title: Toxicity of familial ALS-linked SOD1 mutants from selective recruitment to spinal mitochondria.
abstract: One cause of amyotrophic lateral sclerosis (ALS) is mutation in ubiquitously expressed copper/zinc superoxide dismutase (SOD1), but the mechanism of toxicity to motor neurons is unknown. Multiple disease-causing mutants, but not wild-type SOD1, are now demonstrated to be recruited to mitochondria, but only in affected tissues. This is independent of the copper chaperone for SOD1 and dismutase activity. Highly preferential association with spinal cord mitochondria is seen in human ALS for a mutant SOD1 that accumulates only to trace cytoplasmic levels. Despite variable proportions that are successfully imported, nearly constant amounts of SOD1 mutants and covalently damaged adducts of them accumulate as apparent import intermediates and/or are tightly aggregated or crosslinked onto integral membrane components on the cytoplasmic face of those mitochondria. These findings implicate damage from action of spinal cord-specific factors that recruit mutant SOD1 to spinal mitochondria as the basis for their selective toxicity in ALS.
authors.affiliation: Ludwig Institute for Cancer Research, Department of Neurosciences, Medicine, and Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.forename: Concepción
authors.initials: C
authors.lastname: Lillo
authors.forename: P Andreas
authors.initials: PA
authors.lastname: Jonsson
authors.forename: Christine
authors.initials: C
authors.lastname: Vande Velde
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Ward
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Miller
authors.forename: Jamuna R
authors.initials: JR
authors.lastname: Subramaniam
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Rothstein
authors.forename: Stefan
authors.initials: S
authors.lastname: Marklund
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Thomas
authors.initials: T
authors.lastname: Brännström
authors.forename: Ole
authors.initials: O
authors.lastname: Gredal
authors.forename: Philip C
authors.initials: PC
authors.lastname: Wong
authors.forename: David S
authors.initials: DS
authors.lastname: Williams
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007425:Intracellular Membranes / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D046911:Macromolecular Substances; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D024101:Mitochondrial Proteins / Q000378:metabolism; D018832:Molecular Chaperones / Q000378:metabolism; D016472:Motor Neuron Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D011485:Protein Binding / Q000235:genetics; D017510:Protein Folding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D013116:Spinal Cord / Q000737:chemistry / Q000201:enzymology* / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*; D000072105:Superoxide Dismutase-1
chemical_list: D046911:Macromolecular Substances; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D020033:Protein Isoforms; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1