CuATSM Protects Against the <i>In Vitro</i> Cytotoxicity of Wild-Type-Like Copper–Zinc Superoxide Dismutase Mutants but not Mutants That Disrupt Metal Binding
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Bibliographic record
Abstract
Mutations in the SOD1 gene are associated with some forms of familial amyotrophic lateral sclerosis (fALS). There are more than 150 different mutations in the SOD1 gene that have various effects on the copper–zinc superoxide dismutase (SOD1) enzyme structure, including the loss of metal binding and a decrease in dimer affinity. The copper-based therapeutic CuATSM has been proven to be effective at rescuing neuronal cells from SOD1 mutant toxicity and has also increased the life expectancy of mice expressing the human transgenes SOD1G93A and SOD1G37R. Furthermore, CuATSM is currently the subject of a phase I/II clinical trial in Australia as a treatment for ALS. To determine if CuATSM protects against a broad variety of SOD1 mutations, we used a well-established cell culture model of SOD1-fALS. NSC-34 cells expressing SOD1-EGFP constructs were treated with CuATSM and examined by time-lapse microscopy. Our results show a concentration-dependent protection of cells expressing mutant SOD1A4V over the experimental time period. We tested the efficacy of CuATSM on 10 SOD1-fALS mutants and found that while protection was observed in cells expressing pathogenic wild-type-like mutants, cells expressing a truncation mutant or metal binding region mutants were not. We also show that CuATSM rescue is associated with an increase in human SOD1 activity and a decrease in the level of SOD1 aggregation in vitro. In conclusion, CuATSM has shown to be a promising therapeutic for SOD1-associated ALS; however, our in vitro results suggest that the protection afforded varies depending on the SOD1 variant, including negligible protection to mutants with deficient copper binding.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it