View Full Version : Dysregulation of glucocorticoid receptor co-factors


Amtram
01-12-14, 01:13 PM
This is an open-access report from Nature. Full title: Dysregulation of glucocorticoid receptor co-factors FKBP5, BAG1 and PTGES3 in prefrontal cortex in psychotic illness (http://www.nature.com/srep/2013/131218/srep03539/full/srep03539.html?WT.ec_id=SREP-20131224).

It's not just about psychotic illness - it studied that in particular, but also examined the differences among people with non-psychotic illnesses including bipolar and MDD. The subjects were, well, corpse brains of people with various diagnoses. What was being measured was glucocorticoid receptors in the prefrontal cortex relative to mRNA expression.

This is dense text, but I felt that it is relevant because there have been many discussions of glucose, cortisol, and stress as causative factors in the development of ADHD. This study shows a very robust correlation between genetics and vulnerability to stress, as demonstrated by the expression of glucocorticoid receptors in the PFC of these brains. This study shows positive and negative correlations of specific genes and GRs, as well as a possible SNP implication.

Essentially, what it's showing is that stress response, even when specific stress-implicated chemicals are being discussed, is far more complex than the simple presence or absence of these chemicals. Within this study, there is strong evidence that the genetic predisposition to the behavior of the GRs is highly influential in stress response. In other words, your genetic makeup is a determining factor in your susceptibility to the chemical changes initiated by stress. Changes in levels of glucose or cortisol alone don't determine stress levels. It's how your GRs respond to it that does it, and those GRs are generated on a molecular level.

Because not too many people will be able to slog through the whole thing, here's the introduction, just to give you a taste:

Stress has long been considered a contributor to the onset, symptoms and disease course of psychiatric illness. In support of this hypothesis, dysregulation of hypothalamic-pituitary-adrenal axis activity, under basal conditions and during stress, has been observed in schizophrenia and bipolar disorder. In both illnesses, decreased mRNA expression of the glucocorticoid receptor (GR), the primary receptor responsive to stress-induced cortisol secretion, has been observed using multiple post-mortem tissue cohorts and brain regions. In prefrontal cortex of individuals with schizophrenia and bipolar disorder, increased expression of a truncated GR protein isoform has been reproducibly demonstrated. It is not known whether these molecular stress signaling abnormalities in psychotic illness extend beyond GR, to include other cellular components such as stress receptor co-factors and chaperones which are integral to the stress response in the human brain.

Effective GR-mediated stress signaling relies on the coordinated activity of numerous co-factors and chaperones, which fold GR into a mature state, regulate its affinity for cortisol, facilitate its translocation into the nucleus, and modulate GR-mediated transcriptional activation or repression of target genes . Some of these co-factors and chaperones have been implicated in psychiatric illness. Single nucleotide polymorphisms (SNPs) within the gene for FKBP5, which binds GR and facilitates nuclear translocation, have been linked to bipolar disorder, major depression and post-traumatic stress disorder, and have been associated with impaired cognitive performance in individuals with schizophrenia. Increased FKBP5 gene expression has been reported in the frontal cortex in individuals with major depression, while decreased FKBP5 mRNA and protein have been described in the amygdala in suicide completers. Mood stabilizer treatments for bipolar disorder have been shown to up-regulate BAG1 expression. Hsp70 (HSPA1A) and Hsp90 (HSP90B1) gene SNPs have been associated with schizophrenia and bipolar disorder respectively. Increased mRNA expression of Hsp70 and Hsp27 has been observed in the prefrontal cortex of patients with schizophrenia. Transcriptional changes in important stress chaperones suggest their involvement in psychotic illness, yet these findings have yet to be replicated, while a number of key molecular regulators of stress responsiveness have yet to be examined. Furthermore, since the ability of the brain to respond to stress depends on coordinated modulation of gene expression, the relationships between expression of key stress chaperones and co-factors may illuminate how the GR stress pathway is regulated in cortical neurons to adapt to the demands of a changing environment.

Figure 1: The involvement of key co-factors and chaperones in GR-mediated stress signaling.

http://www.nature.com/srep/2013/131218/srep03539/images_article/srep03539-f1.jpg (http://www.nature.com/srep/2013/131218/srep03539/fig_tab/srep03539_F1.html)

(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.




In this study, we first used RNA sequencing in a cohort of 20 males with schizophrenia and matched controls to test if expression of stress receptor co-factors and chaperone genes FKBP5, FKBP4, PTGES3, BAG1, HSPA1A, HSP90AA1, DNAJB1 and HSPB1 was altered in the dorsolateral prefrontal cortex (DLPFC) of people with schizophrenia. These genes encode the FKBP51, FKBP52, p23, Bag1, Hsp70, Hsp90, Hsp40 and Hsp27 proteins respectively. The DLPFC brain region was employed because the most striking diagnostic differences in GR mRNA and protein expression in psychiatric illness have been evident in that region. We then used qPCR, in an additional independent cohort of up to 35 schizophrenia cases, 34 bipolar disorder cases and 35 controls, to replicate these results and test if any observed changes in stress response-related mRNAs found in schizophrenia were shared with, or distinct in, individuals with bipolar disorder. Thereafter, informed by our mRNA findings, we focused on FKBP5, quantifying FKBP51 protein in schizophrenia and bipolar disorder and explored the possible effects of eight FKBP5 genetic variants on FKBP5 mRNA and FKBP51 protein in the DLPFC. We hypothesized that molecular stress signaling abnormalities in schizophrenia and bipolar disorder may extend beyond GR mRNA and protein to include key co-factors and chaperones, and that relationships between mRNA transcripts would reflect a pathway coordinately dysregulated, resulting in disruption in the fine-tuning of stress responsiveness in the human DLPFC.