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FKBPs and their role in neuronal signaling
BBAGEN-28141; No. of pages: 6; 4C: 4 Biochimica et Biophysica Acta xxx (2015) xxx–xxx
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Review
FKBPs and their role in neuronal signaling☆ Felix Hausch Max Planck Institute of Psychiatry, 80804 Munich, Germany
a r t i c l e
i n f o
Article history: Received 20 October 2014 Received in revised form 10 January 2015 Accepted 12 January 2015 Available online xxxx Keywords: Neuroimmunophilin FKBP51 FK506 Neurite outgrowth Stress-related disorders
a b s t r a c t Background: 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 has remained elusive, which eventually led to a reduced interest in FKBP ligand development. Scope of review: 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. Major conclusions: FKBP51 is the major target accounting for the neuritotrophic effect of neuroimmunophilin ligands. Selectivity against the homolog FKBP52 is essential for optimal neuritotrophic efficacy. General significance: 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 Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Neuroimmunophilin ligands, defined as neuroactive substances binding to proteins of the immunophilin family, have repeatedly been reported to have a variety of effects in models of neuronal function. These findings have translated into advanced drug discovery programs, including clinical trials, but overall these have not met with success. In this review we will discuss possible underlying reasons, focusing on members of the FKBP family and on the pharmacology of their ligands. Effects that are likely mediated through cyclophilins or Pin1 are beyond the scope of this review. Similarly, effects that are likely mediated by an immunosuppressive mechanism are only briefly discussed, where necessary. 2. The rise and fall of the neuroimmunophilin concept In the early 1990s the discovery of FKBP12 as the primary binding partner of the immunosuppressive agents FK506 and rapamycin (Fig. 1A) caused a wave of excitement within the scientific community and triggered substantial interest in the endogenous function of this protein [1]. The subsequent detection of strong FKBP expression in the central nervous system directed research activities towards a role of FKBPs in neuronal processes [2]. In 1994, FK506 was shown to stimulate neurite outgrowth in vitro [3], to reduce ischemic brain damage [4] and ☆ This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. E-mail address: [email protected].
to promote recovery after sciatic nerve crush in rats [5], suggesting FKBP ligands as a novel neuroprotective or neuroregenerative agents. The most prominent effect of FK506 is inhibition of calcineurin, the underlying molecular mechanism for its powerful immunosuppressant activity. However, systemic suppression of the immune system would be highly undesirable for the treatment of CNS disorders. Therefore, the seminal findings that the neuronal effects of FKBP ligands could be at least in part dissociated from inhibition of calcineurin [6,7] thrilled the pharmaceutical industry as it suggested that FKBP-based drugs for CNS diseases might be possible without immunosuppressive side effects. In turn, many pharmaceutical companies started drug discovery programs aimed at the development of novel non-immunosuppressive FKBP ligands [8]. In the following years, several non-immunosuppressive FK506 analogs such as FK1706 and V-10,367 (Fig. 1) became available as tool compounds and were extensively tested in a variety of animal models such as sciatic [6,7,9,10], cavernous [11,12] or optic nerve crush [13], spinal cord injury [14–16], streptozotocin-induced diabetic neuropathy [17, 18], or MPTP- or 6-OHDA-induced degeneration of dopaminergic neurons (Table 1) [19–21]. These studies provided enticing indications that non-immunosuppressive FK506 analogs might be useful for the treatment of various forms of physical nerve injury, painful diabetic neuropathy or Parkinson's disease. However, in 1999 substantial controversies emerged regarding the underlying molecular mechanism of the FK506 analogs used. First, it was shown that FK506 retained its neuritotrophic properties in FKBP12-deficient primary neurons [22, 23], which was clearly at odds with the prevailing hypothesis of FKBP12 as the primary target of neuroimmunophilin ligands. This
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Please cite this article as: F. Hausch, FKBPs and their role in neuronal signaling, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbagen.2015.01.012
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A)
B)
C)
D)
Fig. 1. Key tool substances in neuroimmunophilin research. A) Chemical structures of the prototypic, immunosuppressive FKBP ligands FK506 and rapamycin and semi-synthetic nonimmunosuppressive analogs thereof (FK1706 [55], L-685,818 [84] and 13Me-18OH-ascomycin [10]). B) Chemical structures of the FKBP ligands V-10,367 [85], biricodar [86], (S)-19, and (R)-19 [64]. C) Chemical structures FKBP non-binding compounds timcodar and GPI-1046/GPI-1485 [35]. D) Chemical structures of the FKBP12-selective compound 44 [63], of the FKBP51/52F67V mutant-selective Ligand 1 or the FKBP51-selective ligands SAFit1 and SAFit2 [72].
Please cite this article as: F. Hausch, FKBPs and their role in neuronal signaling, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbagen.2015.01.012
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Table 1 Overview of FK506 derivatives tested in animal models. Indication
FKBP binders FK506
Sciatic nerve crush Cavernous nerve crush Optic nerve crush Spinal cord injury Streptozotocin-induced diabetic neuropathy Parkinson's disease (MPTP or 6-OHDA)
+ + + +
FK1706
FKBP non-binders L-685, 818
13Me-18OH-Asc
V-10,367
+
+
+
Timcodar
V13-661/V13-670
+ + +
notion was substantiated by subsequent recurrent findings that derivatives of previously used neuroimmunophilin ligands such as timcodar retained their neuritotrophic, neuroprotective or neuroregenerative properties although they did not bind to FKBP12 (Table 1) [20,24–26]. A special case in this regard is the substance GPI-1046 (Fig. 1C), which has been described as a potent neuritotrophic agent with activities in numerous animal models of neurological disorders. GPI-1046 was originally reported as a potent FKBP12 inhibitor but this has been challenged by numerous groups [27–32]. GPI-1046 should therefore be regarded as representative of the class of FK506 derivatives devoid of FKBP12 binding. Two members of the FKBP12-non-binding class were eventually investigated in humans. Timcodar (VX-853) has been tested in clinical trials for diabetic neuropathy [33,34]. GPI-1486 [35], the main metabolite of GPI-1046, was tested in clinical trials for Parkinson's disease and for erectile dysfunction after prostatectomy. These compounds were safe in humans but failed to show any clinical benefit. Given that these compounds do not bind FKBP12 or any of its close homologs, no conclusions on the role of FKBPs in these diseases can be made. Taken together, it became clear that inhibition of FKBP12 was not responsible for observed neuronal effects of FK506 or its derivatives and it was unclear if FKBPs were involved at all. These conceptual inconsistencies combined with the disappointing phase II clinical trial results eventually led to the halt of the FKBP-directed drug discovery programs and to a substantial decline in FKBP research in general. 3. Neuronal functions of FKBPs In the beginning neuroimmunophilin research was largely driven by the pharmacology of FKBP ligands and overly focused on FKBP12. In particular, transgenic and molecular biology approaches were strikingly underrepresented until recently. This might be in part due to the technical difficulties with FKBP12 knockout mice, most of which die in utero due to severe cardiac defects [36]. Notably, no neuronal alterations have been observed in the few surviving animals [22]. Unfortunately, no FKBP12-overexpressing mice have been described. To specifically investigate the role of FKBP12 in the brain, Hoefner et al. generated brain-specific FKBP12-deficient knockout mice [37]. An unexpected increase in mTOR pathway activity was observed, possibly due to a de-repressed, basal Akt signaling upstream of mTOR [38,39]. Brainspecific FKBP12 deletion also resulted in enhanced hippocampal longterm potentiation (LTP), one of the key molecular mechanisms for the formation of memory. In behavioral tests brain-deficient FKBP12 mice displayed enhanced contextual fear memory and perseverative behaviors that mimic some aspects of autism or obsessive-compulsive disorder. However, unlike genetic FKBP12 depletion, FKBP12 inhibitors do not enhance the mTOR pathway [39,40]. It is therefore unclear whether inhibition of FKBP12 in the brain will enhance LTP or evoke obsessivecompulsive-like symptoms. Several reports linked FKBP12 to protein aggregation [41]. FKBP12 was shown to bind to the intracellular domain of the amyloid precursor protein (APP), a key player in the pathogenesis of Alzheimer's disease [42]. Overexpression of FKBP12 enhanced the processing of APP to the amyloidogenic Aβ peptide [43]. Importantly, binding to APP and alteration of APP processing were both blocked by FK506.
+ + + +
GPI-1046/GPI-1485 + +
+ + +
FKBP12 was also shown to co-localize with neurofibrillary tangles in brain samples from patients with Alzheimer's disease [44]. The aggregation of a peptide derived from tau, a major component of neurofibrillary tangles, was shown to be prevented in the presence of FKBP12, which depended on its peptidyl-prolyl-isomerase activity [45]. The effect of FKBP12 on the aggregation of full-length tau or in a cellular environment was not tested. The aggregation of α-synuclein, which is thought to contribute to Parkinson's disease, was shown to be enhanced by FKBPs in an FK506sensitive manner in vitro [46] and in cellular models [47]. FKBP12 was identified as the most important FKBP homolog for α-synuclein aggregation [48]. In a proteomic analysis of a mouse model of Huntington's disease FKBP12 was identified as one of the most prominently downregulated proteins in the brains of aged mice [49]. Overexpression of FKBP12 in a cellular model of Huntington's disease reduced the amount of aggregated huntingtin. One of the best described molecular functions of FKBP12 and FKBP12.6 is the stabilization of ryanodine receptors, thereby preventing leaking of Ca2+ ions from the endoplasmatic reticulum [50]. Excessive Ca2+ influx through ryanodine receptors was suggested to contribute to neuronal death in models of Huntington's disease, and overexpression of FKBP12 was shown to prevent this exitotoxicity [51]. Recently, Marks and colleagues investigated the role of the ryanodine receptor 2 (RyR2) in stress-coping behavior [52]. They observed that chronic stress destabilized binding of FKBP12.6 to RyR2 by posttranslational modifications of the latter. In knock-in mice with a regulation-insensitive RyR2 mutant they could show that the FKBP12.6-RyR2 mutant complex is not affected by chronic stress anymore. Moreover, the tool compound S107 known to stabilize the FKBP12.6-RyR2 complex was found to protect from developing chronic stress-induced anxiogenic behavior. While these results are interesting and a role of RyR2 seems evident, the involvement of FKBP12.6 was largely implied by the use of compound S107. In light of the controversies regarding the mechanism of action of S107 [53] or its derivative K201 (JTV519) [54], the role of FKBP12.6 in stress-coping needs to be further defined. After FKBP12 had been devalidated as the target of neuroimmunophilin ligands the larger homolog FKBP52 had been advocated as the relevant target [22,31,55]. This conclusion was originally based on the neuritotrophic effect observed for an anti-FKBP52 antibody in saponin-permeabilized SH-SY5Y cells [22,55]. Mild stimulation of neurite outgrowth was also observed in primary cortical neurons after knockdown of FKBP52 [31]. Mechanistically, the potentiation of neurite outgrowth after FKBP52 inhibition was explained by an activation of steroid hormone receptors. This interpretation, however, is clearly at odds with numerous studies that established FKBP52 as a positive factor for steroid hormone receptors in vitro and in vivo [56]. In all these studies, deletion or reduction of FKBP52 resulted in reduced steroid hormone signaling. The extrapolation of these findings towards a role of FKBP52 in neuronal function is, however, less straightforward. The effects of steroids, especially glucocorticoids, on neurons are complex, involving glucocorticoid and mineralocorticoid receptors with partially overlapping or counteracting functions. Generally, low doses of
Please cite this article as: F. Hausch, FKBPs and their role in neuronal signaling, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbagen.2015.01.012
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glucocorticoids seem to be necessary for neurons in culture and for synaptic plasticity in vivo. On the other hand, high concentrations of glucocorticoids have been reported to be neurotoxic and to contribute to neuronal atrophy after stress. The neuroendocrine analysis of FKBP52 is further complicated by an important peripheral role in progesterone and androgen receptor signaling, leading to a severely compromised sex organ development especially in male FKBP52-deficient mice [56]. A characterization of heterozygous FKBP52+/− mice, which have a normal development, revealed reduced basal but enhanced stress-induced corticosterone levels. FKBP52+/− mice also displayed a mixed behavioral phenotype, with enhanced anxiety in the elevated plus maze test but a more active stress-coping in the forced swim test after chronic stress [57]. For the interpretation of the neuronal role of FBKP52 it is necessary to consider other, steroid receptor-unrelated pathways that are affected by FKBP52. Notably, FKBP52 was found to associate with canonical transient receptor potential channels, which are known to be involved in the chemotrophic guidance of neuronal growth cones. The peptidyl-prolylisomerase-inactive mutant FKBP52F67D/D68V was identified as an inhibitor of TRPC1 and was shown to inhibit netrin-1-induced Ca2 + influx into growth cones or netrin-1-induced turning of growth cones [58]. Similar results were observed with the FK506 derivative GPI-1046, although these findings are difficult to reconcile with the fact that GPI1046 does not bind to the FK506-binding site of FKBPs (see above), including FKBP52 [28]. 4. Neuronal and neuroendocrine functions of FKBP51 It is possible that the role of FKBP52 is cell type-dependent. In contrast to the early reports of FKBP52 as a neurite outgrowth inhibitor, Quinta et al. observed enhanced neurite outgrowth of N2a neuroblastoma cells after overexpression of FKBP52, while FKBP52 knockdown dramatically reduced neurite outgrowth in these cells [59]. In addition, Quinta also investigated the homolog FKBP51 and observed exactly the opposite: FKBP51 overexpression reduced neurite outgrowth while FKBP51 silencing enhanced it. Since FKBP51 and FKBP52 both potently bind FK506 [60], we hypothesized that the contrasting roles of FKBP51 and FKBP52 might have confounded some of the earlier studies with immunophilin ligands [61]. Addressing this question pharmacologically, however, turned out to be difficult since all FK506 analogs prepared so far did not discriminate between FKBP51 and FKBP52 [28, 62–65]. This is in line with the highly conserved FK506-binding site of these two proteins, which show an almost identical structure [66,67]. To tackle this challenge we decided to adopt a chemical biology approach that had been developed to pharmacologically distinguish between FKBP12 and tailor-made FKBP12 mutants [68]. In this system, also called the bump-and-hole-approach, the active site of FKBP12 was enlarged, allowing complementarily enlarged ligands to bind (Fig. 2). Importantly, the larger modification in the engineered ligand would clash with the smaller binding pocket of the wildtype protein,
thereby discriminating against the latter. Similar approaches using engineered orthogonally selective ligand–mutant pairs have been developed to study the role of kinases (analog-sensitive kinase alleles) [69] or of GPCRs (RASSLs [70] or DREADs [71]). FKBP12 mutants fused to proteins of interest have been extensively used in chemical biology, but we are not aware that this method has been used to investigate the biology of FKBPs itself. To adopt this method for FKBP51 and FKBP52 slight chemical modifications of Shield-1, the most advanced ligand for the FKBP12F37V mutant, were necessary to obtain high affinities for the FBKP51F67V and FKBP52F67V mutants [72]. Gratifyingly, the F67V mutation did not affect the pro- or anti-neuritotrophic effect of FKBP52 or FKBP51, respectively. With this well-controlled system at hand, we interrogated the consequence of FKBP51 or FKBP52 inhibition in N2a cells (Fig. 2). Treatment of FKBP51F67V-overexpressing cells with the FKBPF67V-selective ligand 1 completely abrogated the neurite outgrowth-inhibiting effect of FKBP51F67V while cells overexpressing wildtype FKBP51 were not affected at all. Likewise, ligand 1 blocked the pro-neuritotrophic effect of overexpressed FKBP52F67V but not of wildtype FKBP52. This experiment unequivocally established that inhibition of the FK506-binding site of FKBPs can increase but also decrease neurite outgrowth, depending on which FKBP homolog is inhibited. To show that this can lead to a situation where the dual effects of FKBP inhibitors cancel each other we overexpressed FKBP51 and FKBP52 simultaneously [72]. In this setup the anti- and pro-neuritotrophic effects of the two proteins are balanced and neurite outgrowth proceeds at basal levels. Again, selective inhibition of FKBP51 – by overexpressing an FKBP51 F67V /FKBP52 WT combination – enhanced neurite outgrowth while selectively inhibiting FKBP52 in FKBP51WT / FKBP52 F67 -overexpressing cells reduced it. Notably, when both overexpressed FKBPs were inhibited simultaneously – by treating FKBP51 F67V/FKBP52 F67V-overexpressing cells with ligand 1 – no overall change in neurite outgrowth was observed. This proves that for FKBP51/52-unselective ligands their overall effect may be masked if both FKBPs are present in the investigated cells. When studying FKBP51 or FKBP52, selectivity between these two proteins is thus essential. While the bump-and-hole approach is extremely powerful in situations where FKBP51 or FKBP52 can be overexpressed it does not allow interrogating the role of endogenous proteins. In our quest for selective inhibitors for wildtype FKBP51 we were fostered by serendipity. We observed that an analog of ligand 1 retained some affinity for FKBP51 but not for FKBP52 [72]. Cocrystal structure analysis revealed that this analog called iFit1 bound to FKBP51 with an induced-fit binding mode that was not possible for FKBP52. Optimization by medicinal chemistry rapidly enhanced the affinity for this new induced-fit conformation, leading to SAFit1 and SAFit2 (Fig. 1D). These two compounds potently bound FKBP51 (Ki = 4–6 nM) while discriminating N 10,000-fold against FKBP52. These compounds also potently stimulated neurite outgrowth in mouse N2a cells, human SH-SY5Y cells and in primary E18 hippocampal neurons.
Fig. 2. Mutant-ligand pairs to pharmacologically address FKBP51 or FKBP52. Middle: Scheme of the bump-and-hole system for the generation of the FKBP mutant-selective ligand 1. Ligand 1 binds the engineered mutants FKBP51F67V or FKBP52F67V, but not the wildtype counterparts. Left and right: Neurite outgrowth assays in N2a cells. Ligand 1 blocks the anti- and pro-neuritotrophic effects of overexpressed FKBP51F67V or FKBP52F67V. From Ref. [72].
Please cite this article as: F. Hausch, FKBPs and their role in neuronal signaling, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbagen.2015.01.012
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Importantly, no stimulation of neurite outgrowth was observed in FKBP51-deficient neurons, strongly indicating that inhibition of FKBP51 was responsible for the observed effect. In control experiments we observed that several pan-selective FKBP inhibitors like FK506, antascomycin [73], or compounds (S)-19 or (R)19 [64] all stimulated neurite outgrowth in N2a cells (Figs. 1D, 3), in line with the original claims for neuroimmunophilin ligands. However, the related FKBP12-selective inhibitor 44 [63] failed to stimulate neurite outgrowth under the same condition, further supporting the notion that FKBP12 is not involved in the regulation of neurite outgrowth. Interestingly, we noticed that all pan-selective FKBP inhibitors displayed a bellshaped dose–response curve, with enhancement of neurite outgrowth only at medium but not high inhibitor concentrations [64,72]. This phenomenon has previously been observed for other FKBP ligands, other cell types and even in vivo [6,10,19,22,55]. The fact that several chemically distinct FKBP inhibitors display the same bell-shaped dose– response curve strongly suggests that inhibition of an FKBP species is responsible for the neurite-promoting activity at low concentrations as well as for the loss thereof at higher concentrations. In light of the opposing roles of FKBP51 and FKBP52 it is tempting to speculate that inhibition of FKBP51 accounts for the neurite outgrowth stimulation at low concentrations, while additional inhibition of FKBP52 negates the latter. However, an open question is how to reconcile this hypothesis with the equal binding affinities of the pan-selective FKBP ligands for FKBP51 and FKBP52. One possibility may be that the interaction partners of FKBP51 inside the cells are more easily displaced by competitive ligands than the interaction partners of FKBP52. Dedicated mechanistic studies to elucidate the pathways by which FKBP51 inhibit and FKBP52 promote neurite outgrowth are required to address this point. It should be noted that neurite outgrowth assays in cell culture are primarily useful for mechanistic studies. They provide a cellular context that is close to neurons and may involve pathways that are relevant for early steps of neuronal differentiation. The fact that FKBP51 and FKBP52 inhibitors affect cell morphology and differentiation in several cell lines with neuronal properties suggests that FKBP51 may have a more cellintrinsic neuronal role than previously thought. This is important in light of the established role that FKBP51 plays in stress-related psychiatric diseases. Single nucleotide polymorphisms in FKBP5, the gene encoding FKBP51, have repeatedly been associated with an enhanced risk to develop disorders like depression or PTSD — often in combination with early life trauma. The same single nucleotide polymorphisms were also associated with several stress-related endophenotypes including suicidal ideation, aggression, stress-coping, fear perception [74]. Recently, the causal single nucleotide polymorphisms were
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identified, where the risk alleles were shown to enhance FKBP5 expression by translational and epigenetic mechanisms [75]. It is therefore generally accepted that FKBP51 contributes to the pathogenesis of stress-related disorders. Numerous studies in mice have established FKBP51 as an important factor for stress-coping behavior. FKBP51 is a potent inhibitor of the glucocorticoid receptor, which mediates the cellular responses to the stress hormone corticosterone. FKBP51−/− mice had reduced levels of corticosterone [76–78] and an enhanced negative feedback regulation of the hypothalamus–pituitary–adrenal (HPA) axis, an important endocrine stress response system that is often deregulated in depressive patients [79]. FKBP51−/− mice which also had a more active stress-coping behavior [77–80], were protected from the endocrine alterations of chronic stress [81], and had enhanced cognitive flexibility in a reversal learning paradigm [78]. Similarily, mice with a viral reduction of FKBP51 in the amygdala were found to be less anxious [82]. Notably, FKBP51 deletion only affected behavioral traits of glucocorticoid signaling, but not other glucocorticoid receptor-regulated phenotypes such as glucose metabolism or immune markers. No other peripheral abnormalities were found in FKBP51−/− mice suggesting that FKBP51 inhibition may be free from target-related side effects. Taken together, these findings convincingly validated FKBP51 as a potential target for stress-related disorders [83]. With the availability of SAFit2, a brain-permeable FKBP51 inhibitor of the iFit class, we tested the effect of FKBP51 in vivo [72]. SAFit2 reduced corticosterone levels during the peak time of corticosterone secretion, it enhanced glucocorticoid receptor sensitivity at the level of HPA axis regulation, and it enhanced stress coping in the forced swim test, the classical test for antidepressant activity. These effects mimicked earlier observations in FKBP51−/− mice, supporting the concept that SAFit2 works by inhibition of FKBP51. Collectively, these results provided the proof of concept for FKBP51 inhibition as a way to pharmacologically enhance stress coping and stress hormone homeostasis. 5. Summary The role of FKBPs in neuroprotection or neuroregeneration, e.g. after nerve injuries, is unclear. However, FKBP51 has emerged as an important regulator of stress in mammals. It is therefore possible that some of the compounds inspired by the early immunophilin ligands turn out to be useful for the treatment of stress-related disorders. Transparency Document The Transparency document associated with this article can be found, in the online version. Acknowledgements This work was supported in part by the M4 award to FH. References
Fig. 3. Pan-selective FKBP ligands stimulate neurite outgrowth with a bell-shaped dose– response curve. N2a cells were treated with the indicated concentrations of the FKBP inhibitor (S)-19 [64]. Similar results were obtained with several other pan-selective FKBP ligands.
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Please cite this article as: F. Hausch, FKBPs and their role in neuronal signaling, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbagen.2015.01.012
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Please cite this article as: F. Hausch, FKBPs and their role in neuronal signaling, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbagen.2015.01.012
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Review
FKBPs and their role in neuronal signaling☆ Felix Hausch Max Planck Institute of Psychiatry, 80804 Munich, Germany
a r t i c l e
i n f o
Article history: Received 20 October 2014 Received in revised form 10 January 2015 Accepted 12 January 2015 Available online xxxx Keywords: Neuroimmunophilin FKBP51 FK506 Neurite outgrowth Stress-related disorders
a b s t r a c t Background: 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 has remained elusive, which eventually led to a reduced interest in FKBP ligand development. Scope of review: 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. Major conclusions: FKBP51 is the major target accounting for the neuritotrophic effect of neuroimmunophilin ligands. Selectivity against the homolog FKBP52 is essential for optimal neuritotrophic efficacy. General significance: 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 Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. © 2015 Elsevier B.V. All rights reserved.
1. Introduction Neuroimmunophilin ligands, defined as neuroactive substances binding to proteins of the immunophilin family, have repeatedly been reported to have a variety of effects in models of neuronal function. These findings have translated into advanced drug discovery programs, including clinical trials, but overall these have not met with success. In this review we will discuss possible underlying reasons, focusing on members of the FKBP family and on the pharmacology of their ligands. Effects that are likely mediated through cyclophilins or Pin1 are beyond the scope of this review. Similarly, effects that are likely mediated by an immunosuppressive mechanism are only briefly discussed, where necessary. 2. The rise and fall of the neuroimmunophilin concept In the early 1990s the discovery of FKBP12 as the primary binding partner of the immunosuppressive agents FK506 and rapamycin (Fig. 1A) caused a wave of excitement within the scientific community and triggered substantial interest in the endogenous function of this protein [1]. The subsequent detection of strong FKBP expression in the central nervous system directed research activities towards a role of FKBPs in neuronal processes [2]. In 1994, FK506 was shown to stimulate neurite outgrowth in vitro [3], to reduce ischemic brain damage [4] and ☆ This article is part of a Special Issue entitled Proline-directed Foldases: Cell Signaling Catalysts and Drug Targets. E-mail address: [email protected].
to promote recovery after sciatic nerve crush in rats [5], suggesting FKBP ligands as a novel neuroprotective or neuroregenerative agents. The most prominent effect of FK506 is inhibition of calcineurin, the underlying molecular mechanism for its powerful immunosuppressant activity. However, systemic suppression of the immune system would be highly undesirable for the treatment of CNS disorders. Therefore, the seminal findings that the neuronal effects of FKBP ligands could be at least in part dissociated from inhibition of calcineurin [6,7] thrilled the pharmaceutical industry as it suggested that FKBP-based drugs for CNS diseases might be possible without immunosuppressive side effects. In turn, many pharmaceutical companies started drug discovery programs aimed at the development of novel non-immunosuppressive FKBP ligands [8]. In the following years, several non-immunosuppressive FK506 analogs such as FK1706 and V-10,367 (Fig. 1) became available as tool compounds and were extensively tested in a variety of animal models such as sciatic [6,7,9,10], cavernous [11,12] or optic nerve crush [13], spinal cord injury [14–16], streptozotocin-induced diabetic neuropathy [17, 18], or MPTP- or 6-OHDA-induced degeneration of dopaminergic neurons (Table 1) [19–21]. These studies provided enticing indications that non-immunosuppressive FK506 analogs might be useful for the treatment of various forms of physical nerve injury, painful diabetic neuropathy or Parkinson's disease. However, in 1999 substantial controversies emerged regarding the underlying molecular mechanism of the FK506 analogs used. First, it was shown that FK506 retained its neuritotrophic properties in FKBP12-deficient primary neurons [22, 23], which was clearly at odds with the prevailing hypothesis of FKBP12 as the primary target of neuroimmunophilin ligands. This
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Please cite this article as: F. Hausch, FKBPs and their role in neuronal signaling, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbagen.2015.01.012
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A)
B)
C)
D)
Fig. 1. Key tool substances in neuroimmunophilin research. A) Chemical structures of the prototypic, immunosuppressive FKBP ligands FK506 and rapamycin and semi-synthetic nonimmunosuppressive analogs thereof (FK1706 [55], L-685,818 [84] and 13Me-18OH-ascomycin [10]). B) Chemical structures of the FKBP ligands V-10,367 [85], biricodar [86], (S)-19, and (R)-19 [64]. C) Chemical structures FKBP non-binding compounds timcodar and GPI-1046/GPI-1485 [35]. D) Chemical structures of the FKBP12-selective compound 44 [63], of the FKBP51/52F67V mutant-selective Ligand 1 or the FKBP51-selective ligands SAFit1 and SAFit2 [72].
Please cite this article as: F. Hausch, FKBPs and their role in neuronal signaling, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbagen.2015.01.012
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Table 1 Overview of FK506 derivatives tested in animal models. Indication
FKBP binders FK506
Sciatic nerve crush Cavernous nerve crush Optic nerve crush Spinal cord injury Streptozotocin-induced diabetic neuropathy Parkinson's disease (MPTP or 6-OHDA)
+ + + +
FK1706
FKBP non-binders L-685, 818
13Me-18OH-Asc
V-10,367
+
+
+
Timcodar
V13-661/V13-670
+ + +
notion was substantiated by subsequent recurrent findings that derivatives of previously used neuroimmunophilin ligands such as timcodar retained their neuritotrophic, neuroprotective or neuroregenerative properties although they did not bind to FKBP12 (Table 1) [20,24–26]. A special case in this regard is the substance GPI-1046 (Fig. 1C), which has been described as a potent neuritotrophic agent with activities in numerous animal models of neurological disorders. GPI-1046 was originally reported as a potent FKBP12 inhibitor but this has been challenged by numerous groups [27–32]. GPI-1046 should therefore be regarded as representative of the class of FK506 derivatives devoid of FKBP12 binding. Two members of the FKBP12-non-binding class were eventually investigated in humans. Timcodar (VX-853) has been tested in clinical trials for diabetic neuropathy [33,34]. GPI-1486 [35], the main metabolite of GPI-1046, was tested in clinical trials for Parkinson's disease and for erectile dysfunction after prostatectomy. These compounds were safe in humans but failed to show any clinical benefit. Given that these compounds do not bind FKBP12 or any of its close homologs, no conclusions on the role of FKBPs in these diseases can be made. Taken together, it became clear that inhibition of FKBP12 was not responsible for observed neuronal effects of FK506 or its derivatives and it was unclear if FKBPs were involved at all. These conceptual inconsistencies combined with the disappointing phase II clinical trial results eventually led to the halt of the FKBP-directed drug discovery programs and to a substantial decline in FKBP research in general. 3. Neuronal functions of FKBPs In the beginning neuroimmunophilin research was largely driven by the pharmacology of FKBP ligands and overly focused on FKBP12. In particular, transgenic and molecular biology approaches were strikingly underrepresented until recently. This might be in part due to the technical difficulties with FKBP12 knockout mice, most of which die in utero due to severe cardiac defects [36]. Notably, no neuronal alterations have been observed in the few surviving animals [22]. Unfortunately, no FKBP12-overexpressing mice have been described. To specifically investigate the role of FKBP12 in the brain, Hoefner et al. generated brain-specific FKBP12-deficient knockout mice [37]. An unexpected increase in mTOR pathway activity was observed, possibly due to a de-repressed, basal Akt signaling upstream of mTOR [38,39]. Brainspecific FKBP12 deletion also resulted in enhanced hippocampal longterm potentiation (LTP), one of the key molecular mechanisms for the formation of memory. In behavioral tests brain-deficient FKBP12 mice displayed enhanced contextual fear memory and perseverative behaviors that mimic some aspects of autism or obsessive-compulsive disorder. However, unlike genetic FKBP12 depletion, FKBP12 inhibitors do not enhance the mTOR pathway [39,40]. It is therefore unclear whether inhibition of FKBP12 in the brain will enhance LTP or evoke obsessivecompulsive-like symptoms. Several reports linked FKBP12 to protein aggregation [41]. FKBP12 was shown to bind to the intracellular domain of the amyloid precursor protein (APP), a key player in the pathogenesis of Alzheimer's disease [42]. Overexpression of FKBP12 enhanced the processing of APP to the amyloidogenic Aβ peptide [43]. Importantly, binding to APP and alteration of APP processing were both blocked by FK506.
+ + + +
GPI-1046/GPI-1485 + +
+ + +
FKBP12 was also shown to co-localize with neurofibrillary tangles in brain samples from patients with Alzheimer's disease [44]. The aggregation of a peptide derived from tau, a major component of neurofibrillary tangles, was shown to be prevented in the presence of FKBP12, which depended on its peptidyl-prolyl-isomerase activity [45]. The effect of FKBP12 on the aggregation of full-length tau or in a cellular environment was not tested. The aggregation of α-synuclein, which is thought to contribute to Parkinson's disease, was shown to be enhanced by FKBPs in an FK506sensitive manner in vitro [46] and in cellular models [47]. FKBP12 was identified as the most important FKBP homolog for α-synuclein aggregation [48]. In a proteomic analysis of a mouse model of Huntington's disease FKBP12 was identified as one of the most prominently downregulated proteins in the brains of aged mice [49]. Overexpression of FKBP12 in a cellular model of Huntington's disease reduced the amount of aggregated huntingtin. One of the best described molecular functions of FKBP12 and FKBP12.6 is the stabilization of ryanodine receptors, thereby preventing leaking of Ca2+ ions from the endoplasmatic reticulum [50]. Excessive Ca2+ influx through ryanodine receptors was suggested to contribute to neuronal death in models of Huntington's disease, and overexpression of FKBP12 was shown to prevent this exitotoxicity [51]. Recently, Marks and colleagues investigated the role of the ryanodine receptor 2 (RyR2) in stress-coping behavior [52]. They observed that chronic stress destabilized binding of FKBP12.6 to RyR2 by posttranslational modifications of the latter. In knock-in mice with a regulation-insensitive RyR2 mutant they could show that the FKBP12.6-RyR2 mutant complex is not affected by chronic stress anymore. Moreover, the tool compound S107 known to stabilize the FKBP12.6-RyR2 complex was found to protect from developing chronic stress-induced anxiogenic behavior. While these results are interesting and a role of RyR2 seems evident, the involvement of FKBP12.6 was largely implied by the use of compound S107. In light of the controversies regarding the mechanism of action of S107 [53] or its derivative K201 (JTV519) [54], the role of FKBP12.6 in stress-coping needs to be further defined. After FKBP12 had been devalidated as the target of neuroimmunophilin ligands the larger homolog FKBP52 had been advocated as the relevant target [22,31,55]. This conclusion was originally based on the neuritotrophic effect observed for an anti-FKBP52 antibody in saponin-permeabilized SH-SY5Y cells [22,55]. Mild stimulation of neurite outgrowth was also observed in primary cortical neurons after knockdown of FKBP52 [31]. Mechanistically, the potentiation of neurite outgrowth after FKBP52 inhibition was explained by an activation of steroid hormone receptors. This interpretation, however, is clearly at odds with numerous studies that established FKBP52 as a positive factor for steroid hormone receptors in vitro and in vivo [56]. In all these studies, deletion or reduction of FKBP52 resulted in reduced steroid hormone signaling. The extrapolation of these findings towards a role of FKBP52 in neuronal function is, however, less straightforward. The effects of steroids, especially glucocorticoids, on neurons are complex, involving glucocorticoid and mineralocorticoid receptors with partially overlapping or counteracting functions. Generally, low doses of
Please cite this article as: F. Hausch, FKBPs and their role in neuronal signaling, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbagen.2015.01.012
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glucocorticoids seem to be necessary for neurons in culture and for synaptic plasticity in vivo. On the other hand, high concentrations of glucocorticoids have been reported to be neurotoxic and to contribute to neuronal atrophy after stress. The neuroendocrine analysis of FKBP52 is further complicated by an important peripheral role in progesterone and androgen receptor signaling, leading to a severely compromised sex organ development especially in male FKBP52-deficient mice [56]. A characterization of heterozygous FKBP52+/− mice, which have a normal development, revealed reduced basal but enhanced stress-induced corticosterone levels. FKBP52+/− mice also displayed a mixed behavioral phenotype, with enhanced anxiety in the elevated plus maze test but a more active stress-coping in the forced swim test after chronic stress [57]. For the interpretation of the neuronal role of FBKP52 it is necessary to consider other, steroid receptor-unrelated pathways that are affected by FKBP52. Notably, FKBP52 was found to associate with canonical transient receptor potential channels, which are known to be involved in the chemotrophic guidance of neuronal growth cones. The peptidyl-prolylisomerase-inactive mutant FKBP52F67D/D68V was identified as an inhibitor of TRPC1 and was shown to inhibit netrin-1-induced Ca2 + influx into growth cones or netrin-1-induced turning of growth cones [58]. Similar results were observed with the FK506 derivative GPI-1046, although these findings are difficult to reconcile with the fact that GPI1046 does not bind to the FK506-binding site of FKBPs (see above), including FKBP52 [28]. 4. Neuronal and neuroendocrine functions of FKBP51 It is possible that the role of FKBP52 is cell type-dependent. In contrast to the early reports of FKBP52 as a neurite outgrowth inhibitor, Quinta et al. observed enhanced neurite outgrowth of N2a neuroblastoma cells after overexpression of FKBP52, while FKBP52 knockdown dramatically reduced neurite outgrowth in these cells [59]. In addition, Quinta also investigated the homolog FKBP51 and observed exactly the opposite: FKBP51 overexpression reduced neurite outgrowth while FKBP51 silencing enhanced it. Since FKBP51 and FKBP52 both potently bind FK506 [60], we hypothesized that the contrasting roles of FKBP51 and FKBP52 might have confounded some of the earlier studies with immunophilin ligands [61]. Addressing this question pharmacologically, however, turned out to be difficult since all FK506 analogs prepared so far did not discriminate between FKBP51 and FKBP52 [28, 62–65]. This is in line with the highly conserved FK506-binding site of these two proteins, which show an almost identical structure [66,67]. To tackle this challenge we decided to adopt a chemical biology approach that had been developed to pharmacologically distinguish between FKBP12 and tailor-made FKBP12 mutants [68]. In this system, also called the bump-and-hole-approach, the active site of FKBP12 was enlarged, allowing complementarily enlarged ligands to bind (Fig. 2). Importantly, the larger modification in the engineered ligand would clash with the smaller binding pocket of the wildtype protein,
thereby discriminating against the latter. Similar approaches using engineered orthogonally selective ligand–mutant pairs have been developed to study the role of kinases (analog-sensitive kinase alleles) [69] or of GPCRs (RASSLs [70] or DREADs [71]). FKBP12 mutants fused to proteins of interest have been extensively used in chemical biology, but we are not aware that this method has been used to investigate the biology of FKBPs itself. To adopt this method for FKBP51 and FKBP52 slight chemical modifications of Shield-1, the most advanced ligand for the FKBP12F37V mutant, were necessary to obtain high affinities for the FBKP51F67V and FKBP52F67V mutants [72]. Gratifyingly, the F67V mutation did not affect the pro- or anti-neuritotrophic effect of FKBP52 or FKBP51, respectively. With this well-controlled system at hand, we interrogated the consequence of FKBP51 or FKBP52 inhibition in N2a cells (Fig. 2). Treatment of FKBP51F67V-overexpressing cells with the FKBPF67V-selective ligand 1 completely abrogated the neurite outgrowth-inhibiting effect of FKBP51F67V while cells overexpressing wildtype FKBP51 were not affected at all. Likewise, ligand 1 blocked the pro-neuritotrophic effect of overexpressed FKBP52F67V but not of wildtype FKBP52. This experiment unequivocally established that inhibition of the FK506-binding site of FKBPs can increase but also decrease neurite outgrowth, depending on which FKBP homolog is inhibited. To show that this can lead to a situation where the dual effects of FKBP inhibitors cancel each other we overexpressed FKBP51 and FKBP52 simultaneously [72]. In this setup the anti- and pro-neuritotrophic effects of the two proteins are balanced and neurite outgrowth proceeds at basal levels. Again, selective inhibition of FKBP51 – by overexpressing an FKBP51 F67V /FKBP52 WT combination – enhanced neurite outgrowth while selectively inhibiting FKBP52 in FKBP51WT / FKBP52 F67 -overexpressing cells reduced it. Notably, when both overexpressed FKBPs were inhibited simultaneously – by treating FKBP51 F67V/FKBP52 F67V-overexpressing cells with ligand 1 – no overall change in neurite outgrowth was observed. This proves that for FKBP51/52-unselective ligands their overall effect may be masked if both FKBPs are present in the investigated cells. When studying FKBP51 or FKBP52, selectivity between these two proteins is thus essential. While the bump-and-hole approach is extremely powerful in situations where FKBP51 or FKBP52 can be overexpressed it does not allow interrogating the role of endogenous proteins. In our quest for selective inhibitors for wildtype FKBP51 we were fostered by serendipity. We observed that an analog of ligand 1 retained some affinity for FKBP51 but not for FKBP52 [72]. Cocrystal structure analysis revealed that this analog called iFit1 bound to FKBP51 with an induced-fit binding mode that was not possible for FKBP52. Optimization by medicinal chemistry rapidly enhanced the affinity for this new induced-fit conformation, leading to SAFit1 and SAFit2 (Fig. 1D). These two compounds potently bound FKBP51 (Ki = 4–6 nM) while discriminating N 10,000-fold against FKBP52. These compounds also potently stimulated neurite outgrowth in mouse N2a cells, human SH-SY5Y cells and in primary E18 hippocampal neurons.
Fig. 2. Mutant-ligand pairs to pharmacologically address FKBP51 or FKBP52. Middle: Scheme of the bump-and-hole system for the generation of the FKBP mutant-selective ligand 1. Ligand 1 binds the engineered mutants FKBP51F67V or FKBP52F67V, but not the wildtype counterparts. Left and right: Neurite outgrowth assays in N2a cells. Ligand 1 blocks the anti- and pro-neuritotrophic effects of overexpressed FKBP51F67V or FKBP52F67V. From Ref. [72].
Please cite this article as: F. Hausch, FKBPs and their role in neuronal signaling, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbagen.2015.01.012
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Importantly, no stimulation of neurite outgrowth was observed in FKBP51-deficient neurons, strongly indicating that inhibition of FKBP51 was responsible for the observed effect. In control experiments we observed that several pan-selective FKBP inhibitors like FK506, antascomycin [73], or compounds (S)-19 or (R)19 [64] all stimulated neurite outgrowth in N2a cells (Figs. 1D, 3), in line with the original claims for neuroimmunophilin ligands. However, the related FKBP12-selective inhibitor 44 [63] failed to stimulate neurite outgrowth under the same condition, further supporting the notion that FKBP12 is not involved in the regulation of neurite outgrowth. Interestingly, we noticed that all pan-selective FKBP inhibitors displayed a bellshaped dose–response curve, with enhancement of neurite outgrowth only at medium but not high inhibitor concentrations [64,72]. This phenomenon has previously been observed for other FKBP ligands, other cell types and even in vivo [6,10,19,22,55]. The fact that several chemically distinct FKBP inhibitors display the same bell-shaped dose– response curve strongly suggests that inhibition of an FKBP species is responsible for the neurite-promoting activity at low concentrations as well as for the loss thereof at higher concentrations. In light of the opposing roles of FKBP51 and FKBP52 it is tempting to speculate that inhibition of FKBP51 accounts for the neurite outgrowth stimulation at low concentrations, while additional inhibition of FKBP52 negates the latter. However, an open question is how to reconcile this hypothesis with the equal binding affinities of the pan-selective FKBP ligands for FKBP51 and FKBP52. One possibility may be that the interaction partners of FKBP51 inside the cells are more easily displaced by competitive ligands than the interaction partners of FKBP52. Dedicated mechanistic studies to elucidate the pathways by which FKBP51 inhibit and FKBP52 promote neurite outgrowth are required to address this point. It should be noted that neurite outgrowth assays in cell culture are primarily useful for mechanistic studies. They provide a cellular context that is close to neurons and may involve pathways that are relevant for early steps of neuronal differentiation. The fact that FKBP51 and FKBP52 inhibitors affect cell morphology and differentiation in several cell lines with neuronal properties suggests that FKBP51 may have a more cellintrinsic neuronal role than previously thought. This is important in light of the established role that FKBP51 plays in stress-related psychiatric diseases. Single nucleotide polymorphisms in FKBP5, the gene encoding FKBP51, have repeatedly been associated with an enhanced risk to develop disorders like depression or PTSD — often in combination with early life trauma. The same single nucleotide polymorphisms were also associated with several stress-related endophenotypes including suicidal ideation, aggression, stress-coping, fear perception [74]. Recently, the causal single nucleotide polymorphisms were
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identified, where the risk alleles were shown to enhance FKBP5 expression by translational and epigenetic mechanisms [75]. It is therefore generally accepted that FKBP51 contributes to the pathogenesis of stress-related disorders. Numerous studies in mice have established FKBP51 as an important factor for stress-coping behavior. FKBP51 is a potent inhibitor of the glucocorticoid receptor, which mediates the cellular responses to the stress hormone corticosterone. FKBP51−/− mice had reduced levels of corticosterone [76–78] and an enhanced negative feedback regulation of the hypothalamus–pituitary–adrenal (HPA) axis, an important endocrine stress response system that is often deregulated in depressive patients [79]. FKBP51−/− mice which also had a more active stress-coping behavior [77–80], were protected from the endocrine alterations of chronic stress [81], and had enhanced cognitive flexibility in a reversal learning paradigm [78]. Similarily, mice with a viral reduction of FKBP51 in the amygdala were found to be less anxious [82]. Notably, FKBP51 deletion only affected behavioral traits of glucocorticoid signaling, but not other glucocorticoid receptor-regulated phenotypes such as glucose metabolism or immune markers. No other peripheral abnormalities were found in FKBP51−/− mice suggesting that FKBP51 inhibition may be free from target-related side effects. Taken together, these findings convincingly validated FKBP51 as a potential target for stress-related disorders [83]. With the availability of SAFit2, a brain-permeable FKBP51 inhibitor of the iFit class, we tested the effect of FKBP51 in vivo [72]. SAFit2 reduced corticosterone levels during the peak time of corticosterone secretion, it enhanced glucocorticoid receptor sensitivity at the level of HPA axis regulation, and it enhanced stress coping in the forced swim test, the classical test for antidepressant activity. These effects mimicked earlier observations in FKBP51−/− mice, supporting the concept that SAFit2 works by inhibition of FKBP51. Collectively, these results provided the proof of concept for FKBP51 inhibition as a way to pharmacologically enhance stress coping and stress hormone homeostasis. 5. Summary The role of FKBPs in neuroprotection or neuroregeneration, e.g. after nerve injuries, is unclear. However, FKBP51 has emerged as an important regulator of stress in mammals. It is therefore possible that some of the compounds inspired by the early immunophilin ligands turn out to be useful for the treatment of stress-related disorders. Transparency Document The Transparency document associated with this article can be found, in the online version. Acknowledgements This work was supported in part by the M4 award to FH. References
Fig. 3. Pan-selective FKBP ligands stimulate neurite outgrowth with a bell-shaped dose– response curve. N2a cells were treated with the indicated concentrations of the FKBP inhibitor (S)-19 [64]. Similar results were obtained with several other pan-selective FKBP ligands.
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Please cite this article as: F. Hausch, FKBPs and their role in neuronal signaling, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbagen.2015.01.012