Myelin insulation as a risk factor for axonal degeneration in autoimmune demyelinating disease
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Abstract
Axonal degeneration determines the clinical outcome of multiple sclerosis and is thought to result from exposure of denuded axons to immune-mediated damage. Therefore, myelin is widely considered to be a protective structure for axons in multiple sclerosis. Myelinated axons also depend on oligodendrocytes, which provide metabolic and structural support to the axonal compartment. Given that axonal pathology in multiple sclerosis is already visible at early disease stages, before overt demyelination, we reasoned that autoimmune inflammation may disrupt oligodendroglial support mechanisms and hence primarily affect axons insulated by myelin. Here, we studied axonal pathology as a function of myelination in human multiple sclerosis and mouse models of autoimmune encephalomyelitis with genetically altered myelination. We demonstrate that myelin ensheathment itself becomes detrimental for axonal survival and increases the risk of axons degenerating in an autoimmune environment. This challenges the view of myelin as a solely protective structure and suggests that axonal dependence on oligodendroglial support can become fatal when myelin is under inflammatory attack.
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The ability of oligodendrocytes and myelin to provide physical protection and metabolic support is undisputed.
“the ability of oligodendrocytes and myelin to provide physical protection and metabolic support is undisputed.42,43”
From BCAS1-positive oligodendrocytes enable efficient cortical remyelination in multiple sclerosis (2025) · cites this paper as [42]
The Discussion (page not provided) describes oligodendroglial metabolic support of myelinated axons. But it says that “myelin per se does not support axon integrity,” and the Main section challenges the view of myelin as solely protective in autoimmune disease. The unqualified claim that myelin provides undisputed physical protection is therefore not supported. (LLM, conf=0.88)
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Self-citation
- Authors
- Schäffner, E., Bosch-Queralt, M., Edgar, J. M., Lehning, M., Strauß, J., Fleischer, N., Kungl, T., Wieghofer, P., Berghoff, S. A., Reinert, T., Krueger, M., Morawski, M., Möbius, W., Barrantes-Freer, A., Stieler, J., Sun, T., Saher, G., Schwab, M. H., Wrede, C., Frosch, M., Prinz, M., Reich, D. S., Flügel, A., Stadelmann, C., Fledrich, R., Nave, K.-A., & Stassart, R. M.
- Affiliations
- University Hospital Leipzig (DE)
- Max Planck Institute for Multidisciplinary Sciences (DE)
- Universitätsmedizin Göttingen (DE)
- Leipzig University (DE)
- University of Augsburg (DE)
- German Center for Neurodegenerative Diseases (DE)
- Medizinische Hochschule Hannover (DE)
- University of Freiburg (DE)
- National Institutes of Health (US)
- Corresponding author
- Fledrich, Robert
- Nave, Klaus-Armin
- Stassart, Ruth M.
- ORCID
- Bosch-Queralt, Mar
- Edgar, Julia M.
- Fleischer, Niko
- Wieghofer, Peter
- Berghoff, Stefan A.
- Reinert, Tilo
- Morawski, Markus
- Möbius, Wiebke
- Barrantes-Freer, Alonso
- Stieler, Jens
- Sun, Ting
- Saher, Gesine
- Schwab, Markus H.
- Wrede, Christoph
- Frosch, Maximilian
- Prinz, Marco
- Reich, Daniel S.
- Flügel, Alexander
- Stadelmann, Christine
- Fledrich, Robert
- Nave, Klaus-Armin
- Stassart, Ruth M.
- Venue
- Nature Neuroscience
- Published
- 2023-06-29
- Volume
- 26
- Issue
- 7
- Pages
- 1218-1228
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC10322724
- OpenAlex
- W4382630803
- Cited by
- 101
- References
- 58
- Citations by year
- 2026: 32 · 2025: 35 · 2024: 26 · 2023: 7 · 2022: 1
- FWCI
- 19.91
- Type
- journal article
- Language
- en
- Update notices
- addendum (2025-03-11)
- Open access
- hybrid
- doi.org
- Locations
- Nature Neuroscience (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) (acceptedVersion, cc-by-sa)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- DZNE Pub (submittedVersion, cc-by)
- OPUS (Augsburg University) (submittedVersion, cc-by)
- Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Deutsche Forschungsgemeinschaft (SFB 1052, 209933838, TRR274/1 2020, SFB/TRR 274, TRR-274, EXC 2067, STA1389/5-1, EXC 2067‐1, 390729940, EXC 2067/1390729940, 408885537)
- Bundesministerium für Bildung und Forschung (01EJ2203C)
- Boehringer Ingelheim Stiftung
- Medical Research Council (MR/X013073/1)
- National Institute of Neurological Disorders and Stroke
- H2020 European Research Council (101021345, 948857)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
- Keywords
- myelin, axonal degeneration, multiple sclerosis, autoimmune demyelinating disease, oligodendrocytes, myelination, autoimmune encephalomyelitis
- MeSH terms
- Animals, Axons, Encephalomyelitis, Autoimmune, Experimental, Humans, Multiple Sclerosis, Myelin Sheath, Risk Factors, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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