In normal nerves (left), which have proteins called prohibitin axons have thick myelin coatings (black outlines). In contrast, nerves engineered to lack prohibitin in glial cells have axons with very thin myelin or none at all (right). [M. Laura Feltri et al]
In normal nerves (left), which have proteins called prohibitin axons have thick myelin coatings (black outlines). In contrast, nerves engineered to lack prohibitin in glial cells have axons with very thin myelin or none at all (right). [M. Laura Feltri et al]

Since the early part of the 20th century, scientists have been trying to better understand the intricacies surrounding neuronal development. In particular, the process by which glial cells—specifically, Schwann cells—create their fatty insulating layer that encircles the axons of peripheral neurons. While the interactions between these two cell types hold the key to healthy brain function and cognition, studying the discrete mechanisms of these connections has been notoriously difficult.

Yet now, scientists at the University of Buffalo (UB) Hunter James Kelly Research Institute (HJKRI) have developed a new method for what they believe will more precisely capture neuronal interactions. The cellular interactions that trigger the production of myelin are especially hard to pinpoint since the point of contact is essentially buried between the intertwined myelin layers and neuronal plasma membrane.          

“Myelin is made by a glial cell wrapping around an axon cell,” explained senior author M. Laura Feltri, M.D., professor of biochemistry and neurology in the Jacobs School of Medicine and Biomedical Sciences at UB. “To study myelin, you really need to study both cells. The glial cell wraps like a spiral around the axon, so every time you try to study the region of contact between the two cells, you end up studying the whole combination. It's very hard to look just at the interface.”

This work may help to provide much-needed insight into demyelinating diseases such Krabbe Leukodystrophy, MS, and Charcot-Marie-Tooth disease.

“In Krabbe's, for example, the problem is not just that there isn't sufficient myelin, but that the glial cell is not providing proper support to the neuron. But to figure out exactly what's going wrong, we needed a better way to study that interface,” Dr. Feltri noted.

The findings from this study were published recently in Nature Communications through an article entitled “Spatial mapping of juxtacrine axo-glial interactions identifies novel molecules in peripheral myelination.”

The new technique described in the current study involves using the neuron as a trigger to attract glial cells. The researchers use a cell growth system with two chambers, separated by a membrane.

“When the cells in the upper chamber 'recognize' the cells in the bottom chamber, they kind of 'reach' through the holes in the membrane for each other and touch. That is the intersection that we can then isolate and study,” Dr. Feltri explained.

From their study, the researchers discovered a set of novel proteins at that intersection called prohibitins, which, they found, are necessary for the production of myelin.

“Using this method, we can isolate the portion of a cell that comes in contact with another cell, and analyze all the proteins that are present only in this subcellular fraction,” Dr. Feltri stated. “It provides a glimpse into the social life of cells.”

The researchers were excited by their findings and look to continue their work with the hope of better understanding this critical connection between neuronal cells—possibly leading to a druggable target for demyelinating diseases.

“This research has profound implications for glial disease like Krabbe's, Charcot-Marie-Tooth, peripheral neuropathies or Multiple Sclerosis, because the dysfunction of glial cells end up impairing the interactions with neurons, which, as a result, suffer and degenerate causing devastating clinical symptoms,” noted lead author Yannick Poitelon, Ph.D., postdoctoral research scientist at HJKRI. “Similarly, neurodegenerative diseases like Huntington's disease or Lou Gehrig's, that were considered unique diseases of neurons in the past, are now considered diseases of cellular communications between neurons and glial cells.”








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