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Author Notes:

Email: cdickey@health.usf.edu

Conceived and designed the experiments: JJS JO CAD.

Performed the experiments: JO LJB BAN TK EBB.

Analyzed the data: JJS LJB.

Contributed to the writing of the manuscript: JJS SNF TK EBB CAD.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors have declared that no competing interests exist.

Subjects:

Research Funding:

This work was supported by the National Institutes of Health/National Institutes of Neurological Disease and Stroke R01 NS073899 and the American Federation for Aging Research.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • PROTEIN 51 FKBP5
  • GLUCOCORTICOID-RECEPTOR
  • CHRONIC CORTICOSTERONE
  • DEPRESSIVE SYMPTOMS
  • IMMUNOPHILIN FKBP51
  • ALZHEIMERS-DISEASE
  • METABOLIC SYNDROME
  • MAJOR DEPRESSION
  • DISORDERS
  • RATS
  • Mice
  • DNA methylation
  • Depression
  • Animal behavior
  • Post-traumatic Stress Disorder
  • Cognition
  • Epigenetics
  • Glucose tolerance

Age-Associated Epigenetic Upregulation of the FKBP5 Gene Selectively Impairs Stress Resiliency

Tools:

Journal Title:

PLoS ONE

Volume:

Volume 9, Number 9

Publisher:

, Pages e107241-e107241

Type of Work:

Article | Final Publisher PDF

Abstract:

Single nucleotide polymorphisms (SNPs) in the FK506 binding protein 5 (FKBP5) gene combine with traumatic events to increase risk for post-traumatic stress and major depressive disorders (PTSD and MDD). These SNPs increase FKBP51 protein expression through a mechanism involving demethylation of the gene and altered glucocorticoid signaling. Aged animals also display elevated FKBP51 levels, which contribute to impaired resiliency to depressive-like behaviors through impaired glucocorticoid signaling, a phenotype that is abrogated in FKBP5-/-mice. But the age of onset and progressive stability of these phenotypes remain unknown. Moreover, it is unclear how FKBP5 deletion affects other glucocorticoid-dependent processes or if age-associated increases in FKBP51 expression are mediated through a similar epigenetic process caused by SNPs in the FKBP5 gene. Here, we show that FKBP51-mediated impairment in stress resiliency and glucocorticoid signaling occurs by 10 months of age and this increased over their lifespan. Surprisingly, despite these progressive changes in glucocorticoid responsiveness, FKBP5-/-mice displayed normal longevity, glucose tolerance, blood composition and cytokine profiles across lifespan, phenotypes normally associated with glucocorticoid signaling. We also found that methylation of Fkbp5 decreased with age in mice, a process that likely explains the age-associated increases in FKBP51 levels. Thus, epigenetic upregulation of FKBP51 with age can selectively impair psychological stress-resiliency, but does not affect other glucocorticoid-mediated physiological processes. This makes FKBP51 a unique and attractive therapeutic target to treat PTSD and MDD. In addition, aged wild-type mice may be a useful model for investigating the mechanisms of FKBP5 SNPs associated with these disorders.

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This is an Open Access work distributed under the terms of the Creative Commons Universal : Public Domain Dedication License (http://creativecommons.org/publicdomain/zero/1.0/).

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