| Autor: |
Deng HX; Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. h-deng@northwestern.edu, Jiang H, Fu R, Zhai H, Shi Y, Liu E, Hirano M, Dal Canto MC, Siddique T |
| Jazyk: |
angličtina |
| Zdroj: |
Human molecular genetics [Hum Mol Genet] 2008 Aug 01; Vol. 17 (15), pp. 2310-9. Date of Electronic Publication: 2008 Apr 18. |
| DOI: |
10.1093/hmg/ddn131 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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