The Body, Not the Brain, Regulates Sleep

The brain is powerful, but not omnipotent! May you sleep better next time! 😊

"... Now, a new study published in Cell Reports has turned sleep research on its head. Researchers ... reported three key genes that are critical for regulating sleep—not in the brain, but in peripheral tissues.3 The findings demonstrate that sleep is all about protein homeostasis: endoplasmic reticulum (ER) stress and downregulation of protein biosynthesis in peripheral tissues trigger pathways that induce sleep. ..."

From the highlights and abstract:

"Highlights

• A forward genetic screen identifies 3 genes that strongly affect sleep in C. elegans

• Loss of ERAD component SEL-11 in peripheral tissue increases sleep by activating PERK

• Reduction of global translation in peripheral tissue increases sleep

• In mice, loss of Synoviolin/Hrd1, the homolog of SEL-11, increases non-REM sleep

Summary

Sleep is regulated by peripheral tissues under fatigue. The molecular pathways in peripheral cells that trigger systemic sleep-related signals, however, are unclear. Here, a forward genetic screen in C. elegans identifies 3 genes that strongly affect sleep amount: sel-1, sel-11, and mars-1. sel-1 and sel-11 encode endoplasmic reticulum (ER)-associated degradation components, whereas mars-1 encodes methionyl-tRNA synthetase. We find that these machineries function in non-neuronal tissues and that the ER unfolded protein response components inositol-requiring enzyme 1 (IRE1)/XBP1 and protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor-2α (eIF2α)/activating transcription factor-4 (ATF4) participate in non-neuronal sleep regulation, partly by reducing global translation. Neuronal epidermal growth factor receptor (EGFR) signaling is also required. Mouse studies suggest that this mechanism is conserved in mammals. Considering that prolonged wakefulness increases ER proteostasis stress in peripheral tissues, our results suggest that peripheral ER proteostasis factors control sleep homeostasis. Moreover, based on our results, peripheral tissues likely cope with ER stress not only by the well-established cell-autonomous mechanisms but also by promoting the individual’s sleep."

The Body, Not the Brain, Regulates Sleep | The Scientist Magazine® Genetic screens have revealed three peripheral tissue genes that regulate sleep. What does this mean for sleep research?

ER proteostasis regulators cell-non-autonomously control sleep (open access)

Graphical abstract

Figure 1 Dysfunction of SEL-11 or SEL-1 leads to increased sleep