title: Na(v)1.8 channelopathy in mutant mice deficient for myelin protein zero is detrimental to motor axons.
abstract: Myelin protein zero mutations were found to produce Charcot-Marie-Tooth disease phenotypes with various degrees of myelin impairment and axonal loss, ranging from the mild 'demyelinating' adult form to severe and early onset forms. Protein zero deficient homozygous mice ( ) show a severe and progressive dysmyelinating neuropathy from birth with compromised myelin compaction, hypomyelination and distal axonal degeneration. A previous study using immunofluorescence showed that motor nerves deficient of myelin protein zero upregulate the Na(V)1.8 voltage gated sodium channel isoform, which is normally present only in restricted populations of sensory axons. The aim of this study was to investigate the function of motor axons in protein zero-deficient mice with particular emphasis on ectopic Na(V)1.8 voltage gated sodium channel. We combined 'threshold tracking' excitability studies with conventional nerve conduction studies, behavioural studies using rotor-rod measurements, and histological measures to assess membrane dysfunction and its progression in protein zero deficient homozygous mutants as compared with age-matched wild-type controls. The involvement of Na(V)1.8 was investigated by pharmacologic block using the subtype-selective Na(V)1.8 blocker A-803467 and chronically in Na(V)1.8 knock-outs. We found that in the context of dysmyelination, abnormal potassium ion currents and membrane depolarization, the ectopic Na(V)1.8 channels further impair the motor axon excitability in protein zero deficient homozygous mutants to an extent that precipitates conduction failure in severely affected axons. Our data suggest that a Na(V)1.8 channelopathy contributed to the poor motor function of protein zero deficient homozygous mutants, and that the conduction failure was associated with partially reversible reduction of the electrically evoked muscle response and of the clinical function as indicated by the partial recovery of function at rotor-rod measurements. As a consequence of these findings of partially reversible dysfunction, we propose that the Na(V)1.8 voltage gated sodium channel should be considered as a novel therapeutic target for Charcot-Marie-Tooth disease.
authors.affiliation: Institute of Neuroscience and Pharmacology, Panum, University of Copenhagen, Denmark.
authors.forename: Mihai
authors.initials: M
authors.lastname: Moldovan
authors.forename: Susana
authors.initials: S
authors.lastname: Alvarez
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Pinchenko
authors.forename: Dennis
authors.initials: D
authors.lastname: Klein
authors.forename: Finn Cilius
authors.initials: FC
authors.lastname: Nielsen
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.forename: Rudolf
authors.initials: R
authors.lastname: Martini
authors.forename: Christian
authors.initials: C
authors.lastname: Krarup
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology / Q000502:physiology*; D053447:Channelopathies / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D003711:Demyelinating Diseases / Q000235:genetics / Q000503:physiopathology; D005663:Furans / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D018993:Myelin P0 Protein / Q000235:genetics / Q000502:physiology*; D062559:NAV1.8 Voltage-Gated Sodium Channel; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D045442:Rotarod Performance Test; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*; D013979:Tibial Nerve / Q000473:pathology / Q000503:physiopathology*
chemical_list: C520740:A 803467; D000814:Aniline Compounds; D005663:Furans; D018993:Myelin P0 Protein; D062559:NAV1.8 Voltage-Gated Sodium Channel; C568318:Scn10a protein, mouse; D026941:Sodium Channel Blockers; D015222:Sodium Channels