Myelinosome formation represents an early stage of oligodendrocyte damage in multiple sclerosis and its animal model.

Elisa Romanelli,Doron Merkler,Florian E H Matznick,Wolfgang Brück,Mikael Simons,Imke Metz,Marie-Theres Weil,Martin Kerschensteiner,Karl-Klaus Conzelmann,Edgar Meinl,Matthew Routh,Ivana Nikić,Aleksandra Mezydlo,Martin S Weber,Derron Bishop,Thomas Misgeld,Stephanie Potz,Alexander Ghanem,Mario Kreutzfeldt

doi:10.1038/ncomms13275

Abstract

Oligodendrocyte damage is a central event in the pathogenesis of the common neuroinflammatory condition, multiple sclerosis (MS). Where and how oligodendrocyte damage is initiated in MS is not completely understood. Here, we use a combination of light and electron microscopy techniques to provide a dynamic and highly resolved view of oligodendrocyte damage in neuroinflammatory lesions. We show that both in MS and in its animal model structural damage is initiated at the myelin sheaths and only later spreads to the oligodendrocyte cell body. Early myelin damage itself is characterized by the formation of local myelin out-foldings—‘myelinosomes'—, which are surrounded by phagocyte processes and promoted in their formation by anti-myelin antibodies and complement. The presence of myelinosomes in actively demyelinating MS lesions suggests that oligodendrocyte damage follows a similar pattern in the human disease, where targeting demyelination by therapeutic interventions remains a major open challenge.

Highlights

Oligodendrocyte damage is a central event in the pathogenesis of the common neuroinflammatory condition, multiple sclerosis (MS)
Our analysis showed that the proportion of lost myelin exceeded the percentage of oligodendrocyte loss throughout the course of EAE
Damage to oligodendrocytes and their myelin sheaths is the pathological hallmark of MS lesions

Summary

Introduction

Oligodendrocyte damage is a central event in the pathogenesis of the common neuroinflammatory condition, multiple sclerosis (MS). We take advantage of multi-spectral two-photon imaging of axons, oligodendrocytes and myelin in the intact spinal cord, viral labelling of single oligodendrocytes, correlated light and electron microscopy and immune modulation approaches, to show in mouse models of MS: (1) that the initial site of immune attack appears to be myelin rather than the oligodendrocyte soma and that damage spreads centripetally, (2) that one of the early signs of demyelination is the focal formation of bulb-like structures, which we call myelinosomes, that appear on the surface of the myelin sheath and (3) that formation of such myelinosomes is promoted by anti-myelin antibodies and abrogated by complement depletion, compatible with a model of surface opsonization of myelin. This cellular mechanism of oligodendrocyte damage seems to be operational in MS lesions, as we find the same sequence of oligodendrocyte damage, as well as evidence of myelinosome formation by highresolution confocal imaging of actively demyelinating MS lesions

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Conclusion