Oligodendrocyte maturation alters the cell death mechanisms that cause demyelination

Abstract

Myelinating oligodendrocytes die in human disease and early in aging. Despite this, little is known about the mechanisms that govern cell death across the oligodendrocyte lineage. Here we used a combination of intravital imaging, single-cell ablation, and cuprizone intoxication to show that oligodendrocyte maturation dictates the dynamics and mechanisms of death. After single-cell genotoxic damage, oligodendrocyte precursor cells underwent programmed cell death within hours, while mature oligodendrocytes died weeks after the same acute damage. Targeting single cells that were actively undergoing oligodendrocyte generation revealed that a switch in the temporal dynamics and morphological progression of death occurs during differentiation. Consistent with this, cuprizone intoxication initiated a caspase-3-dependent form of rapid cell death in differentiating oligodendrocytes, while mature oligodendrocytes never activated this executioner caspase and exhibited delayed cell death initiation. Thus, oligodendrocyte maturation plays a key role in determining the mechanism of death a cell undergoes in response to the same insult. This means that different strategies are likely necessary to confer protection to the entire oligodendrocyte lineage to enable myelin preservation and facilitate the integration of new oligodendrocytes in aging and disease.