Human Molecular Genetics Advance Access originally published online on April 18, 2008
Human Molecular Genetics 2008 17(15):2310-2319; doi:10.1093/hmg/ddn131
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Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach
1 Davee Department of Neurology and Clinical Neurosciences 2 Department of Pathology 3 Department of Cell and Molecular Biology 4 Institute for Neuroscience, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA 5 National Laboratory of Medical Genetics, Central South University, Changsha, Hunan, China
* To whom correspondence should be addressed at: Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Tarry Building 13-715, 303 E. Chicago Ave, Chicago, IL 60611, USA. Tel: +1 3125034737; Fax: +1 3129080865; Email: h-deng{at}northwestern.edu
Received January 24, 2008; Accepted April 15, 2008
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.
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