Wake-sleep cycles are severely disrupted by diseases affecting cytoplasmic homeostasis

Beesley, Stephen; Kim, Dae Wook; D'Alessandro, Matthew; Jin, Yuanhu; Lee, Kwang-Jun; Joo, Hyunjeong; Yang, Young; Tomko, Robert J.; Faulkner, John A.; Gamsby, Joshua J.; Kim, Jae Kyoung; Lee, Choogon

doi:10.1073/pnas.2003524117

Cited by 40 publications

(65 citation statements)

References 63 publications

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“…This agrees with the observation that circadian rhythmicity requires the robust degradation of the PER protein [86]. The theoretical prediction of the failure of entrainment associated with the accumulation of PER holds with the related observation that sleep-wake cycles are strongly disturbed when the cytoplasm is congested due to accumulation of the PER protein [87].…”

Section: Discussionsupporting

confidence: 88%

“…It occurs in the model when the level of CRY protein is too low compared to PER, as a result of a rate of synthesis which is too low, or of a rate of degradation which is too large, for either or both the Cry mRNA or the CRY protein (Insight #6). It would be interesting to determine whether the sleep disorders associated with the phenomenon of cytoplasmic congestion for the PER protein [86,87] correspond to a non-24 h sleep-wake syndrome.…”

Section: Discussionmentioning

confidence: 99%

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From circadian clock mechanism to sleep disorders and jet lag: Insights from a computational approach

Goldbeter

Leloup

2021

Biochemical Pharmacology

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We present ten insights that can be gained from computational models based on molecular mechanisms for the mammalian circadian clock. These insights range from the conditions in which circadian rhythms occur spontaneously to their entrainment by the light-dark (LD) cycle and to clock-related disorders of the sleep-wake cycle. Endogenous oscillations originate spontaneously from transcription-translation feedback loops involving clock proteins such as PER, CRY, CLOCK and BMAL1. Circadian oscillations occur in a parameter domain bounded by critical values. Outside this domain the circadian network ceases to oscillate and evolves to a stable steady state. This conclusion bears on the nature of arrhythmic behavior of the circadian clock, which may not necessarily be due to mutations in clock genes. Entrainment by the LD cycle occurs in a certain range of parameter values, with a phase that depends on the endogenous period of the circadian clock. A decrease in PER phosphorylation is accompanied by a decrease in endogenous period and a phase advance of the clock; this situation accounts for the familial, advanced sleep phase syndrome (FASPS). The mirror delayed sleep phase syndrome (DSPS) can be accounted for, similarly, by an increase in PER phosphorylation and a rise in autonomous period. Failure of entrainment by the LD cycle in the model corresponds to the non-24 h sleep-wake cycle syndrome, in which the phase of the circadian clock drifts in the course of time. Quasi-periodic oscillations that develop in these conditions sometimes correspond to long-period patterns in which the circadian clock is nearly entrained for long bouts of time before its phase rapidly drifts until a new regime of quasi-entrainment is re-established. In regard to jet lag, the computational approach accounts for the two modes of re-entrainment observed after an advance or delay which correspond, respectively, to an eastward or westward flight: the clock adjusts in a direction similar (orthodromic) or opposite (antidromic) to that of the shift in the LD cycle. Computational modeling predicts that in the vicinity of the switch between orthodromic and antidromic re-entrainment the circadian clock may take a very long time to resynchronize with the LD cycle. Repetitive perturbations of the circadian clock due, for example, to chronic jet lag -a situation somewhat reminiscent of shift work-may lead to quasi-periodic or chaotic oscillations. The latter irregular oscillations can sometimes be observed in normal LD cycles, raising the question of their possible relevance to fragmented sleep patterns observed in narcolepsy. The latter condition, however, appears to originate from disorders in the orexin neural circuit, which promotes wakefulness, rather than from an irregular operation of the circadian clock.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

From circadian clock mechanism to sleep disorders and jet lag: Insights from a computational approach

Goldbeter

Leloup

2021

Biochemical Pharmacology

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“…It should be emphasized that the unidirectional coupling between circadian clock and cell cycle as discussed here, merely functions as a conceptual example of our phenomenological modeling approach. Indeed, in reality, the situation is much more complex, as coupling happens in a bidirectional manner [ 77 , 78 ] and also the circadian clock itself includes bistable switches [ 82 ]. Nevertheless, as with the other examples discussed, certain key aspects of the system’s dynamical behavior can be described using the approach proposed here.…”

Section: Resultsmentioning

confidence: 99%

A modular approach for modeling the cell cycle based on functional response curves

2021

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Modeling biochemical reactions by means of differential equations often results in systems with a large number of variables and parameters. As this might complicate the interpretation and generalization of the obtained results, it is often desirable to reduce the complexity of the model. One way to accomplish this is by replacing the detailed reaction mechanisms of certain modules in the model by a mathematical expression that qualitatively describes the dynamical behavior of these modules. Such an approach has been widely adopted for ultrasensitive responses, for which underlying reaction mechanisms are often replaced by a single Hill function. Also time delays are usually accounted for by using an explicit delay in delay differential equations. In contrast, however, S-shaped response curves, which by definition have multiple output values for certain input values and are often encountered in bistable systems, are not easily modeled in such an explicit way. Here, we extend the classical Hill function into a mathematical expression that can be used to describe both ultrasensitive and S-shaped responses. We show how three ubiquitous modules (ultrasensitive responses, S-shaped responses and time delays) can be combined in different configurations and explore the dynamics of these systems. As an example, we apply our strategy to set up a model of the cell cycle consisting of multiple bistable switches, which can incorporate events such as DNA damage and coupling to the circadian clock in a phenomenological way.

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“…Any discrepancy between experimental and theoretical results shall be useful for our model improvement. Consideration of protein localization and stochastic fluctuation ( Beesley et al, 2020 ; Ghim and Almaas, 2009 ; Kim and Price, 2010 ) would be necessary for more complete modeling in this subject.…”

Section: Discussionmentioning

confidence: 99%

Cost-effective circadian mechanism: rhythmic degradation of circadian proteins spontaneously emerges without rhythmic post-translational regulation

et al. 2021

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Wake-sleep cycles are severely disrupted by diseases affecting cytoplasmic homeostasis

Cited by 40 publications

References 63 publications

From circadian clock mechanism to sleep disorders and jet lag: Insights from a computational approach

From circadian clock mechanism to sleep disorders and jet lag: Insights from a computational approach

A modular approach for modeling the cell cycle based on functional response curves

Cost-effective circadian mechanism: rhythmic degradation of circadian proteins spontaneously emerges without rhythmic post-translational regulation

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