The researchers identified three new genes associated with the regulation of circadian rhythms. A family of genes allows cells to adapt to daily changes in environmental conditions by adjusting their internal “biological clock“, the circadian clock responsible for normal sleep-wake cycles. The new discovery by scientists at the University of Tokyo reveals for the first time that circadian regulation can be directly linked to cellular stress. Circadian rhythms are found in almost all organisms with sensitivity to light. Problems with circadian rhythms in humans are related to diseases such as hypertension (hypertension), metabolic disorders and insomnia. Both shift workers and older people have increased the risk of these diseases due to changes in their circadian clock. The research group responsible for the work is based at the University of Tokyo and led by Professor Yoshitaka Fukada and assistant professor Hikari Yoshitane at the Department of Biological Sciences. The latest results derive from a series of ongoing experiments and continue to be based on the interests of the laboratory in circadian studies. The collaborators led by Professor Hidenori Ichijo of the Graduate School of Pharmaceutical Sciences, have developed the exclusive mice used in the experiments.
Scientists used cells and mice lacking three genes: kinases 1, 2 and 3 for apoptosis (ASK1, ASK2 and ASK3). In both cell and mouse results, ASK genes were necessary to respond to both sudden changes in the environment and gradual changes over time. Cells without ASK genes have not shown changes to their circadian rhythm, which occur in normal cells that grow in environments with too high or too low salt or sugar concentrations. Cells without ASK genes were also impermeable to expected changes after cells accumulated too much oxidative stress. One of the genes responsible for controlling circadian rhythms is CLOCK. It produces a protein that binds DNA together with its partner PER, produced by the Period gene. The team of researchers has seen that the ASK kinases modify the CLOCK protein, varying the affinity for its partner PER. The results in the cells were further supported by observations on mouse behavior. Normal mice can change their wake-up time the next morning after unexpected exposure to light at night, as measured by their activity running on a wheel. Mice without ASK genes have less ability to synchronize their circadian clock with changes in environmental light-darkness cycles.
Many researchers in this field have long suspected that oxidative stress and circadian rhythms are somehow linked, due to the photosynthesis cycles and DNA replication that we also see in ancient organisms. Photosynthesis requires sunlight and creates free radicals that they could damage DNA, so cells postpone DNA replication and cell division until nightfall when photosynthesis stops. Uncontrolled oxidative stress creates potentially toxic environments within cells, due to changes in chemical equilibrium. Besides, ASK proteins are involved in a form of cellular death called apoptosis. They are activated when intracellular ROS increase inappropriately. One ROS sensor is thioredoxin-1 (Trx-1), a small protein that becomes oxidized in attempt to buffer ROS. Once oxidized, it becomes a partner for ASK-1, leading to its activation. ASK-1, in turn triggers a cascade that drives cell death (apoptosis). Since a chronic lack of sleep has been linked to cognitive decline in the late age, it would be a good hypothesis to test if sleep deprivation would kill brain neurons by the cascade oxidative stress-ASK proteins. Neuronal loss would, in time, compromise higher functions like memory, mood and cognition.
Dr. Fukada commented: “We are very excited about our results because we can approach the origin of the circadian clock by linking oxidative stress and circadian regulation through ASK genes. The dream is to have a tool to regulate the circadian rhythms. Basic science such as our research can show suggestions for the subsequent work of drug discovery aimed at the purpose”. The team plans to continue studying the detailed cellular mechanisms linking ASK genes to oxidative stress and the potential methods for influencing the circadian rhythm.
- edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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