MTHFR-deficiency Increases Ischemic Damage Through Reduced Neuronal and Astrocytes Viability and Changes in the Cellular Response (P01-020-19)
Bibliographic record
Abstract
Stroke is a leading cause of disability and death world-wide. Increased levels of homocysteine are associated with risk for stroke. Metheylenetetrahydrofolate reductase (MTHFR) generates methyl groups to aid in the metabolism of homocysteine. A polymorphism in MTHFR (677C→T) has been identified in 5–15% of North American and European populations. Individuals with the TT genotype have elevated homocysteine concentrations and have increased risk of stroke. Using the MTHFR mouse model, the objective of this study was to investigate the mechanisms through which MTHFR deficiency may increase the risk of stroke. We isolated primary neurons and astrocytes cells from MTHFR-deficient mice and exposed cells to hypoxia for 6 hours. Twenty-four hours after damage, we measured cell viability. In vivo, using aged (∼1.5-year-old) male Mthfr+/– and wildtype littermate controls, the sensorimotor cortex was damaged using the photothrombosis model to induce ischemic stroke. Post-operatively, animals were tested on skilled motor function, and brain tissue was processed for analysis. Additionally, in adult male mice using MRI we measured lesion volume two and four weeks after damage. Primary neurons and astrocytes from MTHFR-deficient embryos showed reduced cell viability through increased trypan blue staining and MTT release. In vivo, aged Mthfr+/– mice were impaired in skilled motor function after damage. Using MRI, adult Mthfr+/– brains were more severely damaged compared to wild-type littermates. In vitro and in vivo, we observed increased apoptosis in Mthfr+/– animals. Furthermore, methionine adenosyltransferase II alpha (MAT2A) protein levels were increased in the stroke hemisphere of wild-type mice. In the non-PT hemisphere of Mthfr+/– mice there was an increase in hypoxia induced factor 1 alpha (HIF-1α) protein and growth differentiation factor 11 (GDF11). Together, our results suggest that Mthfr+/– mice are more vulnerable to ischemic stroke damage. This is through reducing neuronal and astrocyte viability after damage, as well as changes in methylation and cellular response. This research was funded by the Natural Sciences and Engineering Research Council, Council of Ontario Universities, and Fonds de la recherché en santé Québec (FRSQ).
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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 | 0.001 | 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".