The molecular mechanisms of myelin disassembly

Abstract

Myelin is characterized by stacking of multiple layers of membrane compacted by MBP. The breakdown of myelin is a pathological hallmark of several autoimmune diseases of the nervous system. To assess the myelin fragmentation patterns in early stages of demyelinating disease, I employed antibody- and toxin-mediated animal models of Multiple Sclerosis and Neuromyelitis optica (NMO). Using electron microscopy of high pressure frozen samples, I could show that the temporary sequence of myelin degeneration in all the models employed starts with the vesiculation of the innermost myelin lamellae. The myelin fragmentation leads to progressive vesiculation of previously compacted myelin until the whole myelin sheath is degenerated. Furthermore, in outside-in models of demyelination, such as experimental autoimmune encephalomyelitis (EAE) and anti-MOG antibody injections, we found additional patterns of fragmentation to a lower percentage that include splitt and vesiculated myelin, as well as bulb formation. The ultrastructural findings on the myelin breakdown are supported by the initial loss of the adaxonal protein myelin associated glycoprotein (MAG) in immunohistochemistry from the demyelinating areas prior to a loss of myelin basic protein (MBP). To elucidate the underlying mechanism of myelin vesiculation, I focused on MBP, a protein essential for myelin assembly. An increase in intracellular calcium levels leads to the disassembly of the MBP network. The pathological phase transition by MBP molecules from a cohesive network to a soluble, non-adhesive state triggers the myelin breakdown. The QD9 antibody detects the pool of MBP molecules that are detached from the membrane and is not able to self-interact any longer. I propose that the aberrant phase transition of MBP leads to a destabilization of the myelin membrane in NMO, and possibly other demyelinating diseases. Therefore, our data sheds light on the mechanisms of myelin disassembly and might prove useful in understanding how myelin is affected in several, yet incurable diseases, like NMO and Multiple Sclerosis.