Demyelinating diseases are life altering. Such diseases are characterized by damages to the protective covering also called myelin sheath that surrounds nerve fibers in your brain and spinal cord. When this protective covering is damaged, nerve impulses slow or even stop, causing neurological problems. Take for example, Multiple Sclerosis (MS) or (ALS) which targets a healthy nervous system and cages the owner in his body. Most of the big pharma companies have put serious efforts in researches to discover miracle drugs that could cure the diseases. But, the hard truth wins every time “ it may be possible to alleviate some of the symptoms for some time with the drugs, but no cure has been found yet. The researchers are now focusing on one fundamental question “ how can be axons be physically remyelinated. To find that out, it is necessary to find out how they get myelinated in the first place.
Neuroscientists are focusing on various molecular pathways that seem to be critical to myelination. However, there is little they can tell us about how axons are myelinated. To understand how it happens, we need to watch it happen in slow-motion.
An interesting thing here is a recent review in the Developmental Cell titled ‘Dynamics and Mechanisms of CNS Myelination’. It took stock of the current state of the art in visualizing what is actually going on here. Even though there are many theories, there is no clear consensus about it. A central issue for Schwann cell myelination in the PNS “ that is how do these cells tackle the problem of radial sorting, is elaborated in a complementary study published in Neuron.
The researchers for the study focussed on the role of the extracellular matrix in starting off the radial sorting. Schwann cells are to some extent responsible for secreting the various laminins, collagens, and heparin sulfate proteoglycans that make up the matrix. A critical level of spike activity in the axons is one of the main triggers to start secretion. The researchers also explored the role a newly defined family of receptors known as aGPCRs (adhesion G protein-coupled receptors) plays.
The highlight of the study is that the authors were able to connect the importance of the large N-terminal extracellular domains of these proteins in interacting with the basal lamina during radial sorting. They did thus by creating various mutants and looking at high resolution EM images. It is interesting to note that getting the makeup of the matrix right is just one small piece of the puzzle. In order to visually see myelination as it happens time lapse fluorescence microscopy is needed and the right labels on the things you want to see.
The good news is that Sue Barnett, from the University of Glasgow has been able to do this using ex vivo preparations of mouse spinal cord. Her group reported that once oligodendrocytes in the CNS get their axon, they spiral around it in a corkscrew fashion. After that there is focal expansion of these processes into short longitudinally extending cuffs which then overlap each other. They call their model, the ”ofiomosaic model”.
It is important to note that it is a spiraling corkscrew process as it has a handedness or polarity. Also, it could be a critical constraint which could influence how adjacent myelin segments interact and organize themselves. Sue added about an interesting thing they noticed, which classically isn’t supposed to happen at all, was the presence of ‘two myelin internodes’ on an axon in vitro.
Since, the detailed structure of myelinated nodes, paranodes, and internodes is now coming into full view, it will make it tad bit easier to understand what makes these unique membrane elements work, and the forms they take both in the PNS and the CNS.