RESEARCH HORIZONS: Molecular Plasticity and Recovery of Function in Multiple Sclerosis

by Lakshmi Bangalore

Patients with the relapsing-remitting form of multiple sclerosis (MS) can experience symptom-free intervals that sometimes range in the order of years, despite the persistence of demyelinated lesions within their nerve fibers. Such a recovery of function after injury to the brain and spinal cord is called a remission. Remissions can occur despite the absence of myelin, and have been attributed to the redistribution of key molecules within the nerve membrane in an adaptive response to enable recovery of function.

As early as the 1980s, laboratory studies performed at the PVA-Eastern Paralyzed Veterans Association Center for Neuroscience and Regeneration Research in West Haven, Connecticut, revealed that after myelinated nerve fibers lose their myelin, they show remarkable plasticity (i.e., redistribution) by inserting tens of thousands of sodium channels into the exposed nerve membrane. Sodium channels are tiny barrel-shaped protein conglomerates within the nerve membrane that work like batteries to generate and transmit nerve signals that make us feel, think and move. Their strategic positioning at key locations along the length of nerve fibers, combined with the insulating properties of myelin that surrounds nerve fibers, enables nerve signals to be transmitted over long distances with speed and accuracy.

Like batteries that come in different types (AA, AAA, C, D, F and so on), at least 10 different types of sodium channels are at work at various times and places within our bodies. Each of these 10 known sodium channels is built from a unique blueprint and each has its own distinctive way of firing a signal. In normal myelinated nerve fibers, sodium channels are typically present clustered in large numbers at the nodes of Ranvier, small unmyelinated gaps, where they help recharge nerve signals as they jump from node to node, achieving breakneck speeds of up to 330 feet per second! The regions between the nodes are surrounded by tightly rolled-up layers of myelin that serve to preserve the intensity of nerve signals, further ensuring speedy transmission of signals to their destination.

Damage to myelin, as in the case of MS, disrupts transmission of nerve signals leading to hallmark symptoms of impaired vision, muscle weakness, lack of coordination and myriad other neurological problems. However, in patients with the relapsing-remitting form of MS, as the damaged nerve fibers struggle to transmit signals in the absence of myelin, new sodium channels are produced and deployed into the previously myelinated, sodium channel-sparse regions such that signal transmission proceeds uninterrupted. Although the signals along these regions are transmitted a bit slower than normal, they are enough to restore vital functions such as vision, or even the ability to walk in some patients, despite the absence of myelin.

Why don’t all people with MS have remissions? How can we induce production and deployment of new sodium channels into areas of myelin damage? And exactly what types of sodium channels are summoned into action to cope with the damage? Is there a molecular switchboard that controls this operation? These are just a few of the questions that researchers at the PVA-Eastern Paralyzed Veterans Association Center for Neuroscience and Regeneration Research have begun to address, with the ultimate goal of inducing remissions in all people with MS.

In one recent study, using Experimental Allergic Encephalomyelitis (EAE), a model of the relapsing-remitting form of MS in animals, they examined the distribution of sodium channels along the optic nerve, a region commonly affected in MS. The optic nerve transmits signals between the eye and the brain and makes vision possible. As expected, animals with EAE showed a significant loss of myelin along the entire length of their optic nerves. Using powerful new tools of biotechnology, the investigators then took a closer look at the molecular make-up of the damaged optic nerves and compared it to that of normal ones. They found that while clusters of sodium channels of the type 1.6 are present at the nodes of Ranvier in normal optic nerves, there was nearly a 50% drop in such clusters in EAE animals. Interestingly, this reduction in sodium channels of the type 1.6 was accompanied by a marked increase in sodium channels of the type 1.2, a channel found mostly in young, pre-myelinated nerve fibers on their way to maturation. This deployment of sodium channels of type 1.2 and the redistribution of channels along regions of nerve damage suggest a shift to a state in which type 1.2 supports signal transmission just as in immature nerve fibers, allowing signals to proceed, nonetheless.

This work provides the first molecular identification of sodium channels that underlie recovery of function. In a sense, these scientists at the PVA-Eastern Paralyzed Veterans Association Center for Neuroscience and Regeneration Research have identified the “batteries” that are needed to restore transmission of nerve signals in demyelinated nerve fibers. Understanding how the production of these batteries is turned on and off will be the key to inducing remissions in all people with MS. This work may also be relevant to people with spinal cord injury (SCI), especially people with nonpenetrating injuries (sustained in motor vehicle accidents, for instance). In such individuals, even with total loss of function below the level of the injury (clinically complete), failure of signal transmission is primarily due to loss of myelin around the residual nerve fibers that travel through the site of injury.

If nerve cells can be coaxed to produce and dispatch the needed channels to correct places along demyelinated fibers, it may be possible to induce recovery of function in people with MS, as well as in people with nonpenetrating SCI. With that goal in mind, scientists at the PVA-Eastern Paralyzed Veterans Association Center are aggressively following up on these promising new findings.

(This article is based on the study: Craner MJ, Lo AC, Black JA, Waxman SG. Abnormal sodium channel distribution in optic nerve axons in model of inflammatory demyelination. [Journal Article] Brain, 126:1552-61, July 2003)

Lakshmi Bangalore, PhD, is Scientific Liaison Officer at the PVA-Eastern Paralyzed Veterans Association Center for Neuroscience Research in West Haven, Connecticut.