PUBLICATION

Evolutionarily Conserved Regulation of Sleep by the Protein Translational Regulator PERK

Authors
Ly, S., Lee, D.A., Strus, E., Prober, D.A., Naidoo, N.
ID
ZDB-PUB-200403-66
Date
2020
Source
Current biology : CB   30(9): 1639-1648.e3 (Journal)
Registered Authors
Prober, David
Keywords
Drosophila, ER stress, PERK, protein synthesis, protein translation, proteostasis, sleep, unfolded protein response, zebrafish
MeSH Terms
  • Animals
  • Biological Evolution*
  • Cinnamates/pharmacology
  • Drosophila melanogaster
  • Gene Expression Regulation/drug effects
  • Gene Expression Regulation/physiology
  • Neuropeptides/genetics
  • Neuropeptides/metabolism
  • Signal Transduction
  • Sleep/genetics*
  • Sleep/physiology*
  • Thiourea/analogs & derivatives
  • Thiourea/pharmacology
  • Wakefulness/genetics
  • Wakefulness/physiology
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • eIF-2 Kinase/genetics
  • eIF-2 Kinase/metabolism*
PubMed
32169212 Full text @ Curr. Biol.
Abstract
Sleep is a cross-species phenomenon whose evolutionary and biological function remain poorly understood. Clinical and animal studies suggest that sleep disturbance is significantly associated with disruptions in protein homeostasis-or proteostasis-in the brain, but the mechanism of this link has not been explored. In the cell, the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) pathway modulates proteostasis by transiently inhibiting protein synthesis in response to proteostatic stress. In this study, we examined the role of the PERK pathway in sleep regulation and provide the first evidence that PERK signaling is required to regulate normal sleep in both vertebrates and invertebrates. We show that pharmacological inhibition of PERK reduces sleep in both Drosophila and zebrafish, indicating an evolutionarily conserved requirement for PERK in sleep. Genetic knockdown of PERK activity also reduces sleep in Drosophila, whereas PERK overexpression induces sleep. Finally, we demonstrate that changes in PERK signaling directly impact wake-promoting neuropeptide expression, revealing a mechanism through which proteostatic pathways can affect sleep and wake behavior. Taken together, these results demonstrate that protein synthesis pathways like PERK could represent a general mechanism of sleep and wake regulation and provide greater insight into the relationship between sleep and proteostasis.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes