title: Wild-type SOD1 overexpression accelerates disease onset of a G85R SOD1 mouse.
abstract: Approximately 10% of amyotrophic lateral sclerosis (ALS) cases are familial (FALS), and approximately 25% of FALS cases are caused by mutations in Cu/Zn superoxide dismutase type 1 (SOD1). Mutant (MT) SOD1 is thought to be pathogenic because it misfolds and aggregates. A number of transgenic mice have been generated that express different MTSOD1s as transgenes and exhibit an ALS-like disease. Although one study found that overexpression of human wild-type (WT) SOD1 did not affect disease in G85R transgenic mice, more recent reports claim that overexpression of WTSOD1 in other MTSOD1 transgenic mice hastened disease, raising a possibility that the effect of WTSOD1 overexpression in this FALS mouse model is mutant-specific. In order to clarify this issue, we studied the effect of WTSOD1 overexpression in a G85R transgenic mouse that we recently generated. We found that G85R/WTSOD1 double transgenic mice had an acceleration of disease onset and shortened survival compared with G85R single transgenic mice; in addition, there was an earlier appearance of pathological and immunohistochemical abnormalities. The spinal cord insoluble fraction from G85R/WTSOD1 mice had evidence of G85R-WTSOD1 heterodimers and WTSOD1 homodimers (in addition to G85R homodimers) with intermolecular disulfide bond cross-linking. These studies suggest that WTSOD1 can be recruited into disease-associated aggregates by redox processes, providing an explanation for the accelerated disease seen in G85R mice following WTSOD1 overexpression, and suggesting the importance of incorrect disulfide-linked protein as key to MTSOD1 toxicity.
authors.affiliation: Department of Neurology, The University of Chicago Pritzker School of Medicine, IL 60637, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Wang
authors.forename: Han-Xiang
authors.initials: HX
authors.lastname: Deng
authors.forename: Gabriella
authors.initials: G
authors.lastname: Grisotti
authors.forename: Hong
authors.initials: H
authors.lastname: Zhai
authors.forename: Teepu
authors.initials: T
authors.lastname: Siddique
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Roos
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D019281:Dimerization; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020125:Mutation, Missense; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; 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