Ubiquitin proteasome system in circadian rhythm and sleep homeostasis: Lessons from Drosophila

Abstract

Sleep is regulated by two main processes: the circadian clock and sleep homeostasis. Circadian rhythms have been well studied at the molecular level. In the Drosophila circadian clock neurons, the core clock proteins are precisely regulated by post-translational modifications and degraded via the ubiquitinproteasome system (UPS). Sleep homeostasis, however, is less understood; nevertheless, recent reports suggest that proteasome-mediated degradation of core clock proteins or synaptic proteins contributes to the regulation of sleep amount. Here, we review the molecular mechanism of the UPS and summarize the role of protein degradation in the regulation of circadian clock and homeostatic sleep in Drosophila. Moreover, we discuss the potential interaction between circadian clock and homeostatic sleep regulation with a prime focus on E3 ubiquitin ligases.

Genome-wide association analysis of composite sleep health scores in 413,904 individuals

“…SHS-PC1 was the SHS most strongly genetically correlated with accelerometry-based sleep efficiency and duration, suggesting shared genetics with both longer and more efficient objective sleep, with additional genetic correlations suggesting negative relationships with chronic pain, anxiety, and neuroticism. Enrichment analyses identified the ubiquitin proteasome system pathway, important for circadian rhythm regulation and sleep homeostasis 41 , as well as the GABAergic neuronal cell-type, central to neural orchestration of sleep. Overall, these findings suggest a phenotype capturing neurobiological sleep regulation, and support a bidirectional relationship with anxiety 42 via shared GABAergic regulation 43 , while pointing to further mechanisms involving presence or perception of distressing stimuli, including chronic pain.…”