Activation of the mitochondrial unfolded protein response promotes longevity and dopamine neuron survival in Parkinson’s disease models
Bibliographic record
Abstract
While the pathogenesis of Parkinson's disease (PD) is incompletely understood, mitochondrial dysfunction is thought to play a crucial role in disease pathogenesis. Here, we examined the relationship between mitochondrial function and dopamine neuron dysfunction and death using C. elegans mutants for three mitochondria-related genes implicated in monogenic PD (pdr-1/PRKN, pink-1/PINK1 and djr-1.1/DJ-1). We found that pdr-1 and pink-1 mutants exhibit deficits in dopamine-dependent behaviors, but no loss of dopamine neurons, while djr-1.1 mutants showed an increased sensitivity to oxidative stress. In examining mitochondrial morphology and function, we found that djr-1.1 mutants exhibit increased mitochondrial fragmentation leading to decreased rate of oxidative phosphorylation and ATP levels. pdr-1 and pink-1 mutants show an accumulation of dysfunctional mitochondria with age, which leads to activation of the mitochondrial unfolded protein response (mitoUPR). Preventing the upregulation of the mitoUPR with a deletion in atfs-1 results in decreased lifespan and dopamine neuronal loss in pdr-1 and pink-1 mutants but not in wild-type worms. Overall, our results suggest that mutations in pdr-1 and pink-1 cause the accumulation of dysfunctional mitochondria, which activates the mitoUPR to mitigate the detrimental effect of these mutations on dopamine neuron survival.
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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) | 0.001 | 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".