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. 2013 Dec 18:3:3539.
doi: 10.1038/srep03539.

Dysregulation of glucocorticoid receptor co-factors FKBP5, BAG1 and PTGES3 in prefrontal cortex in psychotic illness

Duncan Sinclair  1 , Stu G Fillman  2 , Maree J Webster  3 , Cynthia Shannon Weickert  2
Affiliations

Dysregulation of glucocorticoid receptor co-factors FKBP5, BAG1 and PTGES3 in prefrontal cortex in psychotic illness

Duncan Sinclair et al. Sci Rep. .

Abstract

Molecular abnormalities within the glucocorticoid receptor (GR) stress signaling pathway may confer, or reflect, susceptibility to stress in schizophrenia and bipolar disorder, but the extent of such abnormalities in the brain is not known. Using RNA-Seq and qPCR in two postmortem cohorts totaling 55 schizophrenia, 34 bipolar disorder and 55 control individuals, we identified increased FKBP5 and PTGES3 mRNA expression, and decreased BAG1 mRNA expression, in the prefrontal cortex in schizophrenia cases relative to controls (68.0% [p < 0.001], 26.0% [p < 0.01] and 12.1% [p < 0.05] respectively). We also observed increased FKBP5 and decreased BAG1 mRNA expression in bipolar disorder (47.5% [p < 0.05] and 14.9% [p < 0.005]). There were no diagnostic differences in steady-state FKBP51 protein levels, nor in HSPA1A, HSP90AA1, DNAJB1 or HSPB1 mRNA levels. GR, co-factor and chaperone mRNA levels were strongly correlated. These results reveal coordinated cortical dysregulation of FKBP5, PTGES3, BAG1 and GR genes within the glucocorticoid signaling pathway in psychotic illness.

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Figures

Figure 1
Figure 1. The involvement of key co-factors and chaperones in GR-mediated stress signaling.
(A) Hsp40 and Hsp70 facilitate, while Bag1 impairs, the folding of GR into a low steroid-affinity conformation. Bag1 also aids degradation of the unstable folded GR complex, (B) Hsp90, p23 and FKBP51 stablilise the GR complex in a high affinity state, (C) Displacement of FKBP51 by FKBP52 enables the translocation of the cortisol-bound GR heterocomplex to the nucleus, (D) Within the nucleus, GR activates or represses the transcription of target genes, at GREs or nGREs respectively. Overexpression of Bag1, Hsp90 or p23 can repress GR-responsive gene transcription. Availability of free cortisol (modulated by CBG) and inter-conversion of cortisol to cortisone by 11β-HSD1/2 also impact GR signaling. See Grad and Picard for comprehensive review. Abbreviations: GRE- glucocorticoid response element, nGRE- negative glucocorticoid response element, CBG- cortisol binding globulin, 11β-HSD- 11β-hydroxysteroid dehydrogenase.
Figure 2
Figure 2. Stress signaling co-factor gene expression in the DLPFC.
(A–D) Normalised expression of FKBP5, PTGES3, BAG1 and FKBP4 genes in schizophrenia cases (n = 20) and controls (n = 20) from the Sydney TRC cohort; (E–G) Normalised expression of FKBP5, PTGES3, BAG1 and FKBP4 in schizophrenia cases (n = 35), bipolar disorder cases (n = 31) and controls (n = 34) from the Stanley Array cohort. * p < 0.05, **p < 0.005.
Figure 3
Figure 3. mRNA expression of HSP chaperones in the DLPFC.
(A–D) Normalised expression of HSPA1A, HSP90AA1, DNAJB1 and HSPB1 genes in schizophrenia cases (n = 20) and controls (n = 20) from the Sydney TRC cohort; (E–G) Normalised expression of HSPA1A, HSP90AA1, DNAJB1 and HSPB1 in schizophrenia cases (n = 35), bipolar disorder cases (n = 31) and controls (n = 34) from the Stanley Array cohort.
Figure 4
Figure 4. Correlations between mRNA expression levels of GR-1B, stress signaling co-factors and chaperones in the DLPFC.
Red arrows represent negative correlations, and green arrows positive correlations, in the Stanley Array cohort. While correlations of chaperones/co-factors with GR-1B mRNA are illustrated, very similar correlations with total GR mRNA, GR-1C and GR-1H were seen. *p = 0.05, **p < 0.005, ***p < 0.0005, ****p < 0.00005.
Figure 5
Figure 5. FKBP51 protein expression and FKBP5 genotype effects in the Stanley Array cohort.
(A) representative FKBP51 western blot; (B) FKBP51 protein abundance in schizophrenia, bipolar disorder and control groups; (C) Details of genotyped FKBP5 SNPs. For each SNP, the bases occurring on the minus strand are described; (D) FKBP5 mRNA levels in the DLPFC according to rs4713916 genotype, in CC homozygotes (n = 44), TC heterozygotes (n = 32) and TT homozygotes (n = 9). Abbreviations: C- control, BP- bipolar disorder, SZ- schizophrenia, kDa- kilodaltons, MAF- minor allele frequency, HWE- Hardy-Weinberg Equilibrium.
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References

    1. Walker E. F. & Diforio D. Schizophrenia: A Neural Diathesis-Stress Model. Psychol Rev 104, 667–685 (1997). - PubMed
    1. Arseneault L. et al. Childhood trauma and children's emerging psychotic symptoms: A genetically sensitive longitudinal cohort study. Am J Psych 168, 65–72 (2011). - PMC - PubMed
    1. Khashan A. S. et al. Higher risk of offspring schizophrenia following antenatal maternal exposure to severe adverse life events. Arch Gen Psychiatry 65, 146–152 (2008). - PubMed
    1. Agid O. et al. Environment and vulnerability to major psychiatric illness: A case control study of early parental loss in major depression, bipolar disorder and schizophrenia. Mol Psychiatry 4, 163–172 (1999). - PubMed
    1. Yung A. R. et al. Mapping the onset of psychosis: The Comprehensive Assessment of At-Risk Mental States. Aust NZ J Psychiatry 39, 964–971 (2005). - PubMed

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