Delayed spinocerebellar ataxia in transgenic mice expressing mutant ubiquitin
Bibliographic record
Abstract
Spinocerebellar ataxia type 1 (SCA1) is an incurable neurodegenerative disease resulting from loss of Purkinje neurones within the cerebellum. The ubiquitin proteasome pathway (UPP) has been implicated in SCA1 but the role of proteolysis in the disease is still poorly understood. To further investigate this issue in vivo, genetic crosses were performed between an established mouse model of SCA1 and novel strains expressing elevated levels of wild type or mutant isoforms of ubiquitin. The K48R mutant isoform of ubiquitin (a dominant negative inhibitor of proteolysis) was found to significantly delay the deterioration of Purkinje neurones as evidenced by behavioural, morphological, and molecular indicators. This delay was accompanied by stabilization of p300/CBP, transcriptional mediators whose abundance and activity would otherwise decline in the course of the SCA1 disease, and persistence of protein kinase C gamma (PKCgamma), a protein involved in Purkinje cell dendritic development that is mutated in one form of spinocerebellar ataxia. Whereas the stabilization of p300/CBP was found to occur at the post-translational level the modulation of PKCgamma was at the level of transcription. These results are consistent with transcriptional dysregulation as a key mechanism in neurodegeneration through loss of p300/CBP. Further, the results suggest that the UPP is a potentially useful target for the development of novel therapies for the treatment of neurodegenerative disease.
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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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| 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 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".