Laboratory of Molecular Neurobiology, School of Life Sciences and Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
Laboratory of Functional and Medicinal Proteomics, School of Life Sciences and Gwangju Institute of Science and Technology (GIST), Gwangju 61005, Republic of Korea.
Brain Res. 2022 Oct 15;1793:148054. doi: 10.1016/j.brainres.2022.148054. Epub 2022 Aug 13.
The mechanisms underlying the vulnerability and resilience of an individual to stress are only partly understood. Response to stress is determined by behavioral and biochemical changes in the brain. Chronic ultra-mild stress (CUMS) induces an anhedonic-like state in mice that resembles symptoms of human depression. This study reports the role of cereblon (CRBN) in regulating the metabolic and antioxidant status of neuronal tissues in the mouse model of CUMS. Intriguingly, Crbn (KO) mice showed resilient responsiveness, both at the behavioral and proteomic levels. Several core behaviors were also differentially altered by CUMS in KO mice. Liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based proteome analysis of whole brain lysate (WBL) showed an enriched chaperonic, metabolic, and antioxidant status in the brains of KO subjects, including several members of DNAJ chaperones, creatine kinase, quinone oxidoreductase, superoxide dismutase (SOD1), glutathione S-transferase Mu (GSTM), peroxiredoxin-6 (PRDX6), and thioredoxin. Pathological phosphorylation as characterized by aggregation of tau and α-synuclein (α-syn) was significantly reduced in the neuronal tissues of KO mouse model of CUMS as compared to wild type (WT) mice. Furthermore, significantly increased SOD1 activity and reduced lipid peroxidation were observed in Crbn-KO systems. Integrated signaling pathways were also identified in CRBN-specific sub-networks constructed from protein-protein interaction analysis by STRING. The present study highlights the roles of CRBN in regulating the stress response (SR) and reshaping metabolic status in the brains of mice exposed to CUMS. A better understanding of the molecular mechanisms of depression and neurodegeneration can improve the development of novel treatments.
个体对压力的脆弱性和弹性的潜在机制尚未完全被理解。对压力的反应取决于大脑中的行为和生化变化。慢性超轻度应激（CUMS）会在小鼠中引起一种类似快感缺失的状态，类似于人类抑郁症的症状。本研究报告了 cereblon（CRBN）在调节 CUMS 小鼠模型中神经元组织代谢和抗氧化状态中的作用。有趣的是，Crbn（KO）小鼠在行为和蛋白质组学水平上都表现出了弹性反应。在 KO 小鼠中，几种核心行为也因 CUMS 而发生了不同的改变。基于液相色谱-串联质谱（LC-MS/MS）的全脑裂解物（WBL）蛋白质组分析显示，KO 组的大脑中存在丰富的伴侣、代谢和抗氧化状态，包括 DNAJ 伴侣蛋白、肌酸激酶、醌氧化还原酶、超氧化物歧化酶 1（SOD1）、谷胱甘肽 S-转移酶 Mu（GSTM）、过氧化物酶 6（PRDX6）和硫氧还蛋白。与野生型（WT）小鼠相比，CUMS KO 小鼠模型的神经元组织中病理性磷酸化（如 tau 和 α-突触核蛋白（α-syn）的聚集）显著减少。此外，在 Crbn-KO 系统中观察到 SOD1 活性显著增加和脂质过氧化减少。通过 STRING 的蛋白质-蛋白质相互作用分析构建的 CRBN 特异性子网络中也鉴定到了整合信号通路。本研究强调了 CRBN 在调节 CUMS 暴露小鼠的应激反应（SR）和重塑大脑代谢状态中的作用。对抑郁症和神经退行性变的分子机制的更好理解可以改善新疗法的开发。
