Short and long sleeping mutants reveal links between sleep and macroautophagy

Abstract

Sleep is a conserved and essential behavior, but its mechanistic and functional underpinnings remain poorly defined. Through unbiased genetic screening in Drosophila, we discovered a novel short-sleep mutant we named argus. Positional cloning and subsequent complementation, CRISPR/Cas9 knock-out, and RNAi studies identified Argus as a transmembrane protein that acts in adult peptidergic neurons to regulate sleep. argus mutants accumulate undigested Atg8a(+) autophagosomes, and genetic manipulations impeding autophagosome formation suppress argus sleep phenotypes, indicating that autophagosome accumulation drives argus short-sleep. Conversely, a blue cheese neurodegenerative mutant that impairs autophagosome formation was identified independently as a gain-of-sleep mutant, and targeted RNAi screens identified additional genes involved in autophagosome formation whose knockdown increases sleep. Finally, autophagosomes normally accumulate during the daytime and nighttime sleep deprivation extends this accumulation into the following morning, while daytime gaboxadol feeding promotes sleep and reduces autophagosome accumulation at nightfall. In sum, our results paradoxically demonstrate that wakefulness increases and sleep decreases autophagosome levels under unperturbed conditions, yet strong and sustained upregulation of autophagosomes decreases sleep, whereas strong and sustained downregulation of autophagosomes increases sleep. The complex relationship between sleep and autophagy suggested by our findings may have implications for pathological states including chronic sleep disorders and neurodegeneration, as well as for integration of sleep need with other homeostats, such as under conditions of starvation.

Balancing Prediction and Surprise: A Role for Active Sleep at the Dawn of Consciousness?

“…Indeed, there is now good evidence that active sleep in flies engages a structure in the central brain called the fan-shaped body, which has been linked to sensory processing (Hu et al, 2018;Sareen et al, 2020) and visual learning and attention (Liu et al, 2006;de Bivort and van Swinderen, 2016;Tainton-Heap et al, 2021). In contrast, quiet sleep in flies may be more important for basic cellular homeostatic processes, such as waste clearance (van Alphen et al, 2021) and repair (Stanhope et al, 2020;Bedont et al, 2021). In this way, active and quiet sleep functions in flies may align logically with some proposed REM and SWS functions in mammals, as outlined above.…”

The Association Between Regular Physical Exercise, Sleep Patterns, Fasting, and Autophagy for Healthy Longevity and Well-Being: A Narrative Review

“…Although it is the fact that autophagy occurs naturally it is very important to set up a research question if the autophagy can be stimulated by some specific triggers. Some research strongly suggests that both fasting (intermittent fasting) and calorie restriction (ketogenic diets) can stimulate autophagy in the human body (Bagherniya et al, 2018 ), as well as, both regular physical activity (Brandt et al, 2018 ) and regular sleeping (Bedont et al, 2021 ).…”

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

“…Further, Argus, a transmembrane protein which is involved in the autophagosome degradation, is expressed in peptidergic neurons. Notably, argus mutants exhibit a short sleep phenotype, indicating the possibility that the degradation of waste products such as proteins in specific neurons could affect sleep (Bedont et al, 2021).…”