Summary: Mature oligodendrocytes, crucial for brain function and myelin production, have an unusually prolonged death process after damage, surviving up to 45 days post-trauma, a stark contrast to the rapid demise of their younger counterparts within 24 hours.
This study illuminates a previously unknown pathway of cell longevity, suggesting a potential shift in strategies for treating aging-related damage and neurodegenerative diseases like multiple sclerosis. By utilizing innovative techniques, including a living-tissue model and a cellular death ray, the team has highlighted the need for tailored approaches in preserving myelin and supporting brain health, challenging the one-size-fits-all treatment paradigm.
Key Facts:
Source: Dartmouth College
For oligodendrocytesthe central nervous system cells critical for brain functionage may not bring wisdom, but it does come with the power to cling to life for much, much longer than scientists knew.
Thatsaccording to a new studyfeatured on the March 27 cover of theJournal of Neuroscience.
Mature oligodendrocytes took a shocking 45 days to die following a fatal trauma that killed younger cells within the expected 24 hours, Dartmouth researchers report. The findings suggest theres a new pathway for efforts to reverse or prevent the damage that aging and diseases such as multiple sclerosis cause to these important cells.
In the brain, oligodendrocytes wrap around the long, skinny connections between nerve cells known as axons, where they produce a lipid membrane called a myelin sheath that coats the axon. Axons transmit the electrical signals that nerve cells use to communicate; myelin sheathslike the plastic coating on a copper wirehelp these signals travel more efficiently.
Old age and neurodegenerative diseases like MS damage oligodendrocytes. When the cells die, their myelin production perishes with them, causing myelin sheaths to break down with nothing to replenish them. This can lead to the loss of motor function, feeling, and memory as neurons lose the ability to communicate.
Scientists have assumed that damaged oligodendrocyteslike all injured cellsinitiate a cellular self-destruct called apoptosis in which the cells kill themselves. But Dartmouth researchers discovered that mature oligodendrocytes can experience an extended life before their death that has never been seen before.
The findings pose the critical question of what in these cells changes as they mature that allows them to persist.
We found that mature cells undertake a pathway that is still controlled, but not the classical programmed cell-death pathway, saidRobert Hill, an assistant professor ofbiological sciencesand corresponding author of the paper.
We think this is showing us what happens in brains as we age and revealing a lot about how these cells die in older people, Hill said.
That unique mechanism is important for us to investigate further. We need to understand why these cells are following this pathway so we can potentially encourage or prevent it, depending on the disease context.
First author Timothy Chapman, who led the project as a PhD candidate in Hills research group, said that efforts to develop treatments for preserving myelin have focused on cultivating young oligodendrocytes and protecting mature ones. But this study suggests the cells may change significantly as they age and that a one-size-fits-all treatment might not work.
In response to the same thing, young cells go one way and old cells go another, said Chapman, who is now a postdoctoral researcher at Stanford University. If you wanted to protect the old cells, you may have to do something completely different than if you wanted to help the young cells mature. Youll likely need a dual approach.
The paper builds on a living-tissue modelthe teamreportedin the journal Nature Neurosciencein March 2023 that allows them to initiate the death of a single oligodendrocyte to observe how the cells around it react.
They reported that when an oligodendrocyte in a young brain died, the cells around it immediately replenished the lost myelin. In a brain equivalent to that of a 60-year-old, however, the surrounding cells did nothing and the myelin was lost.
That model gets us as close as we can get to the cell-death process that happens in the brain, Hill said.
Were able to model the effects of aging really well. Our ability to select a single oligodendrocyte, watch it die, and watch it regenerate or fail to regenerate allows us to understand what drives this process at the cellular level and how it can be controlled.
For the latest study, the researchers used their model to fatally damage oligodendrocyte DNA using what amounts to a cellular death raya photon-based device called 2Phatal that Hill developed. They also used the standard method for removing myelin that uses the copper-based toxin cuprizone as a comparison.
As previous studies have reported, the immature cells died quickly. But the older cells lived on, which the Dartmouth team at first interpreted as a resistance to DNA damage.
The study came into focus when the researchers examined the mature cells 45 days later using a long-term, high-resolution imaging technique developed inthe Hill lab.
Thats when we saw that it wasnt that the cells were resistant to damagethey were experiencing this extended cell death instead, Hill said.
No ones ever checked for cell death that long after DNA damage. Its the only example we can find in the literature where a cell experiences such a traumatic event and sticks around longer than a week, he said.
Because humans have oligodendrocytes for life, the cells are known to accumulate DNA damage and be more resilient than other cells, Chapman said.
Thats why we think this effect is applicable to aging. One reason these cells may persist for such a long time is because theyre used to experiencing this kind of damage naturally in aging, he said.
The study opens the first door of a vast labyrinth of more questions, Hill and Chapman say, such as whether the extended death is a good thing. It may be the equivalent of dysfunctional myelin, which is worse just sitting on an axon than if there was no myelin at all, Hill said. It isolates the cell from the surrounding tissue and essentially starves it of nutrients.
Its almost like there is garbage sitting on the axon for 45 days. Do we want to save that garbage or speed up its removal? We didnt even know that was a question until we saw this, Hill said.
If we understand the cell-death mechanism, maybe we can speed it up and get rid of that dysfunctional myelin, he said. Were always trying to save the cells and save the tissue, but you have to know if theyre worth saving.
The version of record of Oligodendrocyte Maturation Alters the Cell Death Mechanisms That Cause Demyelination was published March 27, 2024, in the Journal of Neuroscience.
Funding: This work was supported by the National Institutes of Health (R01NS122800), the Esther A. and Joseph Klingenstein Fund, the Simons Foundation, and the Department of Biological Sciences at Dartmouth.
Author: Morgan Kelly Source: Dartmouth College Contact: Morgan Kelly Dartmouth College Image: The image is credited to Neuroscience News
Original Research: Closed access. Oligodendrocyte Maturation Alters the Cell Death Mechanisms That Cause Demyelination by Robert Hill et al. Journal of Neuroscience
Abstract
Oligodendrocyte Maturation Alters the Cell Death Mechanisms That Cause Demyelination
Myelinating oligodendrocytes die in human disease and early in aging. Despite this, the mechanisms that underly oligodendrocyte death are not resolved and it is also not clear whether these mechanisms change as oligodendrocyte lineage cells are undergoing differentiation and maturation.
Here, we used a combination of intravital imaging, single-cell ablation, and cuprizone-mediated demyelination, in both female and male mice, to discover that oligodendrocyte maturation dictates the dynamics and mechanisms of cell death.
After single-cell phototoxic damage, oligodendrocyte precursor cells underwent programmed cell death within hours, differentiating oligodendrocytes died over several days, while mature oligodendrocytes took weeks to die. Importantly cells at each maturation stage all eventually died but did so with drastically different temporal dynamics and morphological features.
Consistent with this, cuprizone treatment initiated a caspase-3dependent form of rapid cell death in differentiating oligodendrocytes, while mature oligodendrocytes never activated this executioner caspase.
Instead, mature oligodendrocytes exhibited delayed cell death which was marked by DNA damage and disruption in poly-ADP-ribose subcellular localization. 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 oligodendrocyte maturation is important to consider when designing strategies for preventing cell death and preserving myelin while also enhancing the survival of new oligodendrocytes in demyelinating conditions.
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