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.
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.
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.