| First Author | Schattling B | Year | 2016 |
| Journal | JCI Insight | Volume | 1 |
| Issue | 19 | Pages | e89810 |
| PubMed ID | 27882351 | Mgi Jnum | J:355207 |
| Mgi Id | MGI:7737855 | Doi | 10.1172/jci.insight.89810 |
| Citation | Schattling B, et al. (2016) Activity of Na(V)1.2 promotes neurodegeneration in an animal model of multiple sclerosis. JCI Insight 1(19):e89810 |
| abstractText | 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 Na(V)1.2-encoding gene Scn2a that is known to increase Na(V)1.2-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 Na(V)1.2 activity exacerbates inflammation-induced neurodegeneration irrespective of immune cell alterations and identifies Na(V)1.2 as a promising neuroprotective drug target in multiple sclerosis. |
