- A recent study in Molecular Cell shows that buildup of neuronal DNA damage in zebrafish larvae stimulates sleep.
- PARP1 — the body’s DNA damage antenna — detects neuronal DNA injury, induces sleep, and DNA repair during sleep.
- Future research in humans may clarify the association between sleep disturbances and some neurodegenerative disorders, such as Alzheimer’s or Parkinson’s disease.
Getting the right amount of sleep at the proper times — sleep quality — is vital to good health and essential for survival. Sleep is a complex process that affects the entire body.
It is crucial for brain development and the maintenance of pathways necessary for memory and learning. Sleep also helps support the proper functioning of the heart, lungs, immune system, metabolic processes, and disease defenses.
Circadian rhythms are 24-hour cycles, which sometimes synchronize with external cues, such as light, that control sleep timing, body temperature, hormone release, and metabolism. Sleep-wake homeostasis causes the body to feel tired when it needs sleep, building until sleep.
Preliminary research in animal models suggests that DNA damage to nerves or “DNA breaks” accumulate during wakeful periods, with repair occurring during sleep. However, which cellular mechanisms initiate sleep-wake homeostasis remains a mystery.
This led researchers to perform a series of experiments on zebrafish larvae to identify the cellular triggers behind sleep-wake homeostasis and the role of sleep in facilitating DNA repair.
In an MNT interview, Prof. Lior Appelbaum at The Goodman Faculty of Life Sciences Bar-Ilan Univerisity and co-author of the study explained that DNA damage occurs due to normal processes related to nerve activity, such as thinking.
Prof. Appelbaum also said that sleeping is an intriguing activity from an evolutionary perspective because survival is at risk during sleep. So, there must be a “cost” during the day that drives sleep: “We asked first, ‘Why do we sleep?’ and even further, ‘Why are we tired? What is the cost of wakefulness?'”
He added: “We used zebrafish because it is transparent, amenable to genetic manipulation, and it’s still a vertebrate, which means the brain is […] similar to mammals or even human[s], in brain structure and function. […] Basically, we can visualize repair protein in the cell while the fish is alive, sleeping, and awake, and follow their activity, which was a big breakthrough.”
Additionally, zebrafish larvae are active during the day — diurnal — and their sleep patterns closely resemble those in mammals. Scientists first measured the minimal amount of sleep required to reduce tiredness, or homeostatic sleep pressure, allowing adequate time for DNA repair.
The scientists wondered, “what is the optimal amount of time that a fish needs to sleep in order to repair their DNA,” Prof. Appelbaum explained.
To find out, they exposed the zebrafish larvae to light after different periods of darkness and found that a minimum of 6 hours of continuous sleep was necessary to reduce homeostatic pressure. The researchers then assessed the number of hours of sleep the zebrafish larvae needed to normalize the levels of DNA damage demonstrated in their previous study.
The results indicated that 6 hours was sufficient for the zebrafish larvae to reverse DNA damage that occurred while they were awake. When the zebrafish larvae slept less than 6 hours, they continued to sleep even after exposure to daylight.
These results suggest that neuronal DNA damage dictates how much sleep is needed to overcome tiredness.
In separate experiments, the researchers then induced DNA damage in the zebrafish larvae by stimulating nerve activity and exposing the larvae to UV light.
Scientists found that DNA damage induced by UV light and nerve stimulation also caused the zebrafish larvae to sleep, supporting the hypothesis. Other experiments suggested that DNA damage increased the activity of repair pathways and
When scientists chronically inhibited repair pathways and chromosome dynamics, this caused the zebrafish larvae to sleep. Next, the researchers conducted experiments to uncover the role of a repair protein called PARP1 in zebrafish larvae and mice.
Dr. Appelbaum explained that PARP1 is a “DNA damage detector [which] functions like an antenna. It recruits […] repair protein, and whenever you have […] enough PARP1, it induces sleep behavior, and then during sleep the repair system, [so] you can start the new day with a baseline amount of DNA damage.”
The researchers demonstrated that PARP1 amplification in zebrafish larvae induced sleep and neuronal DNA repair. Reversely, in zebrafish larvae, when scientists inactivated PARP1, it caused wakefulness and lack of DNA repair.
To support the findings, scientists inhibited PARP1 in adult mice and monitored their sleep patterns. They discovered a reduction in non-REM sleep and its intensity.
In an interview with an expert outside the study, Dr. Clifford Segil, DO, a neurologist at Providence Saint John’s Health Center in Santa Monica, CA, commented, “As with most DNA studies or genetic studies, as a clinician, it’s hard to see what any kind of clinical impact this study [would have].”
He added it would be challenging to go “from the test tube to the world, from in vitro to in vivo. […] You’d have to figure out a way to measure DNA damage in a person and damage someone’s DNA during the day [to] see if they sleep more at night.”
Dr. Segil agreed that there might be a potential for future research in humans with neurodegenerative disorders linked to sleep disturbances, such as Alzheimer’s disease.
Dr. Appelbaum suggested:
“One more future direction is to causally link sleep disturbances, the accumulation of neuron damage, cell death, […] to neurodegenerative disease and aging in general.”