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ER proteostasis regulators cell-non-autonomously control sleep.

Taizo Kawano1, Mitsuaki Kashiwagi2, Mika Kanuka1

  • 1International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan.

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|March 16, 2023
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Summary
This summary is machine-generated.

Peripheral tissues regulate sleep through endoplasmic reticulum (ER) stress responses. This study identifies key genes and pathways in non-neuronal cells that control sleep amount, conserved in mammals.

Keywords:
C. elegansCP: Cell biologyCP: NeuroscienceEGFRcell non-autonomousendoplasmic reticulum-associated degradationproteostasissleep

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Area of Science:

  • Molecular Biology
  • Neuroscience
  • Genetics

Background:

  • Sleep regulation is influenced by peripheral tissues, but the underlying molecular mechanisms remain largely unknown.
  • Fatigue and prolonged wakefulness can induce cellular stress, particularly in the endoplasmic reticulum (ER).

Purpose of the Study:

  • To identify molecular pathways in peripheral tissues that regulate systemic sleep.
  • To investigate the role of ER proteostasis in sleep homeostasis.

Main Methods:

  • Forward genetic screen in *C. elegans* to identify genes affecting sleep amount.
  • Analysis of ER unfolded protein response (UPR) components and neuronal signaling pathways.
  • Conservation studies in mammalian models.

Main Results:

  • Identified three genes (sel-1, sel-11, mars-1) crucial for sleep regulation in *C. elegans*.
  • Demonstrated the function of ER-associated degradation and UPR components (IRE1/XBP1, PERK/eIF2α/ATF4) in non-neuronal sleep control.
  • Showed that neuronal epidermal growth factor receptor (EGFR) signaling is also necessary for this process.
  • Evidence suggests conservation of these mechanisms in mammals.

Conclusions:

  • Peripheral ER proteostasis factors play a significant role in controlling sleep homeostasis.
  • Non-neuronal tissues may promote sleep as a mechanism to cope with ER stress induced by prolonged wakefulness.
  • This study reveals a novel link between ER stress response and sleep regulation across species.