Loss of Myelin Basic Protein Function Triggers Myelin Breakdown in Models of Demyelinating Diseases

Abstract

SummaryBreakdown of myelin sheaths is a pathological hallmark of several autoimmune diseases of the nervous system. We employed autoantibody-mediated animal models of demyelinating diseases, including a rat model of neuromyelitis optica (NMO), to target myelin and found that myelin lamellae are broken down into vesicular structures at the innermost region of the myelin sheath. We demonstrated that myelin basic proteins (MBP), which form a polymer in between the myelin membrane layers, are targeted in these models. Elevation of intracellular Ca2+ levels resulted in MBP network disassembly and myelin vesiculation. We propose that the aberrant phase transition of MBP molecules from their cohesive to soluble and non-adhesive state is a mechanism triggering myelin breakdown in NMO and possibly in other demyelinating diseases.

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

“…At least some of these phenomena could be explained by the recent insight that myelin basic protein (MBP), the major protein component of the myelin sheath, transitions from a soluble phase to a cohesive network to allow myelin compaction29. Such a protein phase transition could be locally reversed by pathological impact, allowing individual myelin leaflets to separate and collapse into myelin bulbs30.…”

Antagonistic Functions of MBP and CNP Establish Cytosolic Channels in CNS Myelin

“…A recent technical advance has been the application of high-pressure freezing electron microscopy to biological tissues leading to an enhanced preservation of tissue and cell architecture, including the cytoplasmic spaces within myelin (Möbius et al., 2010, Weil et al., 2016). With this technique, it is possible to visualize within the developing myelin sheath a system of tube-shaped cytoplasmic expansions residing between the compacted layers of myelin (Snaidero et al., 2014).…”

Neuromyelitis Optica: Deciphering a Complex Immune-Mediated Astrocytopathy

“…Moreover, functional recovery and steroid responsivity are more frequently reported for MOG-IgG seropositive ON (18,19,21,23,24). Importantly, the histopathology of brain lesions from MOG-IgG seropositive patients reveal Type 2 MS pathology (25), and MOG-IgG does not produce NMO lesion pathology in the ICI animal model (26,27). …”

“…In EAE (9,13), passive transfer (52) and ICI (12,13,27) NMO models, oligodendrocyte apoptosis and myelin vacuolization are apparent in regions of isolated astrocyte loss before inflammatory cell infiltration. Oligodendroglial cells are relatively preserved 1 hour after ICI of an AQP4 rAb and HC despite significant astrocyte depletion; 3 hours after injection, oligodendrocyte loss is readily apparent but myelin sheaths are spared (13).…”