ATM Deficiency in the Brain and Its Consequences in Microglia and Oligodendrocytes

Mutations in ATM (ataxia-telangiectasia mutated) lead to ataxia-telangiectasia (A-T), a multisystemic disease that includes a prominent neurodegeneration phenotype. While the loss of nerve cells is the most commonly studied cellular feature of this phenotype, non-neuronal cells have independent defects that contribute to the symptoms of A-T. The role of astrocytes has been reported by others and we have previously described the activation of brain microglia in Atm^-/- mouse brain. We now report that the hyper-activation of Atm^-/- microglia creates a pro-inflammatory environment that greatly contributes to the observed neurodegeneration, particularly in cerebellum. ATM deficiency leads to the accumulation of cytosolic DNA, which, in microglial cells, triggers an anti-viral innate immune response via the DNA sensor, STING and the AIM2 inflammasome. A second cell type, the oligodendrocyte, also accumulates DNA damage in the absence of ATM. In the case of these myelin-forming cells, however, the response is cell death resulting in demyelination. In cerebellar tissue of A-T brain, the number of cells of the entire oligodendrocyte lineage (Olig2⁺) as well as mature (CC1⁺) oligodendrocytes are greatly reduced. The severity of this reduction is highly variable across different ATM mutations. The demyelination phenotype is faithfully reproduced in Atm^-/- mice and in KU-60019-treated cultured oligodendrocytes in the absence of neurons. Our findings suggest that ATM is required for survival, differentiation and cell cycle progression in oligodendrocyte progenitors as well as in later developmental stages. mature stages. In summary, the loss of the divergent functions of ATM in the OL lineage may cause myelin pathology independent of neuronal degeneration. Overall, our findings paint a more complex picture of the origins of the neurodegeneration phenotype with important implications for the clinical management of A-T.