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, 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 as well as samples from Atm-/- mice. In healthy human and wild type mouse cerebellum we confirmed the presence of ATM in white matter OLs. In A-T but not age-matched controls, a significant reduction in OL density was coupled with a massive astrogliosis. We found that the extent of this OL pathology was particularly strong in cases with frameshifts or premature termination ATM mutations. Similar pathologies were also found in Atm-/- mice in an age- and gene dose-dependent fashion. In vitro, DNA damage induced by etoposide-induced DSBs or blockade of ATM activity with KU-60019 differentially jeopardized cell cycle control in OL progenitors and mature OLs. Turning to structural analysis in silico, we identified likely interactions between ATM and myelin basic protein as well as myelin regulatory factor and confirm this by immunoprecipitation. These novel OL-specific functions of the ATM protein affect all stages of the OL lineage. They thus provide a cell biological basis for a direct role for ATM in central nervous system myelination and illustrate how the myelin pathology found in A-T is at least in part independent of neuronal degeneration.