title: Superoxide dismutase-1 and other proteins in inclusions from transgenic amyotrophic lateral sclerosis model mice.
abstract: Mutant superoxide dismutase-1 (SOD1) causes amyotrophic lateral sclerosis (ALS) through a cytotoxic mechanism of unknown nature. A hallmark in ALS patients and transgenic mouse models carrying human SOD1 (hSOD1) mutations are hSOD1-immunoreactive inclusions in spinal cord ventral horns. The hSOD1 inclusions may block essential cellular functions or cause toxicity through sequestering of other proteins. Inclusions from four different transgenic mouse models were examined after density gradient ultracentrifugation. The inclusions are complex structures with heterogeneous densities and are disrupted by detergents. The aggregated hSOD1 was mainly composed of subunits that lacked the native stabilizing intra-subunit disulfide bond. A proportion of subunits formed hSOD1 oligomers or was bound to other proteins through disulfide bonds. Dense inclusions could be isolated and the protein composition was analyzed using proteomic techniques. Mutant hSOD1 accounted for half of the protein. Ten other proteins were identified. Two were cytoplasmic chaperones, four were cytoskeletal proteins, and 4 were proteins that normally reside in the endoplasmic reticulum (ER). The presence of ER proteins in inclusions containing the primarily cytosolic hSOD1 further supports the notion that ER stress is involved in ALS.
authors.affiliation: Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bergemalm
authors.forename: Karin
authors.initials: K
authors.lastname: Forsberg
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Srivastava
authors.forename: Karin S
authors.initials: KS
authors.lastname: Graffmo
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.forename: Thomas
authors.initials: T
authors.lastname: Brännström
authors.forename: Gunnar
authors.initials: G
authors.lastname: Wingsle
authors.forename: Stefan L
authors.initials: SL
authors.lastname: Marklund
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1