Mouse Prion Protein Polymorphism Phe-108/Val-189 Affects the Kinetics of Fibril Formation and the Response to Seeding
Bibliographic record
Abstract
Prion diseases are fatal neurodegenerative disorders associated with the polymerization of the cellular form of prion protein (PrP C ) into an amyloidogenic β-sheet infectious form (PrP Sc ). The sequence of host PrP is the major determinant of host prion disease susceptibility. In mice, the presence of allele a ( Prnp a , encoding the polymorphism Leu-108/Thr-189) or b ( Prnp b , Phe-108/Val-189) is associated with short or long incubation times, respectively, following infection with PrP Sc . The molecular bases linking PrP sequence, infection susceptibility, and convertibility of PrP C into PrP Sc remain unclear. Here we show that recombinant PrP a and PrP b aggregate and respond to seeding differently in vitro . Our kinetic studies reveal differences during the nucleation phase of the aggregation process, where PrP b exhibits a longer lag phase that cannot be completely eliminated by seeding the reaction with preformed fibrils. Additionally, PrP b is more prone to propagate features of the seeds, as demonstrated by conformational stability and electron microscopy studies of the formed fibrils. We propose a model of polymerization to explain how the polymorphisms at positions 108 and 189 produce the phenotypes seen in vivo . This model also provides insight into phenomena such as species barrier and prion strain generation, two phenomena also influenced by the primary structure of PrP. Background: Alleles Prnp a and Prnp b of mouse prion protein (PrP) influence the incubation period of prion disease. Results: PrP a and PrP b , products of these alleles, aggregate differently in vitro . Conclusion: The polymorphism at 108/189 influences the oligomeric stages of PrP polymerization. Significance: Elucidating the mechanism of PrP aggregation is relevant to understanding prion disease susceptibility, prion strains, and species barriers.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".