Myelin pathology in ataxia-telangiectasia is the cell-intrinsic consequence of ATM deficiency in the oligodendrocytes

Ataxia-telangiectasia (A-T) is a rare genetic disease caused by mutations in the gene encoding the ATM (ataxia-telangiectasia mutated) protein. Although neuronal degeneration in the cerebellum remains the most prominent sign in A-T pathology, neuroimaging studies reveal myelin abnormalities as early comorbidities. We hypothesize that these myelin defects are the direct consequence of ATM deficiencies in the oligodendrocytes (OL) lineage. We examined samples from ten A-T brains in which the ATM mutations had been mapped by targeted genomic sequencing and from Atm-/- mice. In healthy human cerebellum, we confirmed the presence of ATM in white matter OLs. In A-T, a significant reduction in OL density was found along with a massive astrogliosis. This white matter pathology was recapitulated in Atm-/- mice in an age- and gene dose-dependent fashion. Activated ATM was found expressed both in the nucleus and cytoplasm of OL progenitor cells (OPC) and myelinating mature OL. Its presence in the OL lineage is associated with novel OL-specific functions of the ATM protein affecting all stages of the OL life cycle. Blockage of ATM activity with KU-60019 or inducing DNA damage induced with etoposide altered the cell cycle in self-renewing OPC and triggered ectopic cell cycle re-entry in mature OL in vitro. Further, the differentiation program of OPC is highly sensitive to DNA damage either induced directly or by blocking DNA repair. As much of the impact of ATM deficiency in OL is independent of neuronal loss, our findings have important implications for the complex neurological symptoms of human A-T. HIGHLIGHTSO_LIOligodendrocytes are highly vulnerable to DNA double strand breaks C_LIO_LIATM regulates cell cycle control and differentiation of oligodendrocytes C_LIO_LIMyelin-pathology in Ataxia Telangiectasia is likely the cell-autonomous consequence of ATM deficiency in oligodendrocytes C_LI