White matter integrity in mice\xa0requires continuous myelin synthesis at the inner tongue

Martin Meschkat,Lars Piepkorn,Hauke B Werner,Nhu Thi Ngoc Phan,Anna M Steyer,Paola Agüi-Gonzalez,Boguslawa Sadowski,Kathrin Kusch,Hannelore Ehrenreich,Olaf Jahn,Silvio O Rizzoli,Marie-Theres Weil,Klaus-Armin Nave,Torben Ruhwedel,Wiebke Möbius

doi:10.1038/s41467-022-28720-y

Abstract

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.

Highlights

Myelin, the electrically insulating sheath on axons, undergoes dynamic changes over time
We found numerous myelin proteins reduced in abundance (MBP, proteolipid protein (PLP), myelin-associated glycoprotein (MAG), myelin oligodendrocyte glycoprotein (MOG), CNP, claudin 11 (CLDN11), CD9, and tetraspanin-2 (TSPAN2)) (Fig. 1H), while markers of oligodendrocyte cell bodies were unchanged or slightly elevated (carbonic anhydrase 2 (CAH2), BCAS1, CRYAB) (Fig. 1K)
Based on our results we propose a mechanism of myelin turnover and renewal by which newly synthesized myelin membrane is incorporated into the sheath predominantly in the adaxonal, non-compact myelin compartment at the inner tongue

Summary

Introduction

The electrically insulating sheath on axons, undergoes dynamic changes over time. A study in humans showed that a stable population of mature oligodendrocytes is established in childhood and remains static throughout life[2] Apart from these early differentiated oligodendrocytes, new oligodendrocytes are continuously generated from oligodendrocyte progenitor cells (OPCs) that persist during adulthood[3–6]. As the early differentiated oligodendrocytes are long lived and survive alongside the newly formed cells, it is unlikely that the principal role of adult-born oligodendrocytes is the replacement and turnover of the developmentally formed myelin sheaths[9] Instead, they increase the total number of oligodendrocytes and add additional myelin to the existing white matter[2,9–11]. Targeted disruption of the Plp gene in the adult showed that PLP has a half-life of ~6 months[14] These data suggest that the myelin sheath is turned over and renewed by the respective oligodendrocyte in a continuous but protracted process. Oligodendrocyte processes only loosely associate with axons and fail to establish a stable compact myelin sheath

Methods

Results

Conclusion