Wild-type SOD1 overexpression accelerates disease onset of a G85R SOD1 mouse.
Wild-type SOD1 overexpression accelerates disease onset of a G85R SOD1 mouse.
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野生型 SOD1 过度表达会加速 G85R SOD1 小鼠的疾病发作。
DOI：
10.1093/hmg/ddp085
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发表时间：
2009
影响因子：
3.5
通讯作者：
Roos,RaymondP
中科院分区：
文献类型：
--
作者：
Wang,Lijun;Deng,Han-Xiang;Grisotti,Gabriella;Zhai,Hong;Siddique,Teepu;Roos,RaymondP
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.
