title: Peripheral motor axons of SOD1(G127X) mutant mice are susceptible to activity-dependent degeneration.
abstract: Motor neuron disorders may be associated with mitochondrial dysfunction, and repetitive electrical impulse conduction during energy restriction has been found to cause neuronal degeneration. The aim of this study was to investigate the vulnerability of motor axons of a presymptomatic late-onset, fast-progression SOD1(G127X) mouse model of amyotrophic lateral sclerosis to long-lasting, high-frequency repetitive activity. Tibial nerves were stimulated at ankle in 7 to 8-month-old SOD1(G127X) mice when they were clinically indistinguishable from wild-type (WT) mice. The evoked compound muscle action potentials and ascending compound nerve action potentials were recorded from plantar muscles and from the sciatic nerve, respectively. Repetitive stimulation (RS) was carried out in interrupted trains of 200-Hz for 3h. During the stimulation-sequence there was progressive conduction failure in WT and, to a lesser extent, in the SOD1(G127X). By contrast, 3 days after RS the electrophysiological responses remained reduced in the SOD1(G127X) but recovered completely in WT. Additionally, morphological studies showed Wallerian degeneration in the disease model. Nerve excitability testing by "threshold-tracking" showed that axons recovering from RS had changes in excitability suggestive of membrane hyperpolarization, which was smaller in the SOD1(G127X) than in WT. Our data provide proof-of-principle that SOD1(G127X) axons are less resistant to activity-induced changes in ion-concentrations. It is possible that in SOD1(G127X) there is inadequate energy-dependent Na(+)/K(+) pumping, which may lead to a lethal Na(+) overload.
authors.affiliation: Institute of Neuroscience and Pharmacology, University of Copenhagen, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Alvarez
authors.forename: A
authors.initials: A
authors.lastname: Calin
authors.forename: K S
authors.initials: KS
authors.lastname: Graffmo
authors.forename: M
authors.initials: M
authors.lastname: Moldovan
authors.forename: C
authors.initials: C
authors.lastname: Krarup
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001369:Axons / Q000473:pathology* / Q000502:physiology; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004594:Electrophysiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000473:pathology* / Q000502:physiology; D009154:Mutation; D009410:Nerve Degeneration / Q000473:pathology / Q000503:physiopathology*; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1