Wild-type SOD1 overexpression accelerates disease onset of a G85R SOD1 mouse

• Published in: Human molecular genetics 2009-05, Vol.18 (9), p.1642-1651
• Main Authors: Wang, Lijun, Deng, Han-Xiang, Grisotti, Gabriella, Zhai, Hong, Siddique, Teepu, Roos, Raymond P.
• Format: Article
• Language: English
• Subjects: Amyotrophic Lateral Sclerosis - enzymology; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - pathology; Animals; Biological and medical sciences; Dimerization; Disease Models, Animal; Disease Progression; Female; Fundamental and applied biological sciences. Psychology; Gene Expression; Genetics of eukaryotes. Biological and molecular evolution; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Molecular and cellular biology; Mutation, Missense; Spinal Cord - metabolism; Spinal Cord - pathology; Superoxide Dismutase - chemistry; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddp085

Approximately 10% of amyotrophic lateral sclerosis (ALS) cases are familial (FALS), and ∼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.