title: Dismutase-competent SOD1 mutant accumulation in myelinating Schwann cells is not detrimental to normal or transgenic ALS model mice.
abstract: Mutant superoxide dismutase 1 (SOD1) action within non-neuronal cells is implicated in damage to spinal motor neurons in a genetic form of amyotrophic lateral sclerosis (ALS). Central nervous system glial cells such as astrocytes and microglia drive progression in transgenic mutant SOD1 mice, however, the role of myelinating glia remains unclear. Specifically, peripheral myelinating glial cells are likely candidates for mediating degeneration of distal synapses and axons of motor neurons in ALS. Here, we examine the potential contribution of peripheral axon ensheathing Schwann cells to ALS by constructing transgenic mice expressing dismutase active mutant SOD1(G93A) driven by the myelin protein zero (P0) promoter. In this model, mutant SOD1 accumulation in Schwann cells was comparable to levels in mice ubiquitously expressing a SOD1(G93A) transgene that become paralysed. Growth, locomotion and survival of these P0-SOD1(G93A) mice were indistinguishable from normal animals. There was no evidence for spinal motor neuron loss, distal axonal degeneration and p75 neurotrophin receptor (p75(NTR)) upregulation in the periphery of P0-SOD1(G93A) mice, unlike transgenic SOD1(G93A) mice with presymptomatic p75(NTR) induction and death-signalling. Furthermore, Schwann cells were resistant to mutant SOD1 aggregation in vivo and in transfected primary cultures. Increasing mutant SOD1 synthesis in Schwann cells by cross-breeding transgenic P0-SOD1(G93A) and SOD1(G93A) mice did not affect disease onset or survival. We conclude that dismutase-competent mutant SOD1 accumulation within Schwann cells is not pathological to spinal motor neurons or deleterious to disease course in transgenic ALS model mice, in contrast to astrocytes and microglia.
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, John Radcliffe Hospital, University of Oxford, Oxford OX1 3QX, UK.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Turner
authors.forename: Steven
authors.initials: S
authors.lastname: Ackerley
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
authors.forename: Kevin
authors.initials: K
authors.lastname: Talbot
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D012583:Schwann Cells / Q000201:enzymology* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014162:Transfection
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1