New Research About RhoE Protein Sheds Light on Two Problematic Processes in MS

The RhoE protein has been identified as being important for axons’  myelination and extension in the central nervous system, two processes that go awry in diseases like multiple sclerosis (MS).

The findings stem from Pilar Madrigal’s doctoral thesis, “Role of the small GTPase RhoE in myelination and axonal tracts development.” The work was developed at the CEU Cardenal Herrera University, in Valencia, Spain.

Loss of myelin followed by axonal degeneration are two hallmarks of MS. Myelin is the fat-rich substance that wraps around axons — the long, slender projection of a neuron — and whose job is to transmit information. Both processes are vital for the correct development and function of the central nervous system (brain and spinal cord).

Oligodendrocytes are the myelin-producing cells, and those responsible for myelinating the nerve cells’ axons. A single oligodendrocyte is capable of myelinating multiple axons.

To understand the role of RhoE in these processes, researchers used transgenic mice modified to lack the gene that contains the instructions to make RhoE. They then followed the development of axons in the animals’  nervous system by making the brains transparent. They did this using a “clearance method” called “3D imaging of solvent-cleared organs” (3DISCO).

Results showed that the lack of RhoE reduced the number of myelinated axons, and that even when myelin was present its organization pattern had changed. This, researchers found, was linked with the inability of oligodendrocytes to mature (differentiate) fully into myelin-producing cells.

“[W]e have observed that the brains of rats which do not express the gene that codifies the RhoE protein show severe deficiencies regarding myelination. Specifically, less of their axons have myelin, and those that do, have their myelin organization altered. These problems are caused by the fact that, in the absence of RhoE, the development of oligodendrocytes is modified, and they don’t differentiate as well,” José Terrado Vicente, PhD, one of Madrigal’s doctoral thesis supervisors, said in a press release.

They also found that RhoE was essential for axons’ extension, a key feature of nerve fibers as they conduct electrical impulses to other nerve cells, muscles, and glands. Lack of RhoE caused the axons to suffer severe changes.

In these animals, “the anterior branch of the anterior commissure, one of the main groups of axons which connects both brain hemispheres, is developed erroneously, without reaching its destination nor producing the connection between both olfactory bulbs, which is necessary for the olfactory processes to occur appropriately,” said Terrado.

These findings add to previous evidence from researchers at the ACDC group of the CEU, which showed that RhoE protein was important to the proliferation, capacity to travel (migration), and maturation of neural stem cells — those that have the potential to generate neurons and glial cells (the most abundant cell types in the central nervous system).

Lack of RhoE also caused changes in the motor system, including impaired formation of neuromuscular connections, i.e., the point of contact between muscle fibers and motor neurons.

Overall, the findings shed new light into the mechanisms of a developing central nervous system and what goes awry in diseases like MS.