Piedra, E. T. | bioRxiv Science

bioRxiv2024

Transient upregulation of procaspase-3 during oligodendrocyte fate decisions

Oligodendrocytes are generated throughout life and in neurodegenerative conditions from brain resident oligodendrocyte precursor cells (OPCs). The transition from OPC to oligodendrocyte involves a complex cascade of molecular and morphological states that position the cell to make a fate decision to integrate as a myelinating oligodendrocyte or die through apoptosis. Oligodendrocyte maturation impacts the cell death mechanisms that occur in degenerative conditions, but it is unclear if and how the cell death machinery changes as OPCs transition into oligodendrocytes. Here, we discovered that differentiating oligodendrocytes transiently upregulate the zymogen procaspase-3, equipping these cells to make a survival decision during differentiation. Pharmacological inhibition of caspase-3 decreases oligodendrocyte density, indicating that procaspase-3 upregulation promotes differentiation. Moreover, using procaspase-3 as a marker, we show that oligodendrocyte differentiation continues in the aging cortex and white matter. Taken together, our data establish procaspase-3 as a differentiating oligodendrocyte marker and provide insight into the underlying mechanisms occurring during the decision to integrate or die.

neuroscience↗

bioRxiv2023

Oligodendrocyte maturation alters the cell death mechanisms that cause demyelination

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.

neuroscience↗