The Protein Disulfide Isomerase P4HB/PDIA1 Modulates PrP <sup>C</sup> Levels and Prion Replication
Bibliographic record
Abstract
Abstract Prions are misfolded, self-propagating versions of the cellular prion protein (PrP C ) that cause invariably fatal transmissible neurodegenerative diseases in humans and animals. Little is known about how prions replicate in the brain, including whether other proteins participate in prion replication in vivo . Several members of the protein disulfide isomerase family have been shown to reside in close spatial proximity to PrP C in cells and mice, implying that they could be involved in prion biogenesis. Here, we show that stable knock-down of the protein disulfide isomerase P4HB (also called PDIA1) in prion-susceptible CAD5 cells reduces PrP C levels and results in lower levels of protease-resistant PrP (PrP res ), a marker of infectious prions, following infection with two different prion strains. Partial reduction of P4HB activity using the P4HB-selective inhibitor KSC-34 also decreases PrP C levels in uninfected CAD5 cells whereas treatment of prion-infected CAD5 cells with KSC-34 results in higher levels of PrP res . A proportion of P4HB reaches the cell surface where PrP C is located, and a secreted P4HB variant increases PrP res levels in cells. Collectively, these results suggest that P4HB facilitates prion replication in cells by stabilizing PrP C and potentially acting as a chaperone that directly modulates prion conversion. Thus, targeting P4HB during prion disease may have therapeutic benefit.
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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) | 0.001 | 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".