Journal Article

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 and Siddique Teepu

in Human Molecular Genetics

Volume 17, issue 15, pages 2310-2319
Published in print August 2008 | ISSN: 0964-6906
Published online April 2008 | e-ISSN: 1460-2083 | DOI: https://dx.doi.org/10.1093/hmg/ddn131
Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach

Show Summary Details

Preview

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.

Journal Article.  6792 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.