A CHCHD10 variant causing ALS elicits an unfolded protein response through the IRE1/XBP1 pathway
Bibliographic record
Abstract
Abstract Mutations in CHCHD10 , coding for a mitochondrial intermembrane space protein, are a rare cause of autosomal dominant amyotrophic lateral sclerosis (ALS). Mutation-specific toxic gain of function or haploinsuffuciency models have been proposed to explain pathogenicity. To decipher the metabolic dysfunction associated with the haploinsufficient p.R15L variant we integrated transcriptomic, metabolomic and proteomic data sets in patient cells subjected to nutrient stress. Patient cells had a complex I deficiency resulting in an increased NADH/NAD + ratio, downregulation of the TCA cycle, and a reorganization of one carbon metabolism. This led to phosphorylation of AMPK, activation of an endoplasmic reticulum and mitochondrial unfolded protein response (UPR), and the production of GDF15 and FGF21, which are markers of mitochondrial disease. The endoplasmic reticulum UPR was mediated through the IRE1/XBP1 pathway, and was accompanied by reduced eIF2alpha phosphorylation, dephosphorylation of both JNK isoforms, and up regulation of several dual specific phosphatases. This study demonstrates that loss of CHCHD10 function elicits a striking energy deficit that activates cellular stress pathways, which may underlie the selective vulnerability of motor neurons.
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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) | 0.002 | 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".