Cytoplasmic obstruction disrupts the sleep-wake cycle

Figure 1. PER abundance is reduced in a circadian way through a self-regulating negative feedback cycle. This oscillation allows circadian physiological and behavioral processes, including sleep, to maintain a stable time. Credit: KAIST

KAIST mathematicians and their employees Florida State University based on how aging and diseases such as dementia and obesity cause sleep disorders. Mathematical modeling and a combination of experiments have shown that cytoplasmic occlusion caused by aging, dementia, and / or obesity disrupts circadian rhythms in the human body and leads to irregular sleep patterns. This finding suggests new treatment strategies to address unstable sleep patterns.

The human body regulates sleep schedules according to the ‘circadian rhythms’ regulated by our time-keeping system. This clock explains when our body will rest, creating 24-hour rhythms of a protein called PERIOD (PER) (see Figure 1).

The amount of PER protein increases in the middle of the day and decreases in the remaining half. The principle is that the PER protein, which accumulates in the cytoplasm for several hours, enters the cell nucleus at once and prevents the transcription of PER genes, thereby reducing the amount of PER.

However, in a complex cellular environment in which different materials exist and can interfere with the movement of PER, it remains a mystery how thousands of PER molecules can enter the nucleus at the same time. It would be like finding a way for thousands of workers from all over New York to enter an office building at the same time every day.

Spatial Stochastic Model of Circadian Clock

Figure 2. Spatial stochastic model of circadian clock. After per mRNA, M is converted to a protein (R) in the cytoplasm, R, PER is transferred to the perinucleus, obstructed during hypophosphorylation (ii; gray circle). PER accumulated in the perinucleus is hyperphosphorylated in a cooperative manner (iii). It then enters the nucleus and inhibits the transcriptional activity of activator A (iv). Credit: KAIST

A team of researchers led by Professor Jae Kyoung Kim of KAIST’s Department of Mathematical Sciences solved the mystery by developing a spatial-temporal and probabilistic model describing the motion of PER molecules in a cellular environment.

This study was conducted in collaboration with Professor Choogon Lee from Florida State University, where the experiments were conducted, and the results Data from the National Academy of Sciences (PNAS) last month.

The spatial stochastic model of the joint research group (see Figure 2) described the movement of PER molecules in cells and showed that the PER molecule must be sufficiently condensed around the cell nucleus in order to be phosphorylated at the same time (see Figure 3 Left). Thanks to this phosphorylation synchronization key, thousands of PER molecules can enter the nucleus at the same time every day and maintain stable circadian rhythms.

Cytoplasmic Flux increases PER abundance

Figure 3. In a normal cell (left), the cytoplasmic flow for several hours increases the abundance of PER in the perinucleus (pink region in Figure 2) relative to the peripheral cytoplasm (cyanide region in Figure 2). This results in hyperphosphorylation as a sharp transition in the perinucleus due to co-operation (ii), followed by synchronous nuclear entry in a narrow time window (iii). When a cell is overgrown (right), cytoplasmic flow is inhibited and thus PER does not accumulate in the same gradient as in a normal cell (i). This eliminates PER hyperphosphorylation and nuclear entry (ii and iii) as an acute transition. Credit: KAIST

However, diseases such as aging and / or dementia and obesity prevent the timely condensation of PER molecules around the cell nucleus, causing the cytoplasm to condense with increasing cytoplasmic barriers such as protein aggregates and fat vacuoles (see Figure 3 Right). As a result, the phosphorylation synchronization key does not work, and PER proteins enter the nucleus at irregular times, destabilizing circadian rhythms and sleep cycles.

Professor Kim said, “As a mathematician, I am excited to help develop new treatment strategies that will improve the lives of many patients who suffer from irregular sleep patterns. I hope to use these findings as an opportunity for a more active exchange of ideas and collaboration between the mathematical and biological sciences. ”

Reference: Stephen Beesley, Dae Wook Kim, Matthew D’Alessandro, Yuanhu Jin, Kwangjun Lee, Hyunjeong Joo, Yang Young, Robert J. Tomko Jr, John Faulkner, “Appropriate sleep cycles are severely impaired by diseases that affect cytoplasmic homeostasis.” Joshua Gamsby, Jae Kyoung Kim and Choogon Lee, October 26, 2020, Materials of the National Academy of Sciences.
DOI: 10.1073 / pnas.2003524117

This work was supported by the National Institutes of Health and the National Science Foundation in the United States, the International Human Border Science Program, and the National Research Foundation of Korea.

Related articles

Comments

LEAVE A REPLY

Please enter your comment!
Please enter your name here

Share article

Latest articles

Giant ancient fish discovered by accident – Strange-looking and “Absolutely massive!”

An example of what a complete fish fossil coelacanth looks like. This is the German Jurassic. Credit: Professor David Martill, University of...

Next generation robot sequence could screen thousands accurately for COVID-19

A robotics platform designed by researchers in Toronto to help thousands of COVID-19 At the same time, samples have the potential to revolutionize how...

Engineering of the boundary interface between 2D and 3D materials

By David L. Chandler, Massachusetts Institute of Technology March 2, 2021 These images of the “islands” of gold atoms accumulated in the two-dimensional molybdenum sulfide layer...

Why the chemical composition of the sun varies

Linn On August 21, 2017, during a total solar eclipse, the sun's rays appeared in white. From Michael, Oregon. The moon...

Use of underwater telecommunication cables to detect earthquakes

Caltech seismologists working with optics experts at Google have developed a method for using underwater telecommunications cables to detect groundwater. The technique can...

Newsletter

Subscribe to stay updated.