A04 Caspase 6 resistant mutant huntingtin does not rescue the toxic effects of caspase cleavable mutant huntingtin in vivo
Bibliographic record
Abstract
Background The amelioration of behavioural and neuropathological deficits in mice expressing caspase 6 resistant (C6R) mutant huntingtin (mhtt), despite the presence of an expanded polyglutamine track, highlights proteolysis of htt at the 586aa caspase 6 (casp6) site as a key mechanism in the pathology of HD. In order to determine whether C6R mhtt acts as a dominant negative inhibitor of casp6 activation, we crossed C6R mice to the YAC128 HD mouse model. If the neuroprotection observed in C6R mice reflects a dominant negative effect, then similar protection and amelioration of HD related phenotypes may be expected in mice expressing both casp6 cleavable and casp6 resistant mhtt. Results Neuropathological analysis of YAC128/C6R brains reveals a significant decrease in brain weight (p<0.01) and striatal volume (p<0.01) in the YAC128/C6R mice, similar to what is observed in the YAC128 mice (brain weight p<0.05; striatal volume p<0.05). In contrast, and similar to previous findings, C6R brains demonstrated preserved brain weight and striatal volume. Furthermore, the 586aa mhtt fragment is observed in YAC128/C6R brain tissue. Behavioural testing reveals that the YAC128/C6R mice perform similar to YAC128 mice in the open field. Body weight in significantly increased in the YAC128/C6R mice compared with YAC128 due to the increased levels of htt in these mice. Conclusion These data suggest that the lack of an HD phenotype in the C6R mice is due to the absence of the 586aa mhtt fragment and provide additional evidence that the 586aa mhtt fragment plays a critical role in the pathogenesis of HD. This work supports efforts towards casp6 inhibition as a therapeutic treatment for HD.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".