Editors' ChoiceCIRCADIAN CLOCK

Cytoplasmic traffic jams affect circadian timing

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Science Translational Medicine  11 Nov 2020:
Vol. 12, Issue 569, eabf4681
DOI: 10.1126/scitranslmed.abf4681

Abstract

Cytoplasmic crowding may underlie the disruption of the circadian clock in neurodegeneration.

Similar to the commute in a crowded city, the movement of molecules in the cytoplasm can run into “traffic jams.” These molecular events can slow transit through cytoplasmic space, which, like vehicular traffic jams, can be problematic for anything that needs to be in a certain place at a certain time. Arguably, there is no cellular process where timing is more crucial than in the molecular circadian clock, which relies on the precise and collective timing of the nuclear localization and phosphorylation of the PERIOD proteins to impart its daily physiological regulation. However, little is known about the effect cytoplasmic crowding, or viscosity, has on circadian timing.

To study whether cytoplasmic viscosity plays a role in circadian timekeeping, Beesley et al. investigated models of autophagy, where cytoplasmic crowding is well documented, and demonstrated that cytoplasmic viscosity affected the cellular circadian period. This effect extended to both the phosphorylation of the PERIOD proteins as well as sleep/wake rhythms in mice and was relieved by the restoration of PERIOD stoichiometry. In concordance with these findings, an investigation of the clock in a rodent model of Tauopathy, where intracellular tau tangles generate cytoplasmic congestion, also showed period defects.

A limitation of this work is that the disease models investigated have complicated pathophysiology, suggesting that other mechanisms might also play a role in clock regulation. However, the results indicate that movement in three-dimensional space, in particular, the timing of PERIOD nuclear entry, plays an essential role in proper circadian timing. Because many diseases and therapeutics are linked to the circadian clock, including the Alzheimer’s disease model studied here, this finding highlights potential clock–linked disease mechanisms as well as prospective avenues for chronotherapies.

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