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Hum Mol Genet. 2008 Aug 1;17(15):2310-9. doi: 10.1093/hmg/ddn131. Epub 2008 Apr 18.

Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach.

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Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Erratum in

  • Hum Mol Genet. 2009 Feb 1;18(3):594. Han-Xiang, Deng [corrected to Deng, Han-Xiang]; Hujun, Jiang [corrected to Jiang, Hujun]; Ronggen, Fu [corrected to Fu, Ronggen]; Hong, Zhai [corrected to Zhai, Hong]; Yong, Shi [corrected to Shi, Yong]; Erdong, Liu [corrected to Liu, Erdong]; Makito, Hira.


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.

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