Mitochondrial damage revealed by immunoselection for ALS-linked misfolded SOD1
Bibliographic record
Abstract
Mutant superoxide dismutase 1 (SOD1) selectively associates with spinal cord mitochondria in rodent models of SOD1-mediated amyotrophic lateral sclerosis. A portion of mutant SOD1 exists in a non-native/misfolded conformation that is selectively recognized by conformational antibodies. Misfolded SOD1 is common to all mutant SOD1 models, is uniquely found in areas affected by the disease and is considered to mediate toxicity. We report that misfolded SOD1 recognized by the antibody B8H10 is present in greater abundance in mitochondrial fractions of SOD1(G93A) rat spinal cords compared with oxidized SOD1, as recognized by the C4F6 antibody. Using a novel flow cytometric assay, we detect an age-dependent deposition of B8H10-reactive SOD1 on spinal cord mitochondria from both SOD1(G93A) rats and SOD1(G37R) mice. Mitochondrial damage, including increased mitochondrial volume, excess superoxide production and increased exposure of the toxic BH3 domain of Bcl-2, tracks positively with the presence of misfolded SOD1. Lastly, B8H10 reactive misfolded SOD1 is present in the lysates and mitochondrial fractions of lymphoblasts derived from ALS patients carrying SOD1 mutations, but not in controls. Together, these results highlight misfolded SOD1 as common to two ALS rodent animal models and familial ALS patient lymphoblasts with four different SOD1 mutations. Studies in the animal models point to a role for misfolded SOD1 in mitochondrial dysfunction in ALS pathogenesis.
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How this classification was reachedexpand
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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".