Enhanced homeostatic sleep response and decreased neurodegenerative proteins in cereblon knock-out mice

Energy homeostasis and sleep have a bidirectional relationship. Cereblon (CRBN) regulates energy levels by ubiquitinating the AMP-activated protein kinase(AMPK), an energy sensor. However, whether CRBN participates in sleep is unclear. Here, we examine sleep-wake patterns in Crbn^+/+ and Crbn^-/- mice during 24-h baseline, 6-h sleep deprivation (SD), and following 6-h recovery sleep (RS). At baseline, overall sleep patterns are similar between genotypes. However, SD decreases CRBN expression in Crbn^+/+ mice and increases phospho-Tau, phospho-α-synuclein, DNAJA1 (DJ2), and DNAJB1 (DJ1) in both genotypes, with Crbn^-/- mice showing a lesser extent of increase in p-Tau and p-α-synuclein and a higher level of heat shock protein 70 (HSP70), DJ2, and DJ1. During RS, Crbn^-/^- mice show increased slow-wave activity in the low-delta range (0.5-2.5 Hz), suggesting higher homeostatic sleep propensity associated with AMPK hyperactivation. By illuminating the role of CRBN in regulating sleep-wake behaviors through AMPK, we suggest CRBN as a potential therapeutic target for managing sleep disorders and preventing neurodegeneration.