In this revised application, we will investigate how the FK506 binding protein 5 (FKBP5) is up- regulated to coordinate how the brain responds to stress. Since 2004, our team has worked to show that single nucleotide polymorphisms (SNPs) in the FKBP5 gene associate with increased risk of psychopathologies caused by stress, as highlighted in Nature Genetics 36:1319-25 2004 &JAMA 299:1291-305 2008. We have also shown that these risk SNPs increase the levels of FKBP5 through a mechanism that involves demethylation of the FKBP5 gene (Nature Neuroscience. 16:33-41 2013 &Journal of Clinical Investigation 123:4158-69 2013). There are currently 2 other mechanisms besides these SNPs that are known to increase FKBP5 levels in the brain: 1) Stimulation of the glucocorticoid receptor (GR) by the steroid hormone cortisol (corticosterone/CORT), and 2) modulation of the receptor tyrosine kinase EphB2 (Attwood et al. Nature 473:372-5 2011). In our previous work, we found that mice lacking the FKBP5 gene (FKBP5-/- mice) are protected from stress-induced depressive-like phenotypes, and that apart from this improved resiliency, these mice seem very normal. Acute suppression of FKBP5 in the amygdala has also been shown to protect mice from anxiety-like behavior, but there are still gaps in our knowledge about the function and regulation of FKBP5 in the brain. While we know that FKBP5 does reduce resiliency to stress, we do not know whether chronically increased FKBP5 levels in the brain can fully model impaired stress resiliency through a mechanism that is similar to humans carrying risk SNPs. We also do not know how FKBP5 overexpression impacts learning and memory despite clear connections between stress and cognitive function. We know that chronic stress disrupts cognitive processes and electrophysiological function of neurons. But we do not know if stress- induced deficits in cognition, plasticity, hippocampal volume or neurogenesis are mediated by FKBP5. Lastly, we know that FKBP5 expression is up-regulated by GR and EphB2 signaling, and we also know that demethylation of the FKBP5 gene in humans contributes to FKBP5 upregulation. But we do not know how other epigenetic modifying proteins contribute to FKBP5 expression and demethylation, nor do we know how the EphB2 receptor regulates FKBP5 expression through a similar methylation mechanism. To fill these gaps, we will examine the effects of FKBP5 overexpression on stress resiliency and cognitive function, examine the effects of FKBP5 on cognitive and neuronal deficits caused by chronic stress and investigate the mechanisms that control FKBP5 expression. We anticipate that these studies will show the importance of FKBP5 to the brain's stress response, leading to new insights about its role in psychopathologies and cognitive function. We will also define new upstream regulators of FKBP5 expression.
The role that stress plays in mental disorders will be examined in this proposal. We have identified the FKBP5 gene to be a central contributor to depression that arises from stress. The goal here is to determine whether FKBP5 also participates in memory dysfunction and whether strategies aimed at depleting FKBP5 could be beneficial for the treatment of psychological disorders caused by stress.
|Criado-Marrero, Marangelie; Rein, Theo; Binder, Elisabeth B et al. (2018) Hsp90 and FKBP51: complex regulators of psychiatric diseases. Philos Trans R Soc Lond B Biol Sci 373:|
|Sabbagh, Jonathan J; Cordova, Ricardo A; Zheng, Dali et al. (2018) Targeting the FKBP51/GR/Hsp90 Complex to Identify Functionally Relevant Treatments for Depression and PTSD. ACS Chem Biol 13:2288-2299|
|Oroz, Javier; Chang, Bliss J; Wysoczanski, Piotr et al. (2018) Structure and pro-toxic mechanism of the human Hsp90/PPIase/Tau complex. Nat Commun 9:4532|
|Shelton, Lindsey B; Koren 3rd, John; Blair, Laura J (2017) Imbalances in the Hsp90 Chaperone Machinery: Implications for Tauopathies. Front Neurosci 11:724|
|Baker, Jeremy D; Shelton, Lindsey B; Zheng, Dali et al. (2017) Human cyclophilin 40 unravels neurotoxic amyloids. PLoS Biol 15:e2001336|
|Shelton, Lindsey B; Baker, Jeremy D; Zheng, Dali et al. (2017) Hsp90 activator Aha1 drives production of pathological tau aggregates. Proc Natl Acad Sci U S A 114:9707-9712|
|Zheng, Dali; Sabbagh, Jonathan J; Blair, Laura J et al. (2016) MicroRNA-511 Binds to FKBP5 mRNA, Which Encodes a Chaperone Protein, and Regulates Neuronal Differentiation. J Biol Chem 291:17897-906|
|Young, Zapporah T; Rauch, Jennifer N; Assimon, Victoria A et al. (2016) Stabilizing the Hsp70-Tau Complex Promotes Turnover in Models of Tauopathy. Cell Chem Biol 23:992-1001|
|Lindberg, Iris; Shorter, James; Wiseman, R Luke et al. (2015) Chaperones in Neurodegeneration. J Neurosci 35:13853-9|
|Fontaine, Sarah N; Sabbagh, Jonathan J; Baker, Jeremy et al. (2015) Cellular factors modulating the mechanism of tau protein aggregation. Cell Mol Life Sci 72:1863-79|
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