Activity of NaV1.2 promotes neurodegeneration in an animal model of multiple sclerosis
Benjamin Schattling, … , Dirk Isbrandt, Manuel A. Friese
Benjamin Schattling, … , Dirk Isbrandt, Manuel A. Friese
Published November 17, 2016
Citation Information: JCI Insight. 2016;1(19):e89810. https://doi.org/10.1172/jci.insight.89810.
View: Text | PDF
Research Article Neuroscience

Activity of NaV1.2 promotes neurodegeneration in an animal model of multiple sclerosis

Abstract

Counteracting the progressive neurological disability caused by neuronal and axonal loss is the major unmet clinical need in multiple sclerosis therapy. However, the mechanisms underlying irreversible neuroaxonal degeneration in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) are not well understood. A long-standing hypothesis holds that the distribution of voltage-gated sodium channels along demyelinated axons contributes to neurodegeneration by increasing neuroaxonal sodium influx and energy demand during CNS inflammation. Here, we tested this hypothesis in vivo by inserting a human gain-of-function mutation in the mouse NaV1.2-encoding gene Scn2a that is known to increase NaV1.2-mediated persistent sodium currents. In mutant mice, CNS inflammation during EAE leads to elevated neuroaxonal degeneration and increased disability and lethality compared with wild-type littermate controls. Importantly, immune cell infiltrates were not different between mutant EAE mice and wild-type EAE mice. Thus, this study shows that increased neuronal NaV1.2 activity exacerbates inflammation-induced neurodegeneration irrespective of immune cell alterations and identifies NaV1.2 as a promising neuroprotective drug target in multiple sclerosis.

Authors

Benjamin Schattling, Walid Fazeli, Birgit Engeland, Yuanyuan Liu, Holger Lerche, Dirk Isbrandt, Manuel A. Friese

×

Figure 3

Enhanced NaV1.2 activity results in increased axonal injury and neuronal energy consumption during EAE.

Options: View larger image (or click on image) Download as PowerPoint
Enhanced NaV1.2 activity results in increased axonal injury and neuronal...
Representative histopathological sections and quantification of (A) amyloid precursor protein (App; P = 0.016), (B) neurofilament (P < 0.0001), and (C) hexokinase-1 (HK1; P = 0.023) immunostainings. Dorsal columns and corticospinal tract (A), dorsal columns (B), or gray matter (C) of cervical spinal cord sections were stained from wild-type EAE and M/+ EAE mice 14 days (A; n = 3 mice per group with 2 color-coded slices per animal) or 30 days after immunization (B and C; n = 4 mice per group with 2–5 color-coded slices per animal; normalized to healthy wild-type and M/+ control mice); for each quantification, multiple replicates of data from individual animals were color coded. Scale bar: 20 μm (A and C), 2 μm (B). All data are presented as mean ± SEM. Statistical analyses were performed by Student’s t test; *P < 0.05, **P < 0.01. Color-coding has to be evaluated separately for each graph, i.e., each color represents one particular animal at one specific time point for one particular parameter.