If neurons are wires, myelin is the insulation that wraps around them; without it, current loss occurs and the circuit weakens. This is analogous to what happens in demyelinating diseases such as multiple sclerosis, and to some extent, the cognitive decline that occurs with aging.1
Oligodendrocytes produce the brain’s protective myelin coats. When disease or injury damage this neuronal insulation, the oligodendrocytes respond as the repair crew. However as they age, their ability to generate new oligodendrocyte precursor cells (OPCs) is limited, which makes them less effective at repairing damaged myelin.2,3 Yet, scientists know little about the lifespans of oligodendrocytes, or how they die.
Now, in a study published in The Journal of Neuroscience, researchers tracked oligodendrocytes as they aged and found that mature oligodendrocytes survived longer following DNA damage and underwent a different type of cell death compared to younger cells.4 A new understanding of the oligodendrocyte life cycle may provide a starting point for repairing damaged myelin.
“Despite studying this stuff for decades, we still don’t know how these cells die,” said Jason Plemel, a neuroscientist at the University of Alberta who was not involved in the study. To learn more about the lives of oligodendrocytes, Robert Hill, a neurobiologist at Dartmouth College and coauthor on the study, turned to cell death. While Hill and his team have studied oligodendrocyte cell biology for some time, they had not yet examined death at the single cell level, which led them to this study.
To induce cell death in cortical oligodendrocytes and OPCs of mice, the researchers employed both cuprizone treatment, an established method for inducing demyelination, and a novel technique called two-photon apoptotic targeted ablation (2Phatal), which they targeted to oligodendrocytes.5 Using 2Phatal, they tracked and visualized cell death over a period of 45 days—until now, nobody has followed cell death for so long in living brain tissue.
Regardless of the specific treatment used, the researchers observed age effects in the type of cell death: newly differentiated oligodendrocytes underwent classical caspase-3-dependent apoptosis, whereas mature oligodendrocytes died through a caspase-independent process. Most previous studies have exclusively examined apoptosis as the cell death mechanism in oligodendrocytes.
“[This] is really cool and turns on its head how we thought these [mature] cells died,” said Plemel. “When people have been looking at how mature oligodendrocytes die, it seems they have not been looking with the right tools.”
Similarly, a cell’s age affected its survival. Following either 2Phatal or cuprizone treatment, mature oligodendrocytes took longer to die than OPCs—45 days versus one day—and oligodendrocytes undergoing differentiation died at an intermediate timepoint.
“We can’t find any other examples of this type of cell death progression in the brain, or throughout the body,” said Hill.
It is not yet clear why oligodendrocytes undergo such different cell death processes depending on their age, or why the older cells die more slowly. “It could be that the mature oligodendrocytes lose the machinery needed to go through classical programmed cell death,” said Hill. “Another possibility is that these [mature] cells are metabolically silent and not turning things over as often, which may be why they can survive the catastrophic DNA damage caused by 2Phatal.”
Although researchers still have much to learn about the role of oligodendrocytes in demyelinating diseases, a better understanding of how these cells die could inform better treatments that can prevent both types of cell death to preserve the old oligodendrocytes while integrating the growth of new ones.
