FKBP51,也称为FK506结合蛋白51,是一种分子伴侣和支架蛋白,在调节激素信号和应对胁迫方面具有重要作用。编码FKBP51的FKBP5的遗传变异与越来越多的神经精神疾病有关,这刺激了靶向治疗FKBP51的努力。然而,这些疾病中受FKBP51影响的分子机制和亚解剖区域尚不完全清楚.在这项研究中,我们旨在通过昼夜节律表型分析和分子分析来检验Fkbp5消融的影响.我们的研究结果表明,缺乏FKBP51并没有显着改变昼夜节律,由车轮运行活动检测到,但确实以性别依赖的方式提供了针对压力介导的节律性破坏的保护。Fkbp5KO小鼠的蛋白质变化,通过组织学和蛋白质组学测量,揭示了大脑区域和性别依赖方式的改变。值得注意的是,不管性别,老年Fkbp5KOs显示MYCBP2、FBXO45和SPRYD3水平升高,与神经元细胞粘附和突触完整性有关。此外,5-羟色胺受体信号和S100家族信号等通路在Fkbp5KO小鼠中被差异调节。加权蛋白质相关网络分析确定了与突触传递和神经炎症相关的蛋白质网络。这项工作产生的信息可用于更好地了解衰老和缺乏Fkbp5的情况下大脑的分子变化,这对持续开发针对压力相关疾病的FKBP51聚焦疗法具有重要意义。
FKBP51, also known as FK506-binding protein 51, is a molecular chaperone and scaffolding protein with significant roles in regulating hormone signaling and responding to stress. Genetic variants in FKBP5, which encodes FKBP51, have been implicated in a growing number of neuropsychiatric disorders, which has spurred efforts to target FKBP51 therapeutically. However, the molecular mechanisms and sub-anatomical regions influenced by FKBP51 in these disorders are not fully understood. In this study, we aimed to examine the impact of Fkbp5 ablation using circadian phenotyping and molecular analyses. Our findings revealed that the lack of FKBP51 did not significantly alter circadian rhythms, as detected by wheel-running activity, but did offer protection against stress-mediated disruptions in rhythmicity in a sex-dependent manner. Protein changes in Fkbp5 KO mice, as measured by histology and proteomics, revealed alterations in a brain region- and sex-dependent manner. Notably, regardless of sex, aged Fkbp5 KOs showed elevated MYCBP2, FBXO45, and SPRYD3 levels, which are associated with neuronal-cell adhesion and synaptic integrity. Additionally, pathways such as serotonin receptor signaling and S100 family signaling were differentially regulated in Fkbp5 KO mice. Weighted protein correlation network analysis identified protein networks linked with synaptic transmission and neuroinflammation. The information generated by this work can be used to better understand the molecular changes in the brain during aging and in the absence of Fkbp5, which has implications for the continued development of FKBP51-focused therapeutics for stress-related disorders.