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.

Regulation of AMPK Activity by CRBN Is Independent of the Thalidomide-CRL4CRBN Protein Degradation Axis.

Cereblon (CRBN), a primary target of immune-modulatory imide drugs (IMiDs), functions as a substrate receptor in the CUL4-RBX1-DDB1-CRBN (known as CRL4CRBN) E3 ubiquitin ligase complex. Binding of IMiDs to CRBN redirects the CRL4CRBN E3 ubiquitin ligase to recruit or displace its substrates. Interaction between CRBN and the AMPK α subunit leads to CRL4CRBN-dependent degradation of the γ subunit and inhibits AMPK activity. However, the effect of thalidomide on the function of CRBN as a negative regulator of AMPK through interaction with the α subunit remains unclear. Here, we show that thalidomide does not affect AMPK activation or the binding affinity between CRBN and the AMPK α subunit. Thalidomide had no effect on AMPK activity independent of CRBN expression. The N-terminal region and C-terminal tail of CRBN, which is distinct from the IMiD binding site, were critical for interaction with the AMPK α subunit. The present results suggest that CRL4CRBN negatively regulates AMPK through a pathway independent from the CRBN-IMiD binding region.

Disturbing Effects of Chronic Low-dose 4-Nonylphenol exposing on Gonadal Weight and Reproductive Outcome over One-generation.

4-Nonylphenol (NP) is a surfactant that is a well-known and widespread estrogenic endocrine disrupting chemical (EDC). Although it has been known that the affinity of NP to ERs is low, it has been suggested that low-dose NP has toxicity. In the present study, the endocrine disrupting effects on reproduction, and the weight of gonads, epididymis, and uterus were evaluated with the chronic lower-dose NP exposing. This study was designed by following the OECD test guideline 443 and subjected to a complete necropsy. In male, NP had an effect on the weight of the testis and epididymis in both F0 and F1. In females, NP decreased the weight of ovary and uterus in F0 but not in pre-pubertal F1 pubs. Fertility of male and female in F0 or F1 was no related with NP administration. The number of caudal-epididymal sperm by body weight (BW) was not different between groups in both F0 and F1. Besides, the difference of the sperm number between generations was not detected. The number of ovulated oocytes was similar between groups in F0, but significantly decreased in NP 50 group of F1. The litter size and sex ratios of offspring in F1 and F2 were not different. The accumulated mating rate and gestation period were not affected by the NP administration. Those results shows that chronic lower-dose NP administration has an effect of endocrine disruptor on the weight of gonads and epididymis of F0 and F1 but not in reproduction. Based on the results, it is suggested that chronic lower-dose NP exposing causes endocrine disruption in the weight of gonad and epididymis but not in the reproductive ability of next generations.