By Vignesh Subramanian, Class of 2024

Figure 1: A myelinating oligodendrocyte in a murine brain. 

Oligodendrocytes are specialized glial cells in the central nervous system primarily responsible for myelination, the process of ensheathing the axons of neurons in a lipid-rich membrane known as myelin, which insulates the nerve fibers and speeds up the transmission of the action potentials they conduct. Oligodendrocytes are the products of their lineage’s extensive proliferation, migration, and differentiation, the process in which young stem cells mature into distinct cell types with specific functions. Oligodendrocytes are damaged and die as a result of natural aging or neurodegenerative disease, shutting down their myelin production and ending its replenishment for signaling neurons’ axons, which in turn leads to interruptions in impulse conduction. Differences in how quickly oligodendrocytes at various stages of differentiation may die and cease to support dependent neurons have not been established. 

To understand how the mechanisms of oligodendrocyte death are linked to the extent of their maturation, researchers at Dartmouth College analyzed the effects of single-cell phototoxic damage on the speed of oligodendrocytes’ cell death processes. The researchers exposed one experimental group of mice to two-photon apoptotic targeted ablation (2Phatal), a technique that induces a single cell to trigger its normal programmed death process (apoptosis) and allows its death and downstream effects to be directly observed. Another experimental group underwent cuprizone-mediated demyelination, using the chelating agent cuprizone to induce toxic demyelination – the unraveling of myelin protecting neuronal axons – in a fashion similar to that of the neurodegenerative disease multiple sclerosis. Finally, intravital fluorescence imaging through cranial windows was used to map changes in oligodendrocyte populations temporally. 

The researchers discovered statistically significant differences in how long differentially matured oligodendrocytes took to die following the fatal traumatic insults of either targeted ablation or induced demyelination. While the least developed oligodendrocytes – early precursors known as oligodendrocyte progenitor cells (OPCs) – died within 24 hours, and still-differentiating oligodendrocytes died within the following several days, mature myelinating oligodendrocytes took an average of 45 days to degenerate fully and die. Following tissue analysis, the researchers noted that while OPCs and still-differentiating oligodendrocytes underwent classic caspase-3-dependent apoptosis (driven by a protease cleaving various substrates to promote programmed, non-inflammatory cell death), mature oligodendrocytes’ delayed deaths were driven by disruptions in the localization of poly-ADP-ribose, a molecule critical to DNA repair. The discovery of mature oligodendrocytes’ switch to this separate mechanism of cell death underscores the need for future therapeutics to preserve cell function in multiple degeneration pathways. 

Works Cited:

[1] Chapman, T. W., Kamen, Y., Piedra, E., & Hill, R.A. (2024). Oligodendrocyte maturation alters the cell death mechanisms that cause demyelination. The Journal of Neuroscience, 44(13). doi: 10.1523/JNEUROSCI.1794-23.2024

[2] Image retrieved from: https://www.flickr.com/photos/vculibraries/14064658074