title: Mutant superoxide dismutase-1 indistinguishable from wild-type causes ALS.
abstract: A reason for screening amyotrophic lateral sclerosis (ALS) patients for mutations in the superoxide dismutase-1 (SOD1) gene is the opportunity to find novel mutations with properties that can give information on pathogenesis. A novel c.352C>G (L117V) SOD1 mutation was found in two Syrian ALS families living in Europe. The disease showed unusually low penetrance and slow progression. In erythrocytes, the total SOD1 activity, as well as specific activity of the mutant protein, was equal in carriers of the mutation and family controls lacking SOD1 mutations. The structural stabilities of the L117V mutant and wild-type SOD1 under denaturing conditions were likewise equal, but considerably lower than that of murine SOD1. As analyzed with an ELISA specific for misfolded SOD1 species, no differences were found in the content of misfolded SOD1 protein between extracts of fibroblasts from wild-type controls and from an L117V patient. In contrast, elevated levels of misfolded SOD1 protein were found in fibroblasts from ALS patients carrying seven other mutations in the SOD1 gene. We conclude that mutations in SOD1 that result in a fully stable protein are associated with low disease penetrance for ALS and may be found in cases of apparently sporadic ALS. Wild-type human SOD1 is moderately stable, and was found here to be within the stability range of ALS-causing SOD1 variants, lending support to the hypothesis that wild-type SOD1 could be more generally involved in ALS pathogenesis.
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, Tübingen 72076, Germany.
authors.forename: Matthis
authors.initials: M
authors.lastname: Synofzik
authors.forename: Dario
authors.initials: D
authors.lastname: Ronchi
authors.forename: Isil
authors.initials: I
authors.lastname: Keskin
authors.forename: Ayse N
authors.initials: AN
authors.lastname: Basak
authors.forename: Christian
authors.initials: C
authors.lastname: Wilhelm
authors.forename: Claudio
authors.initials: C
authors.lastname: Gobbi
authors.forename: Anna
authors.initials: A
authors.lastname: Birve
authors.forename: Saskia
authors.initials: S
authors.lastname: Biskup
authors.forename: Chiara
authors.initials: C
authors.lastname: Zecca
authors.forename: Rubén
authors.initials: R
authors.lastname: Fernández-Santiago
authors.forename: Toomas
authors.initials: T
authors.lastname: Kaugesaar
authors.forename: Ludger
authors.initials: L
authors.lastname: Schöls
authors.forename: Stefan L
authors.initials: SL
authors.lastname: Marklund
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
mesh_terms: D000328:Adult; D017668:Age of Onset; D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D004795:Enzyme Stability; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D010375:Pedigree; D017510:Protein Folding; D013482:Superoxide Dismutase / Q000737:chemistry / 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