The Role of FKBPs in Complex Disorders: Neuropsychiatric Diseases, Cancer, and Type 2 Diabetes Mellitus

Abstract

Stress is a common denominator of complex disorders and the FK-506 binding protein (FKBP)51 plays a central role in stress. Hence, it is not surprising that multiple studies imply the involvement of the FKBP51 protein and/or its coding gene, FKBP5, in complex disorders. This review summarizes such reports concentrating on three disorder clusters-neuropsychiatric, cancer, and type 2 diabetes mellitus (T2DM). We also attempt to point to potential mechanisms suggested to mediate the effect of FKBP5/FKBP51 on these disorders. Neuropsychiatric diseases considered in this paper include (i) Huntington's disease for which increased autophagic cellular clearance mechanisms related to decreased FKBP51 protein levels or activity is discussed, Alzheimer's disease for which increased FKBP51 activity has been shown to induce Tau phosphorylation and aggregation, and Parkinson's disease in the context of which FKBP12 is mentioned; and (ii) mental disorders, for which significant association with the single nucleotide polymorphism (SNP) rs1360780 of FKBP5 intron 7 along with decreased DNA methylation were revealed. Since cancer is a large group of diseases that can start in almost any organ or tissue of the body, FKBP51's role depends on the tissue type and differences among pathways expressed in those tumors. The FKBP51-heat-shock protein-(Hsp)90-p23 super-chaperone complex might function as an oncogene or as a tumor suppressor by downregulating the serine/threonine protein kinase (AKt) pathway. In T2DM, two potential pathways for the involvement of FKBP51 are highlighted as affecting the pathogenesis of the disease-the peroxisome proliferator-activated receptor-γ (PPARγ) and AKt.

Keywords: FKBP5; cancer; complex disorders; neuropsychiatric disorders; type 2 diabetes mellitus (T2DM).

Figure 1

The 3-D structure of FKBP12 vs. FKBP51 and FKBP52. Left: Atomic structure of FKBP12-FK506 (https://doi.org/10.2210/pdb1FKJ/pdb, accessed on 29 April 2024). FKBP12 contains the PPIase core domain but not the C-terminal tetratricopeptide repeat (TPR) domain that mediates interaction with Hsp90. Middle: structure of the Large FKBP-like Protein, FKBP51 (https://doi.org/10.2210/pdb1KT1/pdb, accessed on 29 April 2024). Right: Structure of FKBP52 [7]. FKBP51 and FKBP52 share 70% similarity and contain an active PPIase domain, bind Hsp90 through a TPR domain [3], and adopt similar formations.

Figure 2

An illustration of the involvement of FKBPs in complex disorders. Generally, increased FKBP51 enzymatic activity/protein levels and/or FKBP5 mRNA levels are related to negative effects, namely, increased disease severity (and vice versa). Positive effects: (A) Neuropsychiatric diseases—in HD, when FKBP51 protein levels or activity were decreased using genetic or pharmacological approaches, reduced mHTT levels were observed in the isogenic human HD stem cell model [24]. In AD, downregulation of FKBP51 activity (using siRNA) profoundly decreases Tau expression [49]. (B) Cancer—FKBP51 may function as a tumor suppressor in the AKt signaling pathway, through a scaffolding protein that enhances the PH domain and leucine-rich repeat protein phosphatase (PHLPP)–AKt interaction [76,78]. (C) TD2M—compounds that bind/inhibit FKBP51, such as FK506 and the specific inhibitor SAFit, may directly diminish adipogenesis and lipid storage, increase insulin sensitivity, and reduce body mass [80,85]. Negative effects: (D) Neuropsychiatric diseases—in relation to AD, over-expression of the chaperone complex consisting of FKBP51 and HSP90 in mice inhibited proteasomal degradation of Tau and led to Tau accumulation [50]. FKBP52 interacts with Tau through a specific proline-rich region. FKBP52 inhibited microtubule growth and led to oligomerization and aggregation of Tau [52]. In relation to PD, enzymatic activity of FKBP12 increases the formation of α-SYN fibrils at sub-nanomolar concentrations [59]. In relation to psychiatric disorders, low DNA methylation levels were reported in FKBP5’s intron 7 in patients with psychiatric disorders [61] and common allelic variants in this gene were reported to be associated with increased risk of developing affective disorders (anxiety, depression, and PTSD) [18]. (E) Cancer—FKBP5 functions as an oncogene or a tumor suppressor depending on the tissue type and the pathways expressed in those tumors. For example, activation of FKBP5 transcription via the androgen receptor was reported in prostate cancer [67,68]; an FKBP51–Hsp90–p23 super-chaperone complex stimulates androgen-dependent transcription activation and cell growth [70]; FKBP51 is essential for drug-induced NF-κB activation in human leukemia [73]; and FKBP51 was identified as a negative regulator of Akt [75,76]. (F) TD2M—FKBP5 DNA methylation correlated with adiposity, insulin resistance, and systemic inflammation; it also inversely correlated with FKBP5 mRNA levels, which were positively associated with adiposity, metabolic, and inflammatory parameters [82]; increased FKBP5 DNA methylation correlated with higher HbA1c levels [83]. Abbreviations: AD—Alzheimer’s disease; AKt/PKB—RAC-alpha serine/threonine-protein kinase/protein kinase B; HD—Huntington’s disease; HSP90—heat-shock protein 90; IκB—inhibitor of κB; mHTT—mutant huntingtin; NF-κB—nuclear factor kappa-light-chain-enhancer of activated B cells; PD—Parkinson’s disease; PHLPP—Pleckstrin homology (PH) domain leucine-rich repeat protein phosphatase; α-SYN—alpha-synuclein; T2DM—Type 2 diabetes mellitus. A mouse model of PD. mRNA. DNA. Fast proliferating cells (cancer). Over-expression of the chaperone complex consisting of FKBP51 and HSP90. Inhibition. Aggregation of mutant Tau.