Sleep: Dozy Worms and Sleepy Flies

Olofsson, Birgitta; Bono, Mario de

doi:10.1016/j.cub.2008.01.002

Cited by 7 publications

(4 citation statements)

References 17 publications

(38 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In recent years, an important advance in sleep research has been the identification of a sleep state in non-mammalian model systems: namely, the fruit fly ( Drosophila melanogaster ) [20–22], the zebrafish ( Danio rerio ) [23–25] and, most recently, the nematode ( Caenorhabditis elegans ) [26] (see also [27–29]). Crucial to the identification of sleep in these model systems has been the use of behavioral rather than electrophysiological criteria to define the sleep state.…”

Section: Model Systems For the Study Of Sleepmentioning

confidence: 99%

What are microarrays teaching us about sleep?

Mackiewicz

Zimmerman

Shockley

et al. 2009

Trends in Molecular Medicine

View full text Add to dashboard Cite

Many fundamental questions about sleep remain unanswered. The presence of sleep across phyla suggests that it must serve a basic cellular and/or molecular function. Microarray studies, performed in several model systems, have identified classes of genes that are sleep-state regulated. This has led to the following concepts: first, a function of sleep is to maintain synaptic homeostasis; second, sleep is a stage of macromolecule biosynthesis; third, extending wakefulness leads to downregulation of several important metabolic pathways; and, fourth, extending wakefulness leads to endoplasmic reticulum stress. In human studies, microarrays are being applied to the identification of biomarkers for sleepiness and for the common debilitating condition of obstructive sleep apnea. High-throughput approaches to study gene expressionThe search for genes involved in regulation by, and of, sleep and wakefulness and the quest to understand the functions of sleep at the molecular level began a decade before the advent of microarrays. Several candidate genes were studied to elucidate their roles in sleep and wakefulness (for a review, see [1]). Subtractive hybridization carried out on brain mRNA from sleep-deprived rats, performed in the early 1990s, was the first 'high-throughput' attempt to identify such genes [2]. Later, the application of differential display [3] broadened the candidate gene and subtractive hybridization approaches to screen for genes whose functions were poorly characterized or previously unknown.As a result of sequencing efforts, there has been an exponential growth in the amount of information available about the DNA sequence of the human genome (e.g., see [4]) as well as the genomes of various model organisms (e.g., see [5,6]). Consequently, thousands of genes have been discovered, including many novel genes for which sequences were unavailable previously. The role of many of these genes is unknown. This facilitated the advent of microarray approaches.A microarray contains tens of thousands of genes and is a tool for simultaneous measurement of their expression. Significant advances in gene annotations, progress in development and © 2008 Elsevier Ltd. All rights reserved.Corresponding author: Pack, A.I. (pack@mail.med.upenn.edu). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Microarrays in sleep researchMicroarrays offer a new window on the difference between the sleeping and awake brain and hold the promise of facilitating answers to some of the major questions in sleep biology (Box 1; see also [9][10][11]).These questions are releva...

show abstract

Section: Model Systems For the Study Of Sleepmentioning

confidence: 99%

What are microarrays teaching us about sleep?

Mackiewicz

Zimmerman

Shockley

et al. 2009

Trends in Molecular Medicine

View full text Add to dashboard Cite

show abstract

“…C. elegans ($300 neurons) has a quiescent behavioral state during a period called lethargus. [260][261][262] It occurs before each of the four molts and exhibits some aspects of sleep, including higher arousal thresholds and a homeostatic response to mechanical stimulation during lethargus (specifically, an augmented quiescence after stimulation). 260 The periods of lethargus involve alterations of the worm's nervous system, suggesting that lethargus evolved to accommodate specific requirements of such alterations.…”

Section: Protein Fragments and The Size Of A Nervous Systemmentioning

confidence: 99%

“…[260][261][262][263][264] The FG hypothesis predicts higher levels of specific protease-generated protein fragments in some or most C. elegans neurons (and possibly in other cell types as well) shortly before lethargus. If the FG hypothesis proves relevant to the causation and function of sleep in mammals, the resulting understanding could be ''turned around'' by asking whether the lethargus in C. elegans involves the generation and degradation of specific fragments and the remodeling of protein complexes after fragments' removal, and whether these processes are the molecular cause of lethargus.…”

Section: Protein Fragments and The Size Of A Nervous Systemmentioning

confidence: 99%

Augmented generation of protein fragments during wakefulness as the molecular cause of sleep: a hypothesis

Varshavsky

2012

Protein Science

View full text Add to dashboard Cite

Despite extensive understanding of sleep regulation, the molecular-level cause and function of sleep are unknown. I suggest that they originate in individual neurons and stem from increased production of protein fragments during wakefulness. These fragments are transient parts of protein complexes in which the fragments were generated. Neuronal Ca 21 fluxes are higher during wakefulness than during sleep. Subunits of transmembrane channels and other proteins are cleaved by Ca 21 -activated calpains and by other nonprocessive proteases, including caspases and secretases. In the proposed concept, termed the fragment generation (FG) hypothesis, sleep is a state during which the production of fragments is decreased (owing to lower Ca 21 transients) while fragment-destroying pathways are upregulated. These changes facilitate the elimination of fragments and the remodeling of protein complexes in which the fragments resided. The FG hypothesis posits that a proteolytic cleavage, which produces two fragments, can have both deleterious effects and fitness-increasing functions. This (previously not considered) dichotomy can explain both the conservation of cleavage sites in proteins and the evolutionary persistence of sleep, because sleep would counteract deleterious aspects of protein fragments. The FG hypothesis leads to new explanations of sleep phenomena, including a longer sleep after sleep deprivation. Studies in the 1970s showed that ethanol-induced sleep in mice can be strikingly prolonged by intracerebroventricular injections of either Ca 21 alone or Ca 21 and its ionophore (Erickson et al., Science 1978;199:1219-1221 Harris, Pharmacol Biochem Behav 1979;10:527-534; Erickson et al., Pharmacol Biochem Behav 1980;12:651-656). These results, which were never interpreted in connection to protein fragments or the function of sleep, may be accounted for by the FG hypothesis about molecular causation of sleep.

show abstract

“…Further, while organisms such as neurospora and plants show daily cycles of activity, a definition of sleep has not been extended to these species, although a recent study has revealed a sleep-like state in Caenorhabditis elegans called lethargus [ 36 ]. Common sleep pathways in these organisms have involved dopamine [ 37 , 38 ], cyclic AMP response element-binding protein (CREB) [ 39 , 40 ], voltage-dependent potassium channels [ 33 , 41 ], gamma-aminobutyric acid (GABA) [ 42 ], and the epidermal growth factor [ 43 , 44 ].…”

Section: Sleep In Other Organismsmentioning

confidence: 99%