White matter integrity in mice requires continuous myelin synthesis at the inner tongue

• Published in: Nature communications Vol. 13; no. 1; pp. 1163 - 18
• Main Authors: Meschkat, Martin, Steyer, Anna M., Weil, Marie-Theres, Kusch, Kathrin, Jahn, Olaf, Piepkorn, Lars, Agüi-Gonzalez, Paola, Phan, Nhu Thi Ngoc, Ruhwedel, Torben, Sadowski, Boguslawa, Rizzoli, Silvio O., Werner, Hauke B., Ehrenreich, Hannelore, Nave, Klaus-Armin, Möbius, Wiebke
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04.03.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/19; 14/28; 631/378/2596; 631/378/2606; 82/58; Ablation; Animals; Axons; Axons - metabolism; Basic Medicine; Biosynthesis; Electron microscopy; Humanities and Social Sciences; Integrity; Mass spectrometry; Mass spectroscopy; Medicine; Medicinska och farmaceutiska grundvetenskaper; Membranes; Mice; Microscopy; Molecular biology; multidisciplinary; Myelin; Myelin Sheath - metabolism; Neurosciences; Oligodendrocytes; Oligodendroglia; Physiology; Proteins; Recombination; Rodents; Science; Science (multidisciplinary); Scientific imaging; Sheaths; Substantia alba; Synthesis; Tongue; White Matter
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-28720-y

Myelin, the electrically insulating sheath on axons, undergoes dynamic changes over time. However, it is composed of proteins with long lifetimes. This raises the question how such a stable structure is renewed. Here, we study the integrity of myelinated tracts after experimentally preventing the formation of new myelin in the CNS of adult mice, using an inducible Mbp null allele. Oligodendrocytes survive recombination, continue to express myelin genes, but they fail to maintain compacted myelin sheaths. Using 3D electron microscopy and mass spectrometry imaging we visualize myelin-like membranes failing to incorporate adaxonally, most prominently at juxta-paranodes. Myelinoid body formation indicates degradation of existing myelin at the abaxonal side and the inner tongue of the sheath. Thinning of compact myelin and shortening of internodes result in the loss of about 50% of myelin and axonal pathology within 20 weeks post recombination. In summary, our data suggest that functional axon-myelin units require the continuous incorporation of new myelin membranes. Myelin is formed of proteins of long half-lives. The mechanisms of renewal of such a stable structure are unclear. Here, the authors show that myelin integrity requires continuous myelin synthesis at the inner tongue, contributing to the maintenance of a functional axon-myelin unit.