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

Abstract

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. fragment | extracellular | intracellular | proteolysis | sleep S leep is universal among mammals and other vertebrates.Animals with much smaller nervous systems, such as insects, also sleep (1-8). Mechanisms that control sleep include circadian circuits, which underlie daily rhythms of sleep and other biological variables (9). However, circadian aspects of sleep do not define it entirely, because sleep has the homeostatic property of becoming longer after sleep deprivation (10, 11). In mammals, birds, and lizards, two alternating modes of sleep have been identified, the non-rapid eye movement (NREM) sleep and the rapid eye movement (REM) sleep (12,13). The depth of NREM sleep is yet another sleep variable. In adult humans, NREM sleep occupies ∼80% of the total sleep time. For recent reviews of sleep, see refs. 14-20.Despite advances in the understanding of neuronal circuits as well as genes, proteins, short peptides, and other compounds that regulate sleep, it is largely unknown why sleep exists and what it is for. Maladaptive aspects of sleep include elevated dangers of predation during sleep, the neglect of territorial defense and foraging for food, and the loss of parental care and mating opportunities. It is unknown what features of sleep did not allow these fitness costs to ca...

The hypothalamic link between arousal and sleep homeostasis in mice

“…An alternative possibility is that sleep propensity may be enhanced if some of the strong wake-promoting areas are inhibited, consistent with the idea that sleep represents a default state of a neural network or the whole organism (46,64). Therefore, even if accumulation of sleep need, in some form, occurs globally (51,52,(65)(66)(67)(68)(69)(70)(71)(72)(73)(74), it is likely that state switching is initiated from a relatively limited set of brain circuits, which have the capacity to integrate sleep-wake history-related signals with other ecological and homeostatic demands. While the biological substrate of global sleep homeostasis remains unclear, the question of which brain areas are involved in encoding the time spent awake or asleep seems tractable (41,50,51).…”

Ubiquitin proteasome system in circadian rhythm and sleep homeostasis: Lessons from Drosophila

“…Additionally, the calpains and caspases are present at post‐synaptic densities (PSDs) and cleave post‐synaptic proteins (Varshavsky, 2019b). The resultant cleaved proteins generate two fragments: a protein containing a new N‐terminus and a protein containing a new C‐terminus (Varshavsky, 2019b). The new N‐terminus and C‐terminus function as degrons, which are the targets of ubiquitin‐dependent degradation (Varshavsky, 2019a).…”

“…Aggregation of such degradation byproducts leads to neural injury and ultimately the Alzheimer's disease (Mattson, 1994). Moreover, Varshavsky hypothesized that the fragmented proteins cleaved by proteases accumulate when the organism is awake and are degraded by the proteasome system during the night (Varshavsky, 2012(Varshavsky, , 2019b. Additionally, the calpains and caspases are present at post-synaptic densities (PSDs) and cleave post-synaptic proteins (Varshavsky, 2019b).…”

“…Moreover, Varshavsky hypothesized that the fragmented proteins cleaved by proteases accumulate when the organism is awake and are degraded by the proteasome system during the night (Varshavsky, 2012(Varshavsky, , 2019b. Additionally, the calpains and caspases are present at post-synaptic densities (PSDs) and cleave post-synaptic proteins (Varshavsky, 2019b). The resultant cleaved proteins generate two fragments: a protein containing a new N-terminus and a protein containing a new C-terminus (Varshavsky, 2019b).…”

“…These facts imply that the elevated levels of synaptic proteins induce sleep to eliminate the accumulated synaptic protein, which may be one of the primary functions of sleep. Varshavsky hypothesized that another function of sleep is to eliminate the fragmented proteins at the synapse accumulated while awake (Varshavsky, 2012(Varshavsky, , 2019b. According to this hypothesis, fragmented proteins are eliminated by the UPS.…”