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Evolutionarily Conserved Regulation of Sleep by the Protein Translational Regulator PERK

Ly, Sarah and Lee, Daniel A. and Strus, Ewa and Prober, David A. and Naidoo, Nirinjini (2020) Evolutionarily Conserved Regulation of Sleep by the Protein Translational Regulator PERK. Current Biology, 30 (9). pp. 1639-1648. ISSN 0960-9822. https://resolver.caltech.edu/CaltechAUTHORS:20200313-142322891

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.cub.2020.02.030DOIArticle
ORCID:
AuthorORCID
Lee, Daniel A.0000-0001-7411-2740
Prober, David A.0000-0002-7371-4675
Additional Information:© 2020 Elsevier. Received 2 August 2019, Revised 16 January 2020, Accepted 12 February 2020, Available online 12 March 2020. The authors thank Sarah Hou and Sophie Leon for assistance in data collection. This study was funded by NIGMS (R01GM123783) to N.N. Data and Code Availability: The custom MATLAB and C+ code used to analyze Drosophila sleep data has been described previously [59]. This study did not generate large datasets. Further information and requests for experimental data should be directed to and be fulfilled by the Lead Contact, Nirinjini Naidoo (naidoo@pennmedicine.upenn.edu). Author Contributions: S.L. and N.N. conceived the project. S.L., D.A.L., D.A.P., and N.N. were responsible for the study design and manuscript writing. S.L., D.A.L., and E.S. performed the experiments and analyzed data. D.A.P. and N.N. provided the resources for the project. The authors declare no competing interests.
Funders:
Funding AgencyGrant Number
NIHR01GM123783
Subject Keywords:sleep; Drosophila; zebrafish; protein synthesis; protein translation; PERK; proteostasis; unfolded protein response; ER stress
Issue or Number:9
Record Number:CaltechAUTHORS:20200313-142322891
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200313-142322891
Official Citation:Sarah Ly, Daniel A. Lee, Ewa Strus, David A. Prober, Nirinjini Naidoo, Evolutionarily Conserved Regulation of Sleep by the Protein Translational Regulator PERK, Current Biology, Volume 30, Issue 9, 2020, Pages 1639-1648.e3, ISSN 0960-9822, https://doi.org/10.1016/j.cub.2020.02.030. (http://www.sciencedirect.com/science/article/pii/S0960982220302037)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:101909
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:16 Mar 2020 14:10
Last Modified:05 May 2020 20:41

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