Journal
HUMAN MOLECULAR GENETICS
Volume 18, Issue 9, Pages 1642-1651Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddp085
Keywords
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Funding
- ALS Association [1211]
- Muscular Dystrophy Association [4346]
- National Institutes of Health [NS40308, NS050641, NS046535]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS040308, R01NS046535, R01NS050641] Funding Source: NIH RePORTER
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Approximately 10% of amyotrophic lateral sclerosis (ALS) cases are familial (FALS), and similar to 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.
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