 locus change the activity of the amino acid transporter and might thus influence its neuronal function and the risk for stress-related psychiatric disorders. As statistically significant association for rare variants might only be achieved in extremely large samples (N >70,000) functional exploration may shed light on putatively disease-relevant variants.
    PLoS ONE 07/2013; 8(7):e68645. DOI:10.1371/journal.pone.0068645 · 3.53 Impact Factor
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    ABSTRACT: FK506-binding proteins (FKBP) belong to the immunophilin family and are best known for their ability to enable the immunosuppressive properties of FK506 and rapamycin. For rapamycin, this is achieved by inducing inhibitory ternary complexes with the kinase mTOR. The essential accessory protein for this gain-of-function was thought to be FKBP12. We recently showed that this view might be too restricted, since larger FK506-binding proteins can functionally substitute for FKBP12 in mammalian cells. Recent studies have also shown that FK506-binding proteins can modulate Akt-mTOR signaling in the absence of rapamycin. Here we discuss the role of FK506-binding proteins for the mechanism of rapamycin as well as their intrinsic actions on the Akt/mTOR pathway.
    Cell cycle (Georgetown, Tex.) 07/2013; 12(15). DOI:10.4161/cc.25508 · 5.01 Impact Factor
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    ABSTRACT: The design of efficient ligands remains a key challenge in drug discovery. In the quest for lead-like ligands for the FK506-binding protein 51 (FKBP51), we designed two new classes of bicyclic sulfonamides to probe the contribution of conformational energy in these ligands. The [4.3.1] scaffold had consistently higher affinity compared to the [3.3.1] or monocyclic scaffolds, which could be attributed to better preorganization of two key recognition motifs. Surprisingly, the binding of the rigid [4.3.1] scaffold was enthalpy-driven and entropically disfavored compared to the flexible analogues. Cocrystal structures at atomic resolution revealed that the sulfonamide nitrogen in the bicyclic scaffolds can accept an unusual hydrogen bond from Tyr(113) that mimics the putative FKBP transition state. This resulted in the first lead-like, functionally active ligand for FKBP51. Our work exemplifies how atom-efficient ligands can be achieved by careful conformational control even in very open and thus difficult binding sites such as FKBP51.
    Journal of Medicinal Chemistry 05/2013; 56(10). DOI:10.1021/jm400087k · 5.48 Impact Factor

Publication Stats

328 Citations
312.66 Total Impact Points

Institutions

  • 2015
    • Max Planck Institute of Neurobiology
      München, Bavaria, Germany
  • 2008–2015
    • Max Planck Institute of Psychiatry
      München, Bavaria, Germany
  • 2013
    • Max Planck Institute of Biochemistry
      • Department of Cellular Biochemistry
      München, Bavaria, Germany