O'Malley Heather A, Shreiner Andrew B, Chen Gwo-Hsiao, Huffnagle Gary B, Isom Lori L
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.
Mol Cell Neurosci. 2009 Feb;40(2):143-55. doi: 10.1016/j.mcn.2008.10.001. Epub 2008 Nov 1.
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.
多发性硬化症（MS）是一种中枢神经系统疾病，包括脱髓鞘和轴突退变。电压门控性钠离子通道在MS及其动物模型实验性自身免疫性脑脊髓炎（EAE）中表达和分布异常。有观点认为，脱髓鞘轴突上钠离子通道的上调会导致MS/EAE中的轴突丢失。我们推测钠离子通道β2亚基（由Scn2b编码）参与了MS/EAE的发病机制，因为β2负责调节神经元中通道细胞表面的表达水平。我们在C57BL/6背景的Scn2b(+/+)和Scn2b(-/-)小鼠中诱导了非复发性EAE。与野生型相比，Scn2b(-/-)小鼠的EAE症状严重程度和致死率显著降低，轴突变性和轴突丢失也明显减少。Scn2b(-/-)小鼠的外周免疫细胞群体、T细胞增殖、细胞因子释放以及免疫细胞向中枢神经系统的浸润在EAE反应中均正常，这表明Scn2b失活不会损害免疫功能。我们的数据表明，β2的缺失在EAE中具有神经保护作用，可防止脱髓鞘反应导致的钠离子通道上调。
