SKA2 Enhances Stress-related Glucocorticoid Receptor Signaling Through FKBP4-FKBP5 Interactions in Neurons

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2024 Dec 20

PMID 39705315

Authors

Jakob Hartmann

Claudia Klengel

Larissa J Dillmann

Erin E Hisey

Kathrin Hafner

Rammohan Shukla

Marina Soliva Estruch

Thomas Bajaj

Tim Ebert

Katharine G Mabbott

Luise Rostin

Alexandra Philipsen

William A Carlezon Jr

Barbara Gisabella

Robert E McCullumsmith

John M Vergis

Torsten Klengel

Sabina Berretta

Nikolaos P Daskalakis

Harry Pantazopoulos

Nils C Gassen

Kerry J Ressler

Affiliations

Soon will be listed here.

Abstract

Genes involved in regulating the hypothalamic-pituitary-adrenal (HPA) axis, including the glucocorticoid receptor (GR), are linked to various stress-related psychopathologies including bipolar disorder as well as other mood and trauma-related disorders. The protein product of the cell cycle gene, is a GR interaction partner in peripheral cells. However, the precise roles of SKA2 in stress and GR signaling in the brain, specifically in nonreplicating postmitotic neurons, and its involvement in HPA axis regulation remain unclear. Here, we demonstrate, using diverse in vitro cell assays, a mechanism by which SKA2 promotes GR signaling through enhancing GR-FKBP4 interaction leading to dissociation of FK506-bindingprotein 51 (FKBP5) from the complex. FKBP4 and FKBP5 are cochaperones known to regulate GR function in opposite directions. Notably in mice, SKA2 in neurons of the paraventricular nucleus of the hypothalamus is crucial for HPA axis responsiveness and for maintaining the negative feedback loop underlying allostasis. Moreover, we show that SKA2 expression is increased in postmortem human hippocampus and amygdala from individuals with BD. Our study highlights a critical role of SKA2 in HPA axis function, adds to the understanding of the molecular basis of stress-related psychiatric disorders, and points to potential targets for intervention.

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