Molecular Basis for Axonal Degeneration

Axonal degeneration contributes to permanent neurological damage in people with MS and is therefore an area of intense investigation within our laboratories. We are particularly interested in identifying molecules and mechanisms that predispose demeylinated CNS axons to further damage and degradation.

Our earlier work with cells in vitro demonstrated that a massive surge of calcium into the axons triggered by sodium influx via sodium channels causes the sodium-calcium exchanger to operate in reverse, ultimately leading to axonal damage. Gathering clues from this earlier work, we asked if the combined presence of both a sodium channel and the sodium-calcium exchanger correlated with areas of widespread axonal damage in the rodent EAE model.

Analysis of the optic nerve tissue by immunohistochemistry, revealed that the combined presence of both a sodium channel (of the type1.6, which has the propensity to stay open longer than other channels) and the sodium-calcium exchanger (NCX) in nearly 75% of the damaged axons. These findings are consistent with the hypothesis that together a sodium channel and NCX participates in a cascade that leads to axonal degeneration. Most recently, in a study published in the Proceedings of the National Academy of Science, we examined spinal cord tissue obtained postmortem from patients with primary progressive MS. Consistent with what we observed in the EAE model, we found a strong link between axonal injury and the presence of Nav1.6 and NCX.

These results are the first observations in humans of molecules that contribute to axonal degeneration and therefore represent an important milestone. Future experiments will examine how these molecular changes along injured axons correlate with clinical status in EAE, and if targeting these molecules will lead to better treatments and improved prognosis in people with MS.

Craner MJ, Newcombe J, Black JA, Hartle C, Cuzner ML, Waxman SG. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. PNAS 2004 May 25;101(21):8168-73.

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