Abstract：
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.
摘要：
个人对压力的脆弱性和复原力的潜在机制只有部分理解。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）在小鼠中诱导类似人类抑郁症症状的无张力状态。本研究报道了小脑（CRBN）在CUMS小鼠模型中调节神经元组织的代谢和抗氧化状态的作用。有趣的是，Crbn-/-（KO）小鼠表现出弹性反应，在行为和蛋白质组水平。CUMS在KO小鼠中也差异改变了几种核心行为。基于液相色谱和串联质谱（LC-MS/MS）的全脑裂解物（WBL）的蛋白质组分析显示，新陈代谢，以及KO受试者大脑中的抗氧化状态，包括几个DNAJ伴侣,肌酸激酶，醌氧化还原酶,超氧化物歧化酶（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，在CUMS的KO小鼠模型的神经元组织中，以tau和α-突触核蛋白（α-syn）聚集为特征的病理磷酸化显着降低。此外，在Crbn-KO系统中观察到SOD1活性显着增加，脂质过氧化降低。在通过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了整合的信号通路。本研究强调了CRBN在调节暴露于CUMS的小鼠大脑中的应激反应（SR）和重塑代谢状态中的作用。更好地了解抑郁症和神经变性的分子机制可以改善新型治疗方法的开发。
