Effects of cereblon on stress-activated redox proteins and core behavior.

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.