Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger.
Although voltage-gated sodium channels are known to be deployed along experimentally demyelinated axons, the molecular identities of the sodium channels expressed along axons in human demyelinating diseases such as multiple sclerosis (MS) have not been determined. Here we demonstrate changes in the expression of sodium channels in demyelinated axons in MS, with Nav1.6 confined to nodes of Ranvier in controls but with diffuse distribution of Nav1.2 and Nav1.6 along extensive regions of demyelinated axons within acute MS plaques. Using triple-labeled fluorescent immunocytochemistry, we also show that Nav1.6, which is known to produce a persistent sodium current, and the Na+/Ca2+ exchanger, which can be driven by persistent sodium current to import damaging levels of calcium into axons, are colocalized with beta-amyloid precursor protein, a marker of axonal injury, in acute MS lesions. Our results demonstrate the molecular identities of the sodium channels expressed along demyelinated and degenerating axons in MS and suggest that coexpression of Nav1.6 and Na+/Ca2+ exchanger is associated with axonal degeneration in MS.
Craner
Matthew J
MJ
Department of Neurology and Paralyzed Veterans of America/Eastern Paralyzed Veterans Association Neuroscience Research Center, Yale School of Medicine, New Haven, CT 06510, USA.
Newcombe
Jia
J
Black
Joel A
JA
Hartle
Caroline
C
Cuzner
M Louise
ML
Waxman
Stephen G
SG
D000208:Acute Disease; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D001369:Axons / Q000378:metabolism* / Q000473:pathology*; D003711:Demyelinating Diseases / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology*; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
D016564:Amyloid beta-Protein Precursor; D062551:NAV1.2 Voltage-Gated Sodium Channel; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568251:SCN2A protein, human; C100681:SCN8A protein, human; D015222:Sodium Channels; D019831:Sodium-Calcium Exchanger; D012964:Sodium