For the first time, a team of Yale researchers has identified a previously unrecognized molecular change in the neurons of multiple sclerosis (MS) patients, which may contribute to some of the debilitating symptoms that characterize the disease.

The Yale team, working within the PVA/EPVA Center for Neuroscience Research at the West Haven VA Medical Center, includes Joel Black, Sulayman Dib-Hajj and Dr. Stephen Waxman, all from Yale's Department of Neurology.

"A major objective is the development of new therapies that will restore function by returning vision, coordination and the ability to walk in patients with MS," says Waxman, chair of the Department of Neurology. "These new findings do not get us there, but they may be a step in that direction."

Past research has shown that normal cerebellar functioning depends on precise firing of electrical impulses in Purkinje cells -- the large, rounded nerve cells that constitute the primary output cells of the cerebellum. These newest findings, published in Proceedings of the National Academy of Sciences, suggest that mistuning of Purkinje cells, because of abnormal ion channel expression, may contribute to clinical abnormalities of demyelinating diseases such as MS.

In MS, some of the body's immune cells attack the brain's nerve fibers and strip away the myelin sheath, which insulates the axons. Without the myelin sheath's protective coating, it becomes difficult for the nerves to send messages between different parts of the brain and from the brain to other parts of the body. With each attack there is new brain damage, including demyelination and axonal degeneration, which can accumulate over time. MS symptoms can include muscle weakness or paralysis, loss of vision, loss of coordination, fatigue, pain and memory loss.

It is commonly believed that the clinical abnormalities seen in MS are caused by demyelination and axonal degeneration, but the new results suggest that these structural injuries do not necessarily underlie all of the clinical abnormalities seen in MS. In this study, the Yale team wanted to find out whether there are molecular changes within neurons that might affect their function in MS.

They found there is a change in sodium channel expression in neurons within the brains of mice in which an MS-like disease had been induced, as well as in the brains of humans with MS. These findings suggest that abnormal patterns of neuronal ion channel expression may contribute to clinical abnormalities such as ataxia -- loss or lack of muscular coordination -- in MS.

The Yale team, in collaboration with researchers at the Institute of Neurology at University College in London, studied a molecule called Sensory Neuron Specific (SNS), which is a member of a family of sodium channels. Sodium channels are specialized protein molecules which act as "molecular batteries" within nerve cells, producing the electrical current needed to generate impulses. Within the uninjured nervous system, SNS is only produced in sensory neurons outside the spinal cord. Waxman says the SNS sodium channel is also special because it displays a depolarized voltage dependence, slower activation and inactivation kinetics, and more rapid recovery from inactivation than classical "fast" sodium channels.

The Yale team showed that SNS channels, which are normally present only in sensory neurons outside of the central nervous system, are present within the central nervous system, within Purkinje cells of the cerebellum, in mouse models of MS, and in humans with MS.

The experiments were carried out both in mice with Experimental Allergic Encephalomyelitis, and in postmortem tissue from patients with MS, using probes that recognize, and specifically bind to, the mRNA which carries the blueprint for the SNS sodium channel. The Yale team also used antibodies which recognize and label the SNS protein itself. This permitted them to determine the types of cells within the nervous system that produce the SNS channel.

"Different types of sodium channels all act as batteries, but they respond differently to various stimuli, and they turn on and off with different speeds," Waxman notes. "The new results suggest that the presence of SNS channels within Purkinje cells, where they are not normally present, may mistune the Purkinje cells, causing them to fire with abnormal rhythms. This would, in turn, be expected to lead to dysfunction of the cerebellum, which causes loss of coordination."

Waxman says that since the findings were novel, a first step is for them to be replicated by others. "Then we will have to use physiological methods to directly study the effect of the abnormal presence of SNS channels in Purkinje cells," he says. "If we are right and the SNS channels interfere with Purkinje cell function, then a next step would be to see whether drugs could be developed to block the SNS channels. A long-term objective of this research is the development of new therapies for symptoms such as loss of coordination in MS patients. Much work remains to be done before we can approach this goal."

The research was carried out as part of the Yale-London Collaboration, a research collaboration between Yale and University College in London that was launched two years ago.

-- By Karen Peart

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