Metformin inhibits RAN translation through PKR pathway and mitigates disease in <i>C9orf72</i> ALS/FTD mice
Why this work is in the frame
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Bibliographic record
Abstract
Significance Repeat-associated non-AUG (RAN) proteins accumulate in patient brains and contribute to a growing number of neurodegenerative diseases. There is an urgent need to understand why expression of these proteins does not require canonical or near-cognate AUG start codons and to develop ways to block RAN protein production. We show several types of repeat-expansion RNAs activate the double-stranded RNA-dependent protein kinase (PKR) pathway and that blocking PKR reduces RAN protein levels in cells. PKR is activated in C9orf72 ALS/FTD human and mouse brains and PKR inhibition using AAV-PKR-K296R or the FDA-approved drug metformin decreases RAN protein levels and improves disease in ALS/FTD mice. Targeting PKR using gene therapy or metformin are promising therapeutic approaches for C9orf72 ALS/FTD and other expansion diseases.
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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 | 0.000 | 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) | 0.000 | 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