Fkbp5 gene deletion: Circadian rhythm profile and brain proteomics in aged mice.

IF 8 1区 医学 Q1 CELL BIOLOGY Aging Cell Pub Date : 2024-09-03 DOI:10.1111/acel.14314
Niat T Gebru, Jennifer Guergues, Laura A Verdina, Jessica Wohlfahrt, Shuai Wang, Debra S Armendariz, Marsilla Gray, David Beaulieu-Abdelahad, Stanley M Stevens, Danielle Gulick, Laura J Blair
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Abstract

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.

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Fkbp5 基因缺失:老龄小鼠的昼夜节律特征和脑蛋白质组学
FKBP51 又称 FK506 结合蛋白 51,是一种分子伴侣和支架蛋白,在调节激素信号传导和应对压力方面发挥着重要作用。编码 FKBP51 的 FKBP5 基因变异与越来越多的神经精神疾病有关,这促使人们努力以 FKBP51 为治疗靶点。然而,FKBP51在这些疾病中的分子机制和亚解剖区域尚未完全清楚。在这项研究中,我们旨在利用昼夜表型和分子分析研究 Fkbp5 消减的影响。我们的研究结果表明,FKBP51的缺失不会显著改变昼夜节律(通过轮跑活动检测),但却能以性别依赖的方式保护昼夜节律免受压力介导的破坏。通过组织学和蛋白质组学测量,Fkbp5 KO 小鼠的蛋白质变化显示了大脑区域和性别依赖性的改变。值得注意的是,无论性别如何,年老的 Fkbp5 KOs 都显示出 MYCBP2、FBXO45 和 SPRYD3 水平的升高,而这些蛋白与神经元-细胞粘附和突触完整性有关。此外,在 Fkbp5 KO 小鼠中,5-羟色胺受体信号转导和 S100 家族信号转导等通路也受到了不同程度的调节。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。这项工作所产生的信息可用于更好地了解衰老过程中和Fkbp5缺失时大脑的分子变化,这对继续开发以FKBP51为重点的治疗应激相关疾病的药物具有重要意义。
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来源期刊
Aging Cell
Aging Cell Biochemistry, Genetics and Molecular Biology-Cell Biology
自引率
2.60%
发文量
212
期刊介绍: Aging Cell is an Open Access journal that focuses on the core aspects of the biology of aging, encompassing the entire spectrum of geroscience. The journal's content is dedicated to publishing research that uncovers the mechanisms behind the aging process and explores the connections between aging and various age-related diseases. This journal aims to provide a comprehensive understanding of the biological underpinnings of aging and its implications for human health. The journal is widely recognized and its content is abstracted and indexed by numerous databases and services, which facilitates its accessibility and impact in the scientific community. These include: Academic Search (EBSCO Publishing) Academic Search Alumni Edition (EBSCO Publishing) Academic Search Premier (EBSCO Publishing) Biological Science Database (ProQuest) CAS: Chemical Abstracts Service (ACS) Embase (Elsevier) InfoTrac (GALE Cengage) Ingenta Select ISI Alerting Services Journal Citation Reports/Science Edition (Clarivate Analytics) MEDLINE/PubMed (NLM) Natural Science Collection (ProQuest) PubMed Dietary Supplement Subset (NLM) Science Citation Index Expanded (Clarivate Analytics) SciTech Premium Collection (ProQuest) Web of Science (Clarivate Analytics) Being indexed in these databases ensures that the research published in Aging Cell is discoverable by researchers, clinicians, and other professionals interested in the field of aging and its associated health issues. This broad coverage helps to disseminate the journal's findings and contributes to the advancement of knowledge in geroscience.
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