Loss of Na+ channel beta2 subunits is neuroprotective in a mouse model of multiple sclerosis.
Multiple sclerosis (MS) is a CNS disease that includes demyelination and axonal degeneration. Voltage-gated Na+ channels are abnormally expressed and distributed in MS and its animal model, Experimental Allergic Encephalomyelitis (EAE). Up-regulation of Na+ channels along demyelinated axons is proposed to lead to axonal loss in MS/EAE. We hypothesized that Na+ channel beta2 subunits (encoded by Scn2b) are involved in MS/EAE pathogenesis, as beta2 is responsible for regulating levels of channel cell surface expression in neurons. We induced non-relapsing EAE in Scn2b(+/+) and Scn2b(-/-) mice on the C57BL/6 background. Scn2b(-/-) mice display a dramatic reduction in EAE symptom severity and lethality as compared to wildtype, with significant decreases in axonal degeneration and axonal loss. Scn2b(-/-) mice show normal peripheral immune cell populations, T cell proliferation, cytokine release, and immune cell infiltration into the CNS in response to EAE, suggesting that Scn2b inactivation does not compromise immune function. Our data suggest that loss of beta2 is neuroprotective in EAE by prevention of Na+ channel up-regulation in response to demyelination.
O'Malley
Heather A
HA
Department of Pharmacology, Program in Cellular and Molecular Biology, University of Michigan, 1301 MSRB III, SPC 5632, 1150 W. Medical Center Dr., Ann Arbor, MI 48109, USA.
Shreiner
Andrew B
AB
Chen
Gwo-Hsiao
GH
Huffnagle
Gary B
GB
Isom
Lori L
LL
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000503:physiopathology*; D006023:Glycoproteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009900:Optic Nerve / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D062548:Voltage-Gated Sodium Channel beta-2 Subunit
D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D021122:Protein Subunits; C540272:SCN2B protein, mouse; D015222:Sodium Channels; D062548:Voltage-Gated Sodium Channel beta-2 Subunit; C445081:myelin oligodendrocyte glycoprotein (35-55)