0289 Cereblon Deficiency Increases AMP-Activated Kinase and Homeostatic Sleep Response Mice

Abstract

Abstract Introduction Energy homeostasis and sleep have a bidirectional relationship. Cereblon (CRBN), a substrate receptor of the CRL4 E3 ubiquitin ligase complex, regulates energy levels by ubiquitinating AMP-activated protein kinase (AMPK), a master energy sensor. While CRBN’s role in energy regulation is established, its involvement in sleep remains unclear. Thalidomide, a pharmacological modulator of CRBN, has shown to improve sleep quality, particularly by increasing slow-wave sleep (SWS) and overall sleep efficiency. This study explores the impact of CRBN deletion on sleep-wake patterns and examines parallels to thalidomide’s effects. Methods Sleep-wake patterns were analyzed in Crbn+/+ and Crbn-/- mice under three conditions: 24-hour baseline, 6-hour sleep deprivation (SD), and 6-hour recovery sleep (RS). EEG/EMG recordings quantified sleep architecture, with a focus on slow-wave activity as an indicator of homeostatic sleep drive. Stress-associated proteins, including phospho-Tau, phospho-α-Synuclein, DNAJA1 (DJ2), DNAJB1 (DJ1), and Heat Shock Protein 70 (HSP70), were measured via immunoblotting. Results At baseline, sleep architecture was similar between Crbn+/+ and Crbn-/- mice. Sleep deprivation reduced CRBN expression in Crbn+/+ mice and elevated stress markers such as phospho-Tau, phospho-α-Synuclein, DJ2, and DJ1 in both genotypes. Crbn-/- mice showed a blunted increase in phospho-Tau and phospho-α-Synuclein but higher levels of HSP70, DJ2, and DJ1. During recovery sleep, Crbn-/- mice exhibited significantly increased slow-wave activity, suggesting heightened homeostatic sleep pressure, likely due to AMPK hyperactivation in the absence of CRBN. Conclusion CRBN plays a critical role in regulating sleep homeostasis and recovery sleep, likely through its modulation of AMPK activity and stress protein responses. Interestingly, thalidomide, a CRBN modulator, has been shown to enhance slow-wave sleep and overall sleep quality in clinical studies. This improvement in slow-wave activity parallels the increased SWA observed in Crbn-/- mice during recovery sleep. However, while thalidomide’s effects appear beneficial, the heightened sleep drive in CRBN-deficient mice likely reflects underlying AMPK hyperactivation. This highlights a dual role for CRBN in both promoting energy balance and regulating sleep architecture. Thalidomide or related CRBN modulators could offer therapeutic benefits for improving sleep quality and mitigating neurodegeneration associated with disrupted sleep, while careful attention is needed to avoid unintended effects related to CRBN deficiency. Support (if any)