Dysfunction of cerebellar microglia in Ataxia-telangiectasia

Hadar Levi, Ela Bar, Stav Cohen-Adiv, Suzan Sweitat, Sivan Kanner, Ronit Galron, Yulia Mitiagin, Ari Barzilai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Ataxia-telangiectasia (A-T) is a multisystem autosomal recessive disease caused by mutations in the ATM gene and characterized by cerebellar atrophy, progressive ataxia, immunodeficiency, male and female sterility, radiosensitivity, cancer predisposition, growth retardation, insulin-resistant diabetes, and premature aging. ATM phosphorylates more than 1500 target proteins, which are involved in cell cycle control, DNA repair, apoptosis, modulation of chromatin structure, and other cytoplasmic as well as mitochondrial processes. In our quest to better understand the mechanisms by which ATM deficiency causes cerebellar degeneration, we hypothesized that specific vulnerabilities of cerebellar microglia underlie the etiology of A-T. Our hypothesis is based on the recent finding that dysfunction of glial cells affect a variety of process leading to impaired neuronal functionality (Song et al., 2019). Whereas astrocytes and neurons descend from the neural tube, microglia originate from the hematopoietic system, invade the brain at early embryonic stage, and become the innate immune cells of the central nervous system and important participants in development of synaptic plasticity. Here we demonstrate that microglia derived from Atm−/− mouse cerebellum display accelerated cell migration and are severely impaired in phagocytosis, secretion of neurotrophic factors, and mitochondrial activity, suggestive of apoptotic processes. Interestingly, no microglial impairment was detected in Atm-deficient cerebral cortex, and Atm deficiency had less impact on astroglia than microglia. Collectively, our findings validate the roles of glial cells in cerebellar attrition in A-T.

Original languageEnglish
Pages (from-to)536-557
Number of pages22
Issue number3
StatePublished - Mar 2022


FundersFunder number
German Israeli FoundationI‐192‐418.13‐2014
Joint Italian-Israeli Laboratory on Application of Neuroscience
Joint Italian‐Israeli Laboratory on Application of Neuroscience590308
Israel Science Foundation41/15, 1307/19
Ministry of Science and Technology, Israel3‐14260‐2016


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