Myelin insulation as a risk factor for axonal degeneration in autoimmune demyelinating disease

Schäffner, E. et al. (2023) Myelin insulation as a risk factor for axonal degeneration in autoimmune demyelinating disease. Nature Neuroscience, 26(7), pp. 1218-1228. (doi: 10.1038/s41593-023-01366-9) (PMID:37386131)

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.

• Item Type: Articles
• Additional Information: M.B.Q. was supported by a DFG Walter-Benjamin Position (BO 6252/1-1). J.M.E. was supported by Grant 127 from the UK MS Society. R.F. was supported by a DFG Emmy-Noether fellowship (FL 1025/1-1). Ju.S. and A.F. were funded by DFG grant FL 377/4-1, and A.F. was funded by DFG grant SFB TRR 274/1 2020 A03–408885537 and by a European Research Council (ERC) Advanced Grant (101021345, T-Neuron). K.A.N. was supported by an ERC Advanced Grant, the DFG (SFB TRR 274) and the Adelson Medical Research Foundation (AMRF). D.S.R. was supported by the Intramural Research Program of NINDS and by the AMRF. E.S. was supported by a Boehringer Ingelheim Foundation travel grant. C.S. was supported by the DFG under Germany’s Excellence Strategy (EXC 2067/1-390729940), the SFB TRR 274/1 2020 A03–408885537 (B01) and the DFG grant STA 1389/5-1. R.M.S. was supported by an ERC Starting Grant (948857, AxoMyoGlia) and DFG grant STA 1728/1-1. R.F. and R.M.S. were supported by a DFG grant in SFB 1052, 209933838, subproject C10, and by the German Ministry of Education and Research (BMBF) FKZ 01KC2003B and 01EJ2203C.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Edgar, Professor Julia and Nave, Professor Klaus-Armin
• 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., and Stassart, R. M.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Research Centre: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
• Journal Name: Nature Neuroscience
• Publisher: Nature Research
• ISSN: 1097-6256
• ISSN (Online): 1546-1726
• Published Online: 29 June 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Nature Neuroscience 26(7): 1218-1228
• Publisher Policy: Reproduced under a Creative Commons License