ATF4 activates a transcriptional program that chronically suppresses mTOR activity promoting neurodegeneration in Parkinson’s disease models
Bibliographic record
Abstract
Summary The Integrated Stress Response (ISR) is a cell signaling pathway that enables cells to adapt to diverse cellular stresses. Conversely, during chronic/unmitigated cellular stress the ISR becomes maladaptive and has been implicated in a range of neurodegenerative conditions including Parkinson’s Disease (PD). However, the mechanisms by which maladaptive ISR/ATF4 signaling contributes to neurodegeneration have not been elucidated. In this study we establish a critical mechanism by which chronic ISR activation becomes maladaptive and promotes neurodegeneration in neurotoxin and α- synucleinopathy models of PD in vitro and in vivo . Specifically, we demonstrate that chronic activation of ATF4, the central transcription factor of the ISR, promotes neurodegeneration by regulating the transcriptional induction of SESN2, DDIT4 and Trib3 that co-operate to suppress both mTORC1 and mTORC2 activity. Furthermore, we demonstrate that ATF4-mediated suppression of mTORC1/2 activity promotes dopaminergic neuronal death in PD models by facilitating the activation of the pro- apoptotic BCL-2 family protein PUMA. Taken together, we have discovered a novel maladaptive ISR/ATF4 signaling pathway leading to chronic suppression of mTORC1/2 activity resulting in PUMA-mediated neuronal death that may have therapeutic implications in a range of neurodegenerative conditions that exhibit chronic ISR activation. Abstract Figure
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".