Cystine/Glutamate Exchange Modulates Glutathione Supply for Neuroprotection from Oxidative Stress and Cell Proliferation
Bibliographic record
Abstract
The cystine/glutamate exchanger (xCT) provides intracellular cyst(e)ine for production of glutathione, a major cellular antioxidant. Using xCT overexpression and underexpression, we present evidence that xCT-dependent glutathione production modulates both neuroprotection from oxidative stress and cell proliferation. In embryonic and adult rat brain, xCT protein was enriched at the CSF-brain barrier (i.e., meninges) and also expressed in the cortex, hippocampus, striatum, and cerebellum. To examine the neuroprotective role of xCT, various non-neuronal cell types (astrocytes, meningeal cells, and peripheral fibroblasts) were cocultured with immature cortical neurons and exposed to oxidative glutamate toxicity, a model involving glutathione depletion. Cultured meningeal cells, which naturally maintain high xCT expression, were more neuroprotective than astrocytes. Selective xCT overexpression in astrocytes was sufficient to enhance glutathione synthesis/release and confer potent glutathione-dependent neuroprotection from oxidative stress. Moreover, normally nonprotective fibroblasts could be re-engineered to be neuroprotective with ectopic xCT overexpression indicating that xCT is a key step in the pathway to glutathione synthesis. Conversely, astrocytes and meningeal cells derived from sut/sut mice (xCT loss-of-function mutants) showed greatly reduced proliferation in culture attributable to increased oxidative stress and thiol deficiency, because growth could be rescued by the thiol-donor beta-mercaptoethanol. Strikingly, sut/sut mice developed brain atrophy by early adulthood, exhibiting ventricular enlargement, thinning of the cortex, and shrinkage of the striatum. Our results indicate that xCT can provide neuroprotection by enhancing glutathione export from non-neuronal cells such as astrocytes and meningeal cells. Furthermore, xCT is critical for cell proliferation during development in vitro and possibly in vivo.
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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) | 0.000 | 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 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".