Universität zu Köln

Schattling, Benjamin, Fazeli, Walid, Engeland, Birgit, Liu, Yuanyuan, Lerche, Holger, Isbrandt, Dirk and Friese, Manuel A. ORCID: 0000-0001-6380-2420 (2016). Activity of Na-V 1.2 promotes neurodegeneration in an animal model of multiple sclerosis. JCI Insight, 1 (19). ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 2379-3708

Full text not available from this repository.

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 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schattling, Benjamin UNSPECIFIED UNSPECIFIED UNSPECIFIED Fazeli, Walid UNSPECIFIED UNSPECIFIED UNSPECIFIED Engeland, Birgit UNSPECIFIED UNSPECIFIED UNSPECIFIED Liu, Yuanyuan UNSPECIFIED UNSPECIFIED UNSPECIFIED Lerche, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED Isbrandt, Dirk UNSPECIFIED UNSPECIFIED UNSPECIFIED Friese, Manuel A. UNSPECIFIED orcid.org/0000-0001-6380-2420 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-255621
DOI:	10.1172/jci.insight.89810
Journal or Publication Title:	JCI Insight
Volume:	1
Number:	19
Date:	2016
Publisher:	AMER SOC CLINICAL INVESTIGATION INC
Place of Publication:	ANN ARBOR
ISSN:	2379-3708
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; SPINAL-CORD AXONS; SODIUM-CHANNELS; MOUSE MODEL; PHENYTOIN; DEGENERATION; EXPRESSION; CONDUCTION; NA(V)1.2; MUTATION Multiple languages Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25562