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Nav1.6 promotes inflammation and neuronal degeneration in a mouse model of multiple sclerosis

In multiple sclerosis (MS) and in the experimental autoimmune encephalomyelitis (EAE) model of MS, the Nav1.6 voltage-gated sodium (Nav) channel isoform has been implicated as a primary contributor to axonal degeneration. Following demyelination Nav1.6, which is normally co-localized with the Na /Ca...

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Published in:Journal of neuroinflammation 2019-11, Vol.16 (1), p.215-215, Article 215
Main Authors: Alrashdi, Barakat, Dawod, Bassel, Schampel, Andrea, Tacke, Sabine, Kuerten, Stefanie, Marshall, Jean S, Côté, Patrice D
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Dawod, Bassel
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Tacke, Sabine
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Marshall, Jean S
Côté, Patrice D
description In multiple sclerosis (MS) and in the experimental autoimmune encephalomyelitis (EAE) model of MS, the Nav1.6 voltage-gated sodium (Nav) channel isoform has been implicated as a primary contributor to axonal degeneration. Following demyelination Nav1.6, which is normally co-localized with the Na /Ca exchanger (NCX) at the nodes of Ranvier, associates with β-APP, a marker of neural injury. The persistent influx of sodium through Nav1.6 is believed to reverse the function of NCX, resulting in an increased influx of damaging Ca ions. However, direct evidence for the role of Nav1.6 in axonal degeneration is lacking. In mice floxed for Scn8a, the gene that encodes the α subunit of Nav1.6, subjected to EAE we examined the effect of eliminating Nav1.6 from retinal ganglion cells (RGC) in one eye using an AAV vector harboring Cre and GFP, while using the contralateral either injected with AAV vector harboring GFP alone or non-targeted eye as control. In retinas, the expression of Rbpms, a marker for retinal ganglion cells, was found to be inversely correlated to the expression of Scn8a. Furthermore, the gene expression of the pro-inflammatory cytokines Il6 (IL-6) and Ifng (IFN-γ), and of the reactive gliosis marker Gfap (GFAP) were found to be reduced in targeted retinas. Optic nerves from targeted eyes were shown to have reduced macrophage infiltration and improved axonal health. Taken together, our results are consistent with Nav1.6 promoting inflammation and contributing to axonal degeneration following demyelination.
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subjects Analysis
Animals
Encephalitis
Encephalomyelitis
Encephalomyelitis, Autoimmune, Experimental - genetics
Encephalomyelitis, Autoimmune, Experimental - metabolism
Encephalomyelitis, Autoimmune, Experimental - pathology
Experimental autoimmune encephalitis
Female
Ganglion cysts
Gene expression
Genes
Inflammation
Inflammation - genetics
Inflammation - metabolism
Inflammation - pathology
Macrophages
Mice
Mice, Transgenic
Multiple sclerosis
NAV1.6 Voltage-Gated Sodium Channel - genetics
NAV1.6 Voltage-Gated Sodium Channel - metabolism
Nerve Degeneration - genetics
Nerve Degeneration - metabolism
Nerve Degeneration - pathology
Neuritis
Neurons
Neurons - metabolism
Neurons - pathology
Optic neuritis
Physiological aspects
Retinal Ganglion Cells - metabolism
Retinal Ganglion Cells - pathology
Scn8a
Sodium channel
title Nav1.6 promotes inflammation and neuronal degeneration in a mouse model of multiple sclerosis
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