
Research
One focus of the Electron Microscopy City Campus is on the study of myelin, a membranous multilayer structure that constitutes the so-called white matter in the brain. Myelin is produced by oligodendrocytes in the central nervous system (CNS) and by Schwann cells in the peripheral nervous system (PNS). The myelin sheath is a key element of long axons, as it accelerates the speed of nerve conduction up to 100 times due to saltatory action potential propagation, compared to non-myelinated axons. Apart from that, the myelin sheath fulfils protective and supportive functions for the myelinated axons.
In studying the biology and function of myelinating glial cells in the CNS, we focus on the mechanism of myelin biogenesis, maintenance and remodelling. One striking feature that becomes visible with electron microscopy is the solid and non-dynamic appearance of the structure. Furthermore, it is known that the myelin proteins are very slowly turned over. To better understand this mechanism of myelin remodelling, we have used an inducible knock-out strategy in the adult age and followed the spatial and temporal changes in the myelin ultrastructure (Meschkat et al, 2022).
Based on the close relationship between the myelin sheath and the ensheathed axon, also called the axo-glia unit, pathological changes in the myelinating glial cells can affect axonal integrity. Within the Department of Neurogenetics and in collaboration with national and international partners, we are investigating pathological morphological changes in different myelin mutants to better understand the function of intact myelin, as well as disease patterns in leukodystrophies and in aging processes. The consequences of impaired myelin function are investigated in demyelinating disease models such as multiple sclerosis (van den Bosch et al, 2023) and neuromyelitis optica (Weil et al., 2016 and 2017, Winkler et al., 2021) or in models of hereditary diseases with disturbed myelination such as spastic paraplegia type 2 (Steyer et al., 2020 and 2023).
Apart from mouse models of human diseases, we are also interested in understanding the evolutionary aspects of myelination. To address questions in myelin evolution, we have chosen a jawless model species, the sea lamprey Petromyzon marinus, which does not form myelin but provides possible clues through parallels to ancestors before the emergence of myelin in the evolution of vertebrates (Weil et al., 2018). We are also looking at myelin formation in other species, such as the small skate (Leucoraja erinacea) (Möbius et al., 2021).
References:
Meschkat M, Steyer AM, Weil MT, Kusch K, Jahn O, Piepkorn L, Agüi-Gonzalez P, Phan NTN, Ruhwedel T, Sadowski B, Rizzoli SO, Werner HB, Ehrenreich H, Nave KA, Möbius W. (2022) White matter integrity in mice requires continuous myelin synthesis at the inner tongue. Nat Commun. 2022 Mar 4;13(1):1163. doi: 10.1038/s41467-022-28720-y. PMID: 35246535
Möbius W, Hümmert S, Ruhwedel T, Kuzirian A, Gould R. (2021) New Species Can Broaden Myelin Research: Suitability of Little Skate, Leucoraja erinacea. Life (Basel). 2021 Feb 11;11(2):136. doi:10.3390/life11020136. PMID: 33670172
Steyer AM, Buscham TJ, Lorenz C, Hümmert S, Eichel-Vogel MA, Schadt LC, Edgar JM, Köster S, Möbius W, Nave KA, Werner HB. (2023) Focused ion beam-scanning electron microscopy links pathological myelin outfoldings to axonal changes in mice lacking Plp1 or Mag. Glia. 2023 Mar;71(3):509-523. doi: 10.1002/glia.24290. Epub 2022 Nov 10. PMID: 36354016
Steyer AM, Ruhwedel T, Nardis C, Werner HB, Nave K-A, Möbius W. (2020): Pathology of myelinated axons in the PLP-deficient mouse model of spastic paraplegia type 2 revealed by volume imaging using focused ion beam-scanning electron microscopy. J Struc Biol, 2020 May 1;210(2):107492. doi: 10.1016/j.jsb.2020.107492.
van den Bosch A, Hümmert S, Steyer AM, Ruhwedel T, Hamann J, Smolders J, Nave KA, Stadelmann C, Maarten K, Möbius W, Huitinga I. Ultrastructural axon-myelin unit alterations in MS correlate with inflammation. Ann Neurol 2023;93:856–870. doi.org/10.1002/ana.26585 PMID: 36565265
Weil M-T, Heibeck S, Töpperwien M, tom Dieck S, Ruhwedel T, Salditt T, Rodicio MC, Morgan JR, Nave K-A, Möbius W and Werner HB. (2018) Axonal Ensheathment in the Nervous System of Lamprey: Implications for the Evolution of Myelinating Glia. Journal of Neuroscience 18 July 2018, 38 (29) 6586-6596 doi: 10.1523/JNEUROSCI.1034-18.2018. Epub 2018 Jun 25. PMID: 29941446
Weil M-T, Möbius W, Winkler A, Ruhwedel T, Wrzos C, Romanelli E, Bennett JL, Enz L, Goebels N, Nave KA, Kerschensteiner M, Schaeren-Wiemers N, Stadelmann C, Simons M. (2016) Loss of Myelin Basic Protein Function Triggers Myelin Breakdown in Models of Demyelinating Diseases. Cell Rep. Jul 12;16(2):314-22. doi: 10.1016/j.celrep.2016.06.008. Epub 2016 Jun 23. PMID: 27346352
Weil, M-T, Ruhwedel, T, Möbius W, and Simons, M. (2017) Intracerebral injections and ultrastructural analysis of high-pressure frozen brain tissue. Curr. Protoc. Neurosci. 78:2.27.1-2.27.18. doi: 10.1002/cpns.22. PMID: 28046202
Winkler A, Wrzos C, Haberl M, Weil MT, Gao M, Möbius W, Odoardi F, Thal DR, Chang M, Opdenakker G, Bennett JL, Nessler S, Stadelmann C. (2021) Blood-brain barrier resealing in neuromyelitis optica occurs independently of astrocyte regeneration. J Clin Invest. 2021 Mar 1;131(5):e141694. doi: 10.1172/JCI141694. PMID: 33645550