Neuronal pentraxin 1 depletion delays neurodegeneration and extends life in Sandhoff disease mice
Bibliographic record
Abstract
GM2 gangliosidoses are a group of lysosomal storage disorders which include Sandhoff disease and Tay-Sachs disease. Dysregulation of glutamate receptors has been recently postulated in the pathology of Sandhoff disease. Glutamate receptor association with neuronal pentraxins 1 and 2, and the neuronal pentraxin receptor facilitates receptor potentiation and synaptic shaping. In this study, we have observed an upregulation of a novel form of neuronal pentraxin 1 (NP1-38) in the brains of a mouse model of Sandhoff disease and Tay-Sachs disease. In order to determine the impact of NP1 on the pathophysiology of Sandhoff disease mouse models, we have generated an Np1-/-Hexb-/- double knockout mouse, and observed extended lifespan, improved righting reflex and enhanced body condition relative to Hexb-/- mice, with no effect on gliosis or apoptotic markers in the CNS. Sandhoff mouse brain slices reveals a reduction in AMPA receptor-mediated currents, and increased variability in total glutamate currents in the CA1 region of the hippocampus; Np1-/-Hexb-/- mice show a correction of this phenotype, suggesting NP1-38 may be interfering with glutamate receptor function. Indeed, some of the psychiatric aspects of Sandhoff and Tay-Sachs disease (particularly late onset) may be attributed to a dysfunctional hippocampal glutamatergic system. Our work highlights a potential role for synaptic proteins, such as NP1 and glutamate receptors in lysosomal storage diseases.
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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) | 0.000 | 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".