Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach
| Autor: | Han-Xiang, Deng, Deng, Han-Xiang, Hujun, Jiang, Jiang, Hujun, Ronggen, Fu, Fu, Ronggen, Hong, Zhai, Zhai, Hong, Yong, Shi, Shi, Yong, Erdong, Liu, Liu, Erdong, Makito, Hirano, Hirano, Makito, Mauro C, Dal Canto, C Dal Canto, Mauro, Teepu, Siddique, Siddique, Teepu |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
animal diseases
RNA Stability Mutant DNA Mutational Analysis medicine.disease_cause Exon Mice 0302 clinical medicine Superoxide Dismutase-1 Genetics (clinical) Sequence Deletion 0303 health sciences Mutation General Medicine Exons Articles Phenotype Codon Nonsense HMG-CoA reductase Toxicity Erratum Genetically modified mouse medicine.medical_specialty Transgene SOD1 Mice Transgenic Dissection (medical) Biology 03 medical and health sciences Molecular genetics Genetics medicine Animals Humans Amino Acid Sequence RNA Messenger Molecular Biology Gene 030304 developmental biology Superoxide Dismutase Amyotrophic Lateral Sclerosis nutritional and metabolic diseases medicine.disease Molecular biology nervous system diseases Artificial Gene Fusion Disease Models Animal nervous system biology.protein 030217 neurology & neurosurgery |
| Zdroj: | Human Molecular Genetics |
| Popis: | 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: | OpenAIRE |
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