Researchers identify molecules that underlie nerve fiber degeneration in multiple sclerosis patients

Yale researchers and collaborators have identified molecules that underlie nerve fiber degeneration in patients with secondary progressive multiple sclerosis (MS), a disease that cripples nearly three million people worldwide. The new findings are the first observations in humans of molecules that contribute to degeneration of nerve fibers.

Researchers at Yale, the Veterans Administration (VA) and University College London examined postmortem spinal cord tissue from patients with a progressive form of MS in a project supported by the Department of Veterans Affairs, National MS Society, Paralyzed Veterans of America, and the United Spinal Association. Using biomarkers of the damaged nerve fibers, they looked for molecular abnormalities and found a strong link between nerve damage and the presence of two molecules, Nav. 1.6 and NCX, a sodium channel and a sodium-calcium exchanger.

Located on the surface of most nerve fibers, Nav.1.6 controls the flow of sodium into the cell, which in turn triggers the activation of NCX, a molecule that, if unchecked, imports abnormal levels of calcium into the nerve fiber that ultimately lead to its death.

"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," said Stephen Waxman, M.D., the lead investigator, chair of neurology and director of the VA Rehabilitation Research and Development Center in West Haven. "We hope to use these results to design new therapies that will protect vulnerable nerve fibers."

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 that hinder the relay of nerve signals from the brain to the rest of the body.

One of the hallmark features of MS is a relapsing-remitting course in some patients. There is molecular rebuilding of nerve fibers, relay of nerve signals even in the absence of myelin, and recovery of previously lost functions such as the ability to see or walk, as the disease remits. Patients with the relapsing-remitting form of MS are neurologically normal between relapses, and do not develop permanent disability.

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

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