Dysfunction of cerebellar microglia in Ataxia-telangiectasia


Ataxia-telangiectasia is an extremely pleiotropic autosomal recessive human disease caused by null mutations in the ATM gene which codes for the ATM protein kinase. Patients with A-T have a startling sensitivity to the cytotoxic effects of ionizing radiation, and A-T cells display significant chromosomal instability, sensitivity to radiation and radioactive substances, and short telomeres. Ionizing radiation sensitivity is caused by a severe deficiency in the cellular response to DNA double-strand breaks (DSBs), which is brought about by the absence of the ATM protein kinase. The ATM gene has null mutations in both copies in patients with the typical type of A-T. Tens of thousands of DNA lesions per cell every day are induced by endogenous ROS or radicals, which are created during metabolism and pose a serious danger to the stability of the genome. For cellular equilibrium, proper development, and the avoidance of unwarranted cell death, cancer, and early ageing, defense against challenges to genomic integrity is essential. The mutations that result in genomic instability disorders, such as A-T, underscore the significance of the DNA damage response to human health.

DSBs can be brought on by endogenous ROS or DNA-damaging substances, or they can develop as a result of physiological processes like meiotic recombination or V(D)J recombination. ATM is the main transducer of the DSB response network, and DSBs significantly increase ATM’s protein kinase activity. Brain-colonizing microglial cells are involved in neuro-plasticity, host defense, homeostasis, cell migration, debris scavenging, peripheral immune cell recruitment, and immune response modulation. They also continuously monitor the microenvironment. Microglia are capable of migrating and undergoing morphological and functional alterations in response to a number of stimuli. Microglial cells are polarized (activated) by pathological stimuli like cytokines, chemokines, and growth factors which are crucial in the CNS’s degeneration or repair. In brain degenerative diseases microglial actively contribute to neuronal destruction and their over- or under-activation can have devastating and cumulative neurotoxic effects. According to earlier research, microglia may contribute to the loss of cerebellar Purkinje cells in A-T. After an illness or injury, microglia are quickly drawn to the damaged area where they engulf—or phagocytose—debris and unwanted or dead cells. Microglia are essential for the immunological response to infection or injury, but they also release cytokines and neurotoxic proteins that contribute to pathological neuroinflammation.

In a new study published in Glia, Israeli scientists: Hadar Levi, PhD candidate Ela Bar, Stav Cohen-Adiv, Suzan Sweitat, Dr. Sivan Kanner, Ronit Galron, Yulia Mitiagin, and Professor Ari Barzilai from Tel Aviv University reported that the phagocytosis, cell migration, ROS production, neurotrophic factor secretion, and mitochondrial activity of microglia are considerably reduced in the cerebellum but not in the cerebral cortex. Additionally, there are noticeable differences in how Atm deficiency affects cerebellar and cerebral cortical astroglia. These findings support the idea that microglia and astrocytes are diverse cell populations with distinct regional features. This theory is supported by data showing that microglia have different turnover rates, extent of self-renewal, growth factor release, metabolism, and radiosensitivities under physiological and harmful conditions, as well as differences in functions like synaptic modelling, myelination, and vascular remodelling.

On the other hand, cerebellar homeostasis can be altered by Atm deficit in microglia in a way that speeds up cerebellar death. Previous findings where ATM inhibition produced significant structural damage to cultured neurons most likely through the production of neurotoxic chemicals showed the significance of fully functioning microglia for neuronal survival. The discovery that a particular class of microglial cells dynamically surveys Purkinje neurons supports the idea that microglia play a critical role in the survival and functioning of Purkinje cells. Results from the current study also reveals that Atm absence especially hinders cerebellar growth, resulting in the concentration of immature amoeboid cells, as microglial maturation proceeds more quickly in the cerebral cortex than in the cerebellum. These findings support the idea that the pure primary tissue cultures of microglia accurately depict the consequences of Atm loss on microglial cells.

The new study concluded that Atm deficiency substantially reduced cerebellar microglia’s ability to operate. In comparison to wild-type cerebellar microglia, Atm-deficient cerebellar microglia exhibit defective phagocytosis, faster cell migration, raised levels of ROS, increased mitochondrial mass, and lower membrane potential in culture. However, the loss of Atm did not cause the cerebral cortical microglia to malfunction. The findings are consistent with the working theory that ATM inactivation decreases the protective functions of cerebellar glial cells but not of cerebral cortical glial cells, causing the cerebellar atrophy seen in A-T patients.


Levi H, Bar E, Cohen‐Adiv S, Sweitat S, Kanner S, Galron R, Mitiagin Y, Barzilai A. Dysfunction of cerebellar microglia in Ataxiatelangiectasia. Glia. 2022 Mar;70(3):536-57.

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