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Published May 28, 2019 | Published + Supplemental Material
Journal Article Open

On the cause of sleep: Protein fragments, the concept of sentinels, and links to epilepsy


The molecular-level cause of sleep is unknown. In 2012, we suggested that the cause of sleep stems from cumulative effects of numerous intracellular and extracellular protein fragments. According to the fragment generation (FG) hypothesis, protein fragments (which are continually produced through nonprocessive cleavages by intracellular, intramembrane, and extracellular proteases) can be beneficial but toxic as well, and some fragments are eliminated slowly during wakefulness. We consider the FG hypothesis and propose that, during wakefulness, the degradation of accumulating fragments is delayed within natural protein aggregates such as postsynaptic densities (PSDs) in excitatory synapses and in other dense protein meshworks, owing to an impeded diffusion of the ∼3,000-kDa 26S proteasome. We also propose that a major function of sleep involves a partial and reversible expansion of PSDs, allowing an accelerated destruction of PSD-localized fragments by the ubiquitin/proteasome system. Expansion of PSDs would alter electrochemistry of synapses, thereby contributing to a decreased neuronal firing during sleep. If so, the loss of consciousness, a feature of sleep, would be the consequence of molecular processes (expansions of protein meshworks) that are required for degradation of protein fragments. We consider the concept of FG sentinels, which signal to sleep-regulating circuits that the levels of fragments are going up. Also discussed is the possibility that protein fragments, which are known to be overproduced during an epileptic seizure, may contribute to postictal sleep and termination of seizures. These and related suggestions, described in the paper, are compatible with current evidence about sleep and lead to testable predictions.

Additional Information

© 2019 National Academy of Sciences. Published under the PNAS license. Contributed by Alexander Varshavsky, April 2, 2019 (sent for review March 21, 2019; reviewed by F. Ulrich Hartl, Avram Hershko, and William P. Tansey). I am most grateful to D. Tsao, W. Tansey, D. Anderson, U. Hartl, A. Hershko, J. Raskatov, and O. Sundin for their comments on the manuscript. Studies in the author's laboratory are supported by the NIH Grants DK039520 and GM031530. Author contributions: A.V. designed research, performed research, analyzed data, and wrote the paper. Reviewers: F.U.H., Max Planck Institute of Biochemistry; A.H., Technion–Israel Institute of Technology; and W.P.T., Vanderbilt University School of Medicine. The author declares no conflict of interest. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1904709116/-/DCSupplemental.

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