From ScienceDaily@1337:3/111 to All on Mon Nov 22 21:30:28 2021
How do we know we're tired?
The PARP1 protein acts as an antenna, signaling the brain that it's time
to sleep and repair DNA
November 22, 2021
Why do we need sleep? New research takes a step towards solving
this mystery by discovering a mechanism of sleep in zebrafish,
with some supporting evidence in mice.
FULL STORY ==========================================================================
Why do humans spend a third of their lives sleeping? Why do animals sleep? Throughout evolution sleep has remained universal and essential to all organisms with a nervous system, including invertebrates such as flies,
worms, and even jellyfish. Why animals sleep despite the continuous
threat of predators, and how sleep benefits the brain and single cells
still remains a mystery.
In a new study published in the journal Molecular Cell,researchers
fromIsrael's Bar-Ilan University have moved a step forward towards
solving this mystery by discovering a mechanism of sleep in zebrafish,
with some supporting evidence in mice.
The study was led by Prof. Lior Appelbaum, of Bar-Ilan's Goodman Faculty
of Life Sciences and Gonda (Goldschmied) Multidisciplinary Brain Research Center, along with postdoctoral researcher Dr. David Zada.
When we are awake, homeostatic sleep pressure (tiredness) builds up in
the body. This pressure increases the longer we stay awake and decreases
during sleep, reaching a low after a full and good night's sleep.
What causes homeostatic pressure to increase to a point that we feel we
must go to sleep, and what happens at night that reduces this pressure
to such an extent that we are ready to start a new day? During waking
hours, DNA damage accumulates in neurons. This damage can be caused
by various elements, including UV light, neuronal activity, radiation, oxidative stress, and enzymatic errors. During sleep and waking hours,
repair systems within each cell correct DNA breaks. However, DNA damage
in neurons continues to accumulate during wakefulness, and excessive DNA
damage in the brain can reach dangerous levels that must be reduced. The
study revealed that a sleep recruit DNA repair system promotes efficient
repair so that the day can begin anew.
In a series of experiments, the researchers sought to determine whether
the buildup of DNA damage could be the "driver" that triggers homeostatic pressure and the subsequent sleep state. Using irradiation, pharmacology
and optogenetics, they induced DNA damage in zebrafish to examine how it affects their sleep. With their absolute transparency, nocturnal sleep,
and a simple brain that is similar to humans, zebrafish are a perfect
organism in which to study this phenomenon.
As DNA damage was increased, the need for sleep also increased. The
experiment suggested that at some point the accumulation of DNA damage
reached a maximum threshold, and increased sleep (homeostatic) pressure
to such an extent that the urge to sleep was triggered and the fish went
to sleep. The ensuing sleep facilitated DNA repair, which resulted in
reduced DNA damage.
How many hours of sleep are sufficient? There's nothing like a good
night's sleep. After verifying that accumulated DNA damage is the force
that drives the sleep process, the researchers were eager to learn
whether it's possible to determine the minimum time zebrafish need to
sleep in order to reduce sleep pressure and DNA damage. Since, like
humans, zebrafish are sensitive to light interruption, the dark period
was gradually decreased during the night. After measuring DNA damage and
sleep, it was determined that six hours of sleep per night is sufficient
to reduce DNA damage. Astoundingly, after less than six hours of sleep,
DNA damage was not adequately reduced, and the zebrafish continued to
sleep even during daylight.
PARP1 is an "antenna" that can signal it's time to sleep What is
the mechanism in the brain that tells us we need to sleep in order to facilitate efficient DNA repair? The protein PARP1, which is part of the
DNA damage repair system, is one of the first to rapidly respond. PARP1
marks DNA damage sites in cells, and recruits all relevant systems to
clear out DNA damage. In accordance with DNA damage, clustering of
PARP1 in DNA break sites increases during wakefulness and decreases
during sleep. Through genetic and pharmacological manipulation,
the overexpression and knockdown of PARP1 revealed not only that
increasing PARP1 promoted sleep, but also increased sleep-dependent
repair. Conversely, inhibition of PARP1 blocked the signal for DNA damage repair. As a result, the fish weren't fully aware that they were tired,
didn't go to sleep, and no DNA damage repair occurred.
To strengthen the findings on zebrafish, the role of PARP1 in regulating
sleep was further tested on mice, using EEG, in collaboration with
Prof. Yuval Nir from Tel Aviv University. Just like with zebrafish,
the inhibition of PARP1 activity reduced the duration and quality of
non-rapid eye movement (NREM) sleep. "PARP1 pathways are capable of
signaling the brain that it needs to sleep in order for DNA repair to
occur," says Prof. Appelbaum.
Solving the puzzle In a previous study, Prof. Appelbaum and team used
3D time-lapse imaging to determine that sleep increases chromosome
dynamics. Adding the current piece to the puzzle, PARP1 increases sleep
and chromosome dynamics, which facilitates efficient repair of DNA damage accumulated during waking hours. The DNA maintenance process may not be efficient enough during waking hours in neurons, and therefore requires
an offline sleep period with reduced input to the brain in order to occur.
These latest findings provide a detailed description of the "chain of
events" explaining sleep on the single-cell level. This mechanism may
explain the link between sleep disturbances, aging and neurodegenerative disorders, such as Parkinson's and Alzheimer's. Prof. Appelbaum believes
that future research will help to apply this sleep function to other
animals ranging from lower invertebrates to, eventually, humans.
========================================================================== Story Source: Materials provided by Bar-Ilan_University. Note: Content
may be edited for style and length.
========================================================================== Journal Reference:
1. David Zada, Yaniv Sela, Noa Matosevich, Adir Monsonego, Tali Lerer-
Goldshtein, Yuval Nir, Lior Appelbaum. Parp1 promotes sleep,
which enhances DNA repair in neurons. Molecular Cell, 2021; DOI:
10.1016/ j.molcel.2021.10.026 ==========================================================================