Membrane molecule keeps nerve impulses hopping

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Membrane molecule keeps nerve impulses hopping

http://news.unchealthcare.org/news/2011/January/neurofascin186

New research from the University of North Carolina at Chapel Hill School of

Medicine describes a key molecular mechanism in nerve fibers that ensures the

rapid conductance of nervous system impulses. The findings appear online Jan.

27, 2011 in the journal Neuron.

Our hard-wired nerve fibers or axons rely on an insulating membrane sheath, the

myelin, made up of fatty white matter to accelerate the rate of transmission of

electrical impulses from the brain to other parts of the body.

Myelin thus acts to prevent electrical current from leaking or prematurely

leaving the axon. However, the myelin surrounding the axon isn't continuous;

there are regularly spaced unmyelinated gaps about 1 micrometer wide along the

axon. These unmyelinated regions named as nodes of Ranvier are where electrical

impulses hop from one node to the next along the axon, at rates as fast as 160

meters per second (360 mph).

Determining exactly how the nodes of Ranvier function and how they are

assembled, has fired the interest of neuroscientists for more than a century, "

said UNC neuroscientist Manzoor Bhat, PhD, Professor of Cell and Molecular

Physiology in the UNC Neuroscience Research Center. " The answers may also

provide important clues to the development of targeted treatments for multiple

sclerosis and other disorders involving demyelination and/or disorganization of

nodes of Ranvier. "

Bhat and colleagues focused on a protein called Neurofascin 186, which

accumulates in the membranes of axons at the nodes of Ranvier. Together with

proteins Ankyrin-G and sodium channels, these molecules form a complex that

facilitates passage of sodium ions through the channels in axons, thus making

them paramount for the propagation of nerve impulses along myelinated nerve

fibers.

Bhat's team had previously identified a homolog of Neurofascin in laboratory

studies of Drosophila nerve fibers, and because its in vivo function had not

been clearly defined in a mammalian system, they decided to study the function

of this protein in laboratory mice.

Using targeted gene deletion methods, the UNC scientists genetically engineered

mice lacking Neurofascin 186 in their neurons. " This caused the failure of

sodium channels and Ankyrin-G to accumulate at the nodes of Ranvier. The result

was paralysis, as there was no nerve impulse conductance, " Bhat said.

According to Bhat, Neurofascin is an adhesion molecule that serves as the nodal

organizer. " Its job is to cluster at the nodes of Ranvier. In doing so, it

brings together sodium channels and Ankyrin-G where they interact to form the

nodal complex. And if you don't have this protein, the node is compromised and

there is no impulse propagation along the axon. "

In further analysis, the researchers identified another important function of

the nodes of Ranvier in myelinated nerve cells: to act as barriers to prevent

the invasion of the nodal gap by neighboring paranodal molecular complexes. " So

this tells us that sodium channels, Neurofascin 186, and Ankyrin-G must always

remain in the node to have functional organization. If they don't, the flanking

paranodes will move in and occupy the nodal gap and block nerve conduction, "

Bhat said.

The UNC neuroscientists see clinical implications for human disease. " In MS, for

example, the proteins that make up the nodal complex start diffusing out from

their normal location once you start losing the myelin sheath. If we can restore

the nodal complex in nerve fibers, we may be able to restore some nerve

conduction and function in affected axons. " Their future studies are aimed at

understanding whether the nodal complex could be reorganized and nerve

conduction restored in genetically modified mutant mice.

" The discovery of an essential gap protein is exciting because it opens up the

possibility that tweaking the protein could restore normal gap function in

people with multiple sclerosis and other diseases in which the myelin sheaths

and gaps deteriorate over time, " said Laurie Tompkins, PhD, who oversees

Manzoor Bhat's and other neurogenetics grants at the National Institutes of

Health.

Support for the research came from the National Institute of General Medical

Sciences, the National Institute of Neurological Disorders & Stroke of the

National Institutes of Health and the National Multiple Sclerosis Society.

UNC co-authors are postdoctoral fellow Thaxton, PhD; research

specialist, Anilkumar Pillai; and graduate student, Alaine Pribisco. Dr.

Dupree, assistant professor at Virginia Commonwealth University, collaborated in

these studies.