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Axonal cell death in human MS.

Researchers at the Center for Neuroscience and Regeneration Research at Yale University, together with colleagues at the University College London, have for the first time identified key molecules that underlie nerve-fiber degeneration in patients with secondary-progressive multiple sclerosis (MS). The Center for Neuroscience and Regeneration Research is a collaboration of the Paralyzed Veterans of America (PVA) and United Spinal Association (United Spinal) with Yale University. The center is regarded around the world as a leading laboratory studying the molecular organization of myelinated and demyelinated axons in the spinal cord.

MS is an inflammatory disease of the central nervous system in which myelin (the insulation that surrounds the nerve fibers) is damaged in multiple regions, leaving scars (sclerosis) that hinder the relay of nerve signals from the brain to the rest of the body. Common symptoms of MS include impaired vision, lack of coordination, cognitive dysfunction, pain, numbness, and bladder/bowel problems.

One of MS's hallmark features is its relapsing-remitting course in some patients, with recovery of previously lost functions (such as the ability to see or walk) as the disease remits. The Yale team previously showed that these remissions are due to a molecular rebuilding of nerve fibers after they have lost their myelin, which permits them to relay nerve signals even in the absence of insulation. As a result of this recovery of function, patients with the relapsing-remitting form of MS are neurologically normal between relapses and thus do not develop permanent disability.

However, in progressive forms of the disease, in addition to damage to the myelin insulation, entire lengths of the nerve fibers begin to degenerate, resulting in permanent and irreparable damage. This produces a steady worsening of symptoms and accumulation of disability in the patient.

To understand what causes nerve fibers to degenerate in MS, Yale and VA researchers Stephen G. Waxman, Matthew Craner, and Joel Black examined postmortem spinal-cord tissue obtained from patients with a progressive form of MS, as part of a Yale-London Collaboration on Nervous System Injury and Repair. Using biomarkers to mark the damaged nerve fibers, they looked for molecular abnormalities within them and demonstrated a strong link between the presence of two molecules, Nav1.6 and NCX, and nerve damage.

Present on the surface of most nerve fibers, Nav1.6 controls the flow of sodium into the cell, which, in turn, triggers the activation of NCX, a molecule that if unchecked is capable of importing dangerous levels of calcium into the nerve fiber, ultimately leading to its death. Although previous studies by the Yale researchers identified Nav1.6 and NCX as contributors to degeneration of nerve fibers in animal models of MS, the new findings are the first observations of molecules that contribute to degeneration of nerve fibers in the human disease.

"These results are extremely exciting because they provide, for the first time, important clues about the molecular basis for permanent and irreversible damage in MS," says Principal Investigator Waxrnan, who is also chairman of Neurology at the Yale School of Medicine and director of the VA Rehabilitation R&D Center of Excellence for Restoration of Function in MS and SCI. "We want to prevent the acquisition of disability in people with MS. We hope to use these results to design new therapies that will do that, by protecting vulnerable nerve fibers so they do not degenerate."

This research, supported by the Department of Veterans Affairs (VA), National MS Society (NMSS), and Destination Cure, was published in the May 25, 2004, issue of the journal Proceedings of the National Academy of Sciences (www.pnas.org).
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Title Annotation:Special section: veterans & MS
Author:Bangalore, Lakshmi
Publication:PN - Paraplegia News
Geographic Code:1USA
Date:Feb 1, 2005
Words:594
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