Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach.
Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach.
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DOI：
10.1093/hmg/ddn131
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发表时间：
2008-08-01
影响因子：
3.5
通讯作者：
Siddique T
中科院分区：
文献类型：
--
作者：
Deng HX;Jiang H;Fu R;Zhai H;Shi Y;Liu E;Hirano M;Dal Canto MC;Siddique T
Mutations in Cu,Zn superoxide dismutase (SOD1) are associated with amyotrophic lateral sclerosis (ALS). Among more than 100 ALS-associated SOD1 mutations, premature termination codon (PTC) mutations exclusively occur in exon 5, the last exon of SOD1. The molecular basis of ALS-associated toxicity of the mutant SOD1 is not fully understood. Here, we show that nonsense-mediated mRNA decay (NMD) underlies clearance of mutant mRNA with a PTC in the non-terminal exons. To further define the crucial ALS-associated SOD1 fragments, we designed and tested an exon-fusion approach using an artificial transgene SOD1T116X that harbors a PTC in exon 4. We found that the SOD1T116X transgene with a fused exon could escape NMD in cellular models. We generated a transgenic mouse model that overexpresses SOD1T116X. This mouse model developed ALS-like phenotype and pathology. Thus, our data have demonstrated that a ‘mini-SOD1’ of only 115 amino acids is sufficient to cause ALS. This is the smallest ALS-causing SOD1 molecule currently defined. This proof of principle result suggests that the exon-fusion approach may have potential not only to further define a shorter ALS-associated SOD1 fragment, thus providing a molecular target for designing rational therapy, but also to dissect toxicities of other proteins encoded by genes of multiple exons through a ‘gain of function’ mechanism.
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影响因子：
5.3
作者：
Fischer, LR;Culver, DG;Glass, JD
通讯作者：
Glass, JD
影响因子：
6.1
作者：
Ghadge, GD;Wang, LJ;Roos, RP
通讯作者：
Roos, RP
影响因子：
5.3
作者：
Gould, Thomas W.;Buss, Robert R.;Oppenheim, Ronald W.
通讯作者：
Oppenheim, Ronald W.
DOI：
10.1073/pnas.0602048103
发表时间：
2006-05-02
影响因子：
11.1
作者：
Furukawa, Y;Fu, RG;O'Halloran, TV
通讯作者：
O'Halloran, TV
影响因子：
64.8
作者：
ROSEN, DR;SIDDIQUE, T;BROWN, RH
通讯作者：
BROWN, RH