| First Author | Wang L | Year | 2009 |
| Journal | Hum Mol Genet | Volume | 18 |
| Issue | 9 | Pages | 1642-51 |
| PubMed ID | 19233858 | Mgi Jnum | J:147156 |
| Mgi Id | MGI:3839504 | Doi | 10.1093/hmg/ddp085 |
| Citation | Wang L, et al. (2009) Wild type SOD1 overexpression accelerates disease onset of a G85R SOD1 mouse. Hum Mol Genet 18(9):1642-51 |
| abstractText | Approximately 10% of 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 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 to 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 crosslinking. 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. |
