ESPEYB25 8. Adrenals Mechanism of the Year (1 abstracts)
8.1. SKA2 enhances stress-related glucocorticoid receptor signaling through FKBP4-FKBP5 interactions in neurons
Hartmann J , Klengel C , Dillmann LJ , Hisey EE , Hafner K , Shukla R , SolivaEstruch M , Bajaj T , Ebert T , Mabbott KG , Rostin L , Philipsen A , Carlezon WA Jr , Gisabella B , McCullumsmith RE , Vergis JM , Klengel T , Berretta S , Daskalakis NP , Pantazopoulos H , Gassen NC & Ressler KJ
Proc Natl Acad Sci USA. 2024;121(52): e2417728121. doi: 10.1073/pnas.2417728121
Brief summary: This in vitro and in vivo study highlights the role of SKA2 in the regulation of glucocorticoid receptor (GR) signaling within the central nervous system (CNS), hypothalamic-pituitary-adrenal (HPA) axis function and the stress response, and suggests potential targets for therapeutic intervention of stress-related psychiatric disorders.
Comment: Genes involved in the regulation of the HPA axis, including the GR, are associated with various stress-related psychopathologies, such as posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and bipolar disorder (BD) (1-5). The cell cycle gene SKA2, encoding the spindle and kinetochore associated (SKA) complex subunit 2, has been identified as a GR-interacting protein, enhancing the receptor’s nuclear translocation in peripheral cells in vitro (6). SKA2 is a multifunctional scaffolding protein involved in cell cycle regulation, secretory autophagy, as well as GR signaling in peripheral cells. This study examined the precise roles of SKA2 in stress and GR signaling in the brain, and its involvement in HPA axis regulation.
Using diverse in vitro cell assays, the authors demonstrated that SKA2 is expressed throughout the mouse brain including the prefrontal cortex (PFC), periventricular nucleus (PVN), hippocampus and amygdala, associates with GR and acts as a positive regulator of GR signaling. SKA2 promotes GR signaling in neuronal cells through enhanced interaction with FKBP4, a cochaperone known to positively regulate GR function and in opposition to FKBP5, which leads to dissociation of FKBP5 from the complex. Furthermore, knocking down of Ska2 in the PVN of mice alters stress-induced HPA axis activity and delays its negative feedback loop of the HPA axis, which is pivotal in the regulation of stress response, and is often impaired in stress-related disorders. Moreover, SKA2 expression is increased in postmortem human hippocampus and amygdala from individuals with BD, and SKA2 expression may follow a diurnal rhythm, which is shifted and less pronounced in people with BD than healthy controls.
In conclusion, these findings highlight the role of SKA2 in the regulation of GR signaling within the CNS, HPA function and the stress response, provide further insight into the molecular basis of stress-related psychiatric disorders, and suggest potential targets for therapeutic intervention.
References: 1. McEwen BS. Protection and damage from acute and chronic stress: Allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders. Ann. N. Y Acad. Sci. 2024; 1032: 1–7.2. De Kloet ER, Joëls M, Holsboer F. Stress and the brain: From adaptation to disease. Nat. Rev. Neurosci. 2005; 6: 463–475.3. Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat. Rev. Neurosci. 2009; 10: 434–445.4. de Kloet ER, Vreugdenhil E, Oitzl MS, Joëls M. Brain corticosteroid receptor balance in health and disease. Endocr. Rev. 1998; 19: 269–301.5. de Kloet ER, Meijer OC, de Nicola AF, de Rijk RH, Joëls M. Importance of the brain corticosteroid receptor balance in metaplasticity, cognitive performance and neuro-inflammation. Front. Neuroendocrinol. 2018; 49: 124–145.6. Rice L, Waters CE, Eccles J, Garside H, Sommer P, Kay P, Blackhall FH, Zeef L, Telfer B, Stratford I, Clarke R, Singh D, Stevens A, White A, Ray DW. Identification and functional analysis of SKA2 interaction with the glucocorticoid receptor. J Endocrinol. 2008; 198(3): 499-509.
Volume 22
Article tools
My recent searches
My recently viewed abstracts
Authors
ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
© Bioscientifica 2025 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more