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

Deng Han-Xiang*, Jiang Hujun, Fu Ronggen, Zhai Hong, Shi Yong, Liu Erdong, Hirano Makito, C. Dal Canto Mauro, Siddique Teepu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)2310-2319
Number of pages10
JournalHuman molecular genetics
Issue number15
StatePublished - Aug 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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