Hartmann Jakob, Klengel Claudia, Dillmann Larissa J, Hisey Erin E, Hafner Kathrin, Shukla Rammohan, Soliva Estruch Marina, Bajaj Thomas, Ebert Tim, Mabbott Katharine G, Rostin Luise, Philipsen Alexandra, Carlezon William A, Gisabella Barbara, McCullumsmith Robert E, Vergis John M, Klengel Torsten, Berretta Sabina, Daskalakis Nikolaos P, Pantazopoulos Harry, Gassen Nils C, Ressler Kerry J
Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA 02478.
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich 80804, Germany.
Proc Natl Acad Sci U S A. 2024 Dec 24;121(52):e2417728121. doi: 10.1073/pnas.2417728121. Epub 2024 Dec 20.
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.
参与调节下丘脑 - 垂体 - 肾上腺（HPA）轴的基因，包括糖皮质激素受体（GR），与各种应激相关的精神病理学有关，包括双相情感障碍以及其他情绪和创伤相关障碍。细胞周期基因的蛋白质产物，是外周细胞中GR的相互作用伙伴。然而，SKA2在大脑应激和GR信号传导中的确切作用，特别是在非复制的有丝分裂后神经元中，以及它在HPA轴调节中的作用仍不清楚。在这里，我们使用多种体外细胞测定法证明了一种机制，通过该机制SKA2通过增强GR - FKBP4相互作用来促进GR信号传导，从而导致FK506结合蛋白51（FKBP5）从复合物中解离。FKBP4和FKBP5是已知以相反方向调节GR功能的共伴侣。值得注意的是，在小鼠中，下丘脑室旁核神经元中的SKA2对于HPA轴反应性和维持体内平衡基础的负反馈回路至关重要。此外，我们表明，双相情感障碍患者死后海马体和杏仁核中的SKA2表达增加。我们的研究突出了SKA2在HPA轴功能中的关键作用，增进了对应激相关精神障碍分子基础的理解，并指出了潜在的干预靶点。
