Sodium channel expression within chronic multiple sclerosis plaques.
Multiple sclerosis (MS) is characterized by focal destruction of myelin sheaths, gliotic scars, and axonal damage that contributes to the accumulation of nonremitting clinical deficits. Previous studies have demonstrated coexpression of sodium channel Nav1.6 and the sodium-calcium exchanger (NCX), together with beta-amyloid precursor protein (beta-APP), a marker of axonal damage, in degenerating axons within acute MS lesions. Axonal degeneration is less frequent within chronic MS lesions than in acute plaques, although current evidence suggests that axonal loss in chronic lesions ("slow burn") is a major contributor to accumulating disability. It is not known, however, whether axonal degenerations in chronic and acute lesions share common mechanisms, despite radically differing extracellular milieus. In this study, the expression of sodium channels Nav1.2 and Nav1.6 and of NCX was examined in chronic MS plaques within the spinal cord. Nav1.2 immunostaining was not observed along demyelinated axons in chronic lesions but was expressed by scar and reactive astrocytes within the plaque. Nav1.6 immunoreactivity, which was intense at nodes of Ranvier in normal appearing white matter in the same sections, was present in approximately one-third of the demyelinated axons within these plaques in a patchy rather than continuous distribution. NCX was not detected in demyelinated axons within chronic lesions, although it was clearly present within the scar astrocytes surrounding the demyelinated axons. beta-APP accumulation occurred in a small percentage of axons within chronic lesions within the spinal cord, but beta-APP was not preferentially present in axons that expressed Nav1.6. These observations suggest that different mechanisms underlie axonal degeneration in acute and chronic MS lesions, with axonal injury occurring at sites of coexpression of Nav1.6 and NCX in acute lesions but independent of coexpression of these 2 molecules in chronic lesions.
Black
Joel A
JA
Department of Neurology and Paralyzed Veterans of America/United Spinal Association Neuroscience Research Center, Yale University School of Medicine, New Haven, CT, USA. joel.black@yale.edu
Newcombe
Jia
J
Trapp
Bruce D
BD
Waxman
Stephen G
SG
D000368:Aged; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D002102:Cadaver; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000378:metabolism* / Q000473:pathology*; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D012189:Retrospective Studies; D015222:Sodium Channels / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology