title: Copper-binding-site-null SOD1 causes ALS in transgenic mice: aggregates of non-native SOD1 delineate a common feature.
abstract: Cu/Zn superoxide dismutase (SOD1), a crucial cellular antioxidant, can in certain settings mediate toxic chemistry through its Cu cofactor. Whether this latter property explains why mutations in SOD1 cause FALS has been debated. Here, we demonstrate motor neuron disease in transgenic mice expressing a SOD1 variant that mutates the four histidine residues that coordinately bind Cu. In-depth analyses of this new mouse model, previously characterized models and FALS human tissues revealed that the accumulation of detergent-insoluble forms of SOD1 is a common feature of the disease. These insoluble species include full-length SOD1 proteins, peptide fragments, stable oligomers and ubiquitinated entities. Moreover, chaperones Hsp25 and alphaB-crystallin specifically co-fractionated with insoluble SOD1. In cultured cells, all 11 of the FALS variants tested produced insoluble forms of mutant SOD1. Importantly, expression of recombinant peptide fragments of wild-type SOD1 in cultured cells also produced insoluble species, suggesting that SOD1 possesses elements with an intrinsic propensity to aggregate. Thus, modifications to the protein, such as FALS mutations, fragmentation and possibly covalent modification, may simply act to augment a natural, but potentially toxic, propensity to aggregate.
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Jiou
authors.initials: J
authors.lastname: Wang
authors.forename: Hilda
authors.initials: H
authors.lastname: Slunt
authors.forename: Victoria
authors.initials: V
authors.lastname: Gonzales
authors.forename: David
authors.initials: D
authors.lastname: Fromholt
authors.forename: Michael
authors.initials: M
authors.lastname: Coonfield
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism; D001665:Binding Sites; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism*; D006639:Histidine / Q000235:genetics*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D038203:alpha-Crystallin B Chain; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D003300:Copper; D006639:Histidine; D007381:Intermediate Filament Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D038203:alpha-Crystallin B Chain; D000099190:MAP-Kinase-Activated Kinase 2; C059215:CRYAB protein, human; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse