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Updated: Jul 5, 2026
Lumbar Intrathecal Injection of SOD1-ASOs for Precise CNS Targeting and Predictive Efficacy in Human SOD1-G93A ALS Mice
Published on: February 24, 2026
Molecular dissection of ALS-associated toxicity of SOD1 in transgenic mice using an exon-fusion approach
Han-Xiang Deng1, Deng Han-Xiang, Hujun Jiang
1Davee Department of Neurology and Clinical Neurosciences, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA. h-deng@northwestern.edu
Abstract:
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.
Insights
Amyotrophic lateral sclerosis (ALS) is linked to SOD1 mutations. Researchers found a small, 115-amino acid SOD1 fragment can cause ALS, identifying a potential therapeutic target for this neurodegenerative disease.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Mutations in copper-zinc superoxide dismutase (SOD1) are a known cause of amyotrophic lateral sclerosis (ALS).
- The precise molecular mechanisms driving SOD1-related ALS toxicity remain incompletely understood.
- Premature termination codon (PTC) mutations in SOD1 are exclusively found in exon 5, the gene's final exon.
Purpose of the Study:
- To investigate the role of nonsense-mediated mRNA decay (NMD) in clearing mutant SOD1 mRNA.
- To define the smallest toxic fragment of SOD1 responsible for ALS pathogenesis.
- To develop and validate a novel exon-fusion strategy for studying ALS-associated SOD1 fragments.
Main Methods:
- Utilized an exon-fusion approach with a SOD1(T116X) transgene containing a PTC in exon 4.
- Assessed NMD evasion in cellular models with the engineered SOD1 transgene.
- Generated and analyzed a transgenic mouse model overexpressing SOD1(T116X).
Main Results:
- Demonstrated that NMD primarily clears mutant SOD1 mRNA with PTCs in non-terminal exons.
- Showed that the SOD1(T116X) transgene with a fused exon could evade NMD in cellular systems.
- Established that the SOD1(T116X) transgenic mouse model exhibits ALS-like phenotypes and neuropathology.
- Identified a 'mini-SOD1' fragment of 115 amino acids as sufficient to induce ALS, representing the smallest such molecule identified to date.
Conclusions:
- The study identifies a minimal 115-amino acid SOD1 fragment as sufficient to cause ALS.
- The findings suggest that the exon-fusion approach can effectively define smaller toxic protein fragments.
- This research provides a potential molecular target for developing targeted ALS therapies and understanding gain-of-function toxicities in other genetic disorders.
