title: Schwann cells expressing dismutase active mutant SOD1 unexpectedly slow disease progression in ALS mice.
abstract: Neurodegeneration in an inherited form of ALS is non-cell-autonomous, with ALS-causing mutant SOD1 damage developed within multiple cell types. Selective inactivation within motor neurons of an ubiquitously expressed mutant SOD1 gene has demonstrated that mutant damage within motor neurons is a determinant of disease initiation, whereas mutant synthesis within neighboring astrocytes or microglia accelerates disease progression. We now report the surprising finding that diminished synthesis (by 70%) within Schwann cells of a fully dismutase active ALS-linked mutant (SOD1(G37R)) significantly accelerates disease progression, accompanied by reduction of insulin-like growth factor 1 (IGF-1) in nerves. Coupled with shorter disease duration in mouse models caused by dismutase inactive versus dismutase active SOD1 mutants, our findings implicate an oxidative cascade during disease progression that is triggered within axon ensheathing Schwann cells and that can be ameliorated by elevated dismutase activity. Thus, therapeutic down-regulation of dismutase active mutant SOD1 in familial forms of ALS should be targeted away from Schwann cells.
authors.affiliation: Department of Medicine and Neuroscience, Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Christian S
authors.initials: CS
authors.lastname: Lobsiger
authors.forename: Severine
authors.initials: S
authors.lastname: Boillee
authors.forename: Melissa
authors.initials: M
authors.lastname: McAlonis-Downes
authors.forename: Amir M
authors.initials: AM
authors.lastname: Khan
authors.forename: M Laura
authors.initials: ML
authors.lastname: Feltri
authors.forename: Koji
authors.initials: K
authors.lastname: Yamanaka
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology* / Q000517:prevention & control; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D051379:Mice; D009474:Neurons / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000096:biosynthesis* / Q000502:physiology; D000072105:Superoxide Dismutase-1
chemical_list: D007334:Insulin-Like Growth Factor I; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1