Myelin sheaths in the central nervous system can withstand damage and dynamically remodel.
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| Title: | Myelin sheaths in the central nervous system can withstand damage and dynamically remodel. |
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| Authors: | Arafa, Donia (AUTHOR), van de Korput, Julia (AUTHOR), Braaker, Philipp N. (AUTHOR), Higgins, Kieran P. (AUTHOR), Meijns, Niels R. C. (AUTHOR), Marshall-Phelps, Katy L. H. (AUTHOR), Meng, Julia (AUTHOR), Soong, Daniel (AUTHOR), Scalia, Eleonora (AUTHOR), Lathem, Kyle (AUTHOR), Keatinge, Marcus (AUTHOR), Richmond, Claire (AUTHOR), Klingseisen, Anna (AUTHOR), Main, Marja (AUTHOR), Neely, Sarah A. (AUTHOR), Hampton, David W. (AUTHOR), Duncan, Greg J. (AUTHOR), Schenk, Geert J. (AUTHOR), Groot, Marie Louise (AUTHOR), Chandran, Siddharthan (AUTHOR) |
| Source: | Science. 2/12/2026, Vol. 391 Issue 6786, p1-18. 18p. |
| Subjects: | Myelin sheath, Demyelination, Applied sciences, Action potentials, Multiple sclerosis, Brachydanio, Myelination, Central nervous system |
| Abstract: | Myelin damage is a hallmark of several neurological disorders, but how it occurs remains to be fully understood. In this study, we found that early damage in zebrafish and rodent demyelination models is characterized by myelin swelling. We show, through live imaging, that myelin swelling does not always lead to myelin loss and that swellings can sometimes resolve, allowing sheaths to remodel. Increased neuronal activity during early demyelination exacerbates myelin damage, whereas reducing neuronal activity mitigates myelin swelling in both zebrafish and mice. In human multiple sclerosis tissue, myelin swelling is also dynamic and is prominent around active lesions. Our data indicate that myelin swelling is a conserved feature of demyelination and that damage to myelin sheaths can resolve, opening opportunities for targeting human disease. Editor's summary: The loss of myelin (demyelination) in the central nervous system is a hallmark of several neurological disorders. However, it remains unclear how the demyelination process occurs. Using zebrafish models and human tissue, Arafa et al. showed that myelin sheets swell drastically after the induction of damage and before being lost (see the Perspective by Nwangwu and Monje). Live imaging data in zebrafish indicated that myelin sheaths can in some cases withstand extensive damage (swelling) and even recover through morphological remodeling. Pharmacological manipulation of neuronal activity can affect this recovery capacity, suggesting a potential therapeutic opportunity to prevent myelin loss in disease and aging. —Mattia Maroso INTRODUCTION: Myelin is essential for normal central nervous system (CNS) function and is disrupted and/or lost in a range of human diseases. In conditions such as multiple sclerosis (MS) and in animal models of demyelination, the loss of myelin can trigger the regenerative process of remyelination, which is primarily mediated by the generation of new oligodendrocytes. Although much is known about oligodendrocyte generation, myelin formation, and regeneration, we know far less about how myelin responds to damage. For example, it has remained unclear whether damaged myelin sheaths are lost in a similar manner irrespective of insult and to what extent damage necessarily leads to sheath loss. It has also remained unknown whether damaged myelin sheaths of the CNS might even have the capacity to undergo repair. RATIONALE: Motivated by evidence of its adaptability and potential for structural remodeling in the healthy nervous system, we investigated whether myelin in the CNS can withstand damage and possibly recover instead of being lost. We reasoned that if myelin does indeed have a capacity to endure damage and dynamically remodel, then this might create new opportunities to protect myelin from loss and/or to promote its repair in human diseases. RESULTS: Using a variety of zebrafish and rodent demyelination models in which damage was induced in distinct ways, we identified myelin swelling as an early hallmark of myelin damage that preceded overt myelin loss. Using longitudinal live imaging in zebrafish and a rodent organotypic cortical slice culture model, we found that myelin sheath swelling did not necessarily prefigure myelin loss and that damage to sheaths could resolve over time. These observations indicated that damaged myelin has a capacity for dynamic structural remodeling. Given that cell and tissue swelling is driven by disruption to ion and fluid homeostasis, we investigated whether neuronal activity might influence demyelination. Through a range of behavioral stimulation, optogenetic activation, and pharmacological interventions, we found that increasing neuronal activity exacerbated myelin swelling and decreased oligodendrocyte survival in zebrafish. Conversely, reducing neuronal activity significantly mitigated myelin swelling in both zebrafish and mammalian slice models. Together, these observations indicate that neuronal activity represents a risk factor that can exacerbate early myelin pathology. Extending these findings to humans, we analyzed postmortem MS tissue and found that swellings were prevalent in active and chronic active lesions, suggesting that myelin swelling represents an evolutionarily conserved feature of demyelination. Live-imaging myelin pathology in acute postmortem MS tissue using high-resolution third harmonic generation imaging further revealed that myelin swelling could change dynamically over time and show signs of resolution in a human context. CONCLUSION: Our findings demonstrate that early myelin damage, which is characterized by myelin swelling, is highly dynamic across species, including through human disease (MS). Our study reveals that damaged myelin has a capacity to remodel, which may represent an evolutionarily conserved mechanism to protect acutely compromised myelin from loss. Targeting such early damage before myelin is lost may offer new therapeutic avenues for demyelinating disorders and for preserving myelin integrity with age. After damage, myelin sheaths swell and can subsequently remodel.: By following oligodendrocytes and their myelin sheaths over time using live imaging in zebrafish, mouse, and postmortem human tissue, we observed that myelin sheath swelling that occurs after damage is dynamic and does not always lead to myelin loss. Neuronal activity increased myelin swelling after damage, whereas reduced activity mitigated myelin swelling. [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | Myelin damage is a hallmark of several neurological disorders, but how it occurs remains to be fully understood. In this study, we found that early damage in zebrafish and rodent demyelination models is characterized by myelin swelling. We show, through live imaging, that myelin swelling does not always lead to myelin loss and that swellings can sometimes resolve, allowing sheaths to remodel. Increased neuronal activity during early demyelination exacerbates myelin damage, whereas reducing neuronal activity mitigates myelin swelling in both zebrafish and mice. In human multiple sclerosis tissue, myelin swelling is also dynamic and is prominent around active lesions. Our data indicate that myelin swelling is a conserved feature of demyelination and that damage to myelin sheaths can resolve, opening opportunities for targeting human disease. Editor's summary: The loss of myelin (demyelination) in the central nervous system is a hallmark of several neurological disorders. However, it remains unclear how the demyelination process occurs. Using zebrafish models and human tissue, Arafa et al. showed that myelin sheets swell drastically after the induction of damage and before being lost (see the Perspective by Nwangwu and Monje). Live imaging data in zebrafish indicated that myelin sheaths can in some cases withstand extensive damage (swelling) and even recover through morphological remodeling. Pharmacological manipulation of neuronal activity can affect this recovery capacity, suggesting a potential therapeutic opportunity to prevent myelin loss in disease and aging. —Mattia Maroso INTRODUCTION: Myelin is essential for normal central nervous system (CNS) function and is disrupted and/or lost in a range of human diseases. In conditions such as multiple sclerosis (MS) and in animal models of demyelination, the loss of myelin can trigger the regenerative process of remyelination, which is primarily mediated by the generation of new oligodendrocytes. Although much is known about oligodendrocyte generation, myelin formation, and regeneration, we know far less about how myelin responds to damage. For example, it has remained unclear whether damaged myelin sheaths are lost in a similar manner irrespective of insult and to what extent damage necessarily leads to sheath loss. It has also remained unknown whether damaged myelin sheaths of the CNS might even have the capacity to undergo repair. RATIONALE: Motivated by evidence of its adaptability and potential for structural remodeling in the healthy nervous system, we investigated whether myelin in the CNS can withstand damage and possibly recover instead of being lost. We reasoned that if myelin does indeed have a capacity to endure damage and dynamically remodel, then this might create new opportunities to protect myelin from loss and/or to promote its repair in human diseases. RESULTS: Using a variety of zebrafish and rodent demyelination models in which damage was induced in distinct ways, we identified myelin swelling as an early hallmark of myelin damage that preceded overt myelin loss. Using longitudinal live imaging in zebrafish and a rodent organotypic cortical slice culture model, we found that myelin sheath swelling did not necessarily prefigure myelin loss and that damage to sheaths could resolve over time. These observations indicated that damaged myelin has a capacity for dynamic structural remodeling. Given that cell and tissue swelling is driven by disruption to ion and fluid homeostasis, we investigated whether neuronal activity might influence demyelination. Through a range of behavioral stimulation, optogenetic activation, and pharmacological interventions, we found that increasing neuronal activity exacerbated myelin swelling and decreased oligodendrocyte survival in zebrafish. Conversely, reducing neuronal activity significantly mitigated myelin swelling in both zebrafish and mammalian slice models. Together, these observations indicate that neuronal activity represents a risk factor that can exacerbate early myelin pathology. Extending these findings to humans, we analyzed postmortem MS tissue and found that swellings were prevalent in active and chronic active lesions, suggesting that myelin swelling represents an evolutionarily conserved feature of demyelination. Live-imaging myelin pathology in acute postmortem MS tissue using high-resolution third harmonic generation imaging further revealed that myelin swelling could change dynamically over time and show signs of resolution in a human context. CONCLUSION: Our findings demonstrate that early myelin damage, which is characterized by myelin swelling, is highly dynamic across species, including through human disease (MS). Our study reveals that damaged myelin has a capacity to remodel, which may represent an evolutionarily conserved mechanism to protect acutely compromised myelin from loss. Targeting such early damage before myelin is lost may offer new therapeutic avenues for demyelinating disorders and for preserving myelin integrity with age. After damage, myelin sheaths swell and can subsequently remodel.: By following oligodendrocytes and their myelin sheaths over time using live imaging in zebrafish, mouse, and postmortem human tissue, we observed that myelin sheath swelling that occurs after damage is dynamic and does not always lead to myelin loss. Neuronal activity increased myelin swelling after damage, whereas reduced activity mitigated myelin swelling. [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adr4661 |
