An unknown role ATR protein regulates neuronal activity

The ATR protein plays an important role in the replication stress response as a regulator of the DNA damage response (DDR) and controls the viability of cells. ATR mutations in humans lead, among other pathologies, to neurological defects; indicating a role still unknown to ATR in non-dividing cells. Researchers at the Leibniz Institute on Aging — Frena Lipmann Institute (FLI) in Jena and the Neuroimmunology Section of Jena University Hospital have shown that ATR suppression in neurons does not affect brain development and formation , but amplifies neuronal activity and increases susceptibility to epilepsy. This study identifies a physiological function of ATR, beyond its DDR role, in the regulation of neuronal activity.

The genome comprises all the genetic information present in a cell and in humans, it is stored in the form of DNA on the chromosomes of the cell nucleus. The genome is continuously exposed to internal and external factors, such as environmental toxins, radiation, and reactive oxygen species, which can cause DNA damage. The resulting damage to the double helix of DNA poses a significant threat to the organism. So, cells they are equipped with sensitive but robust DNA damage response (DDR) machinery that includes not only direct damage repair, but also signaling pathways that control cell survival and therefore protect genome integrity.

The ATR protein (related to Ataxia Telangiectasia and Rad3) is a master regulator that controls DNA damage signaling and DNA repair in response to replication stress during DNA synthesis, and stops the cell cycle when necessary. This means that cells or tissues with a high replication capacity cannot tolerate the loss of ATR, as ATR is facing replication stress. Therefore, complete loss of ATR is lethal to cells and organisms. In contrast, hypomorphic mutations in ATR (partial loss of gene function) cause Seckel syndrome, a disorder of chromosomal instability, in humans. Patients with this syndrome are characterized by dwarfism, developmental delay, microcephaly, and mental retardation. It is also often associated with a senile, progeroid appearance with symptoms of premature aging, suggesting a still unknown role of ATR. So far, however, it is not known how mutations in ATR, which usually treat replication stress, can regulate the neuronal functionality of postmitotics. neurons (cells that do not divide) and explain neurological symptoms such as microcephaly, learning deficits, and intellectual disability.

Using genetically modified mouse models, researchers led by Professor Zhao-Qi Wang, head of the genomic stability research group at the Leibniz Institute on Aging — Fritz Lipmann Institute (FLI) in Jena, in collaboration with Professor Christian Geis, Department of Neuroimmunology, Jena University Hospital, investigated the impact of ATR loss on brain formation and neuron functionality. “If ATR was absent in the embryonic neuronal progenitor or other proliferating cells, the animals had severe neurodevelopmental defects and died shortly after birth,” says Dr. Murat Kirtay, who performed the tests during his doctoral thesis. In contrast, mouse strains, if ATR is lacking in postmitotic neurons, had a normal life expectancy.

“Our study shows that when ATR is removed from undivided cells, the viability of neurons is unaffected and is dispensable for the formation and structure of the mouse brain,” says Dr. Kirtay, first author of the study published in Communications on Nature. That is, if replication stress is spared in cells, the abrogation of the ATR-DDR axis by the loss of ATR is neither toxic to postmitotic neurons nor critical to brain development. .

New role of ATR in postmitotic neurons

However, ATR loss is closely associated with cerebellar defects, as despite seemingly normal cerebellar structure and morphology, mutant mice exhibited surprising locomotor dysfunction. Compared to the control group, they had deficits in their learning ability and grip power, as well as in motor coordination, which was especially noticeable in older mice.

In addition, with age, loss of ATR to neurons caused sporadic non-lethal epileptic seizures, possibly triggered by external stimuli such as handling and cage changes. “Since epilepsy is associated with aberrant synaptic transmission and neuronal activity, this sensitivity to epileptic seizures strongly suggests that altered neuronal activity in mutant mice, which progresses with aging, makes neurons more vulnerable to stress or environmental stimuli, ”says Professor Zhao-Qi Wang .Loss of ATR in neurons causes hyper-excitability and increases susceptibility to seizures. ”Although ATR is known to be an essential regulator of DDR, our study revealed an important and previously unknown physiological function of ‘ATR in neural activity,’ Professor Wang added.

ATR regulates intrinsic neuronal activity

“Despite the normal morphology of the cerebellum and anterior brain, neurons lacking ATR were defective in synaptic function. Electrophysiological analysis of mouse models showed increased intrinsic neuronal activity of neurons, so we conclude that l ‘ATR has a general physiological role in neuronal activity and synaptic function.’ explained Professor Geis. Loss of ATR does not induce DNA damage or activate DDR signaling in neurons, meaning that the observed synaptic defects are independent of DDR signaling. Thus, the study provides information on the causal mechanisms underlying the neurological symptoms of Seckel syndrome, which may provide new strategies for the diagnosis and treatment of multiple pathological symptoms.

“Our study shows that the loss of ATR in neurons is compatible with brain development and life, but it also confers a high susceptibility to epileptic seizures,” says Professor Wang. These neurological defects they manifest mainly during the aging process. “Furthermore, we were able to demonstrate for the first time that ATR has an unknown but major primary function in neuronal functionality and signaling activity that goes far beyond the already known DDR signaling. Therefore, this surprising new discovery is important. for clinicians and scientists in the fields of DNA repair, neurobiology, and neuronal homeostasis. ” ATR is a new regulator of neuronal signaling that can prevent epileptic seizures.

Provided by the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI)