| First Author | Deng HX | Year | 2008 |
| Journal | Hum Mol Genet | Volume | 17 |
| Issue | 15 | Pages | 2310-9 |
| PubMed ID | 18424447 | Mgi Jnum | J:137635 |
| Mgi Id | MGI:3801376 | Doi | 10.1093/hmg/ddn131 |
| Citation | Han-Xiang D, et al. (2008) Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach. Hum Mol Genet 17(15):2310-9 |
| abstractText | 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 SOD1(T116X) that harbors a PTC in exon 4. We found that the SOD1(T116X) transgene with a fused exon could escape NMD in cellular models. We generated a transgenic mouse model that overexpresses SOD1(T116X). 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. |
