Variably protease-sensitive prionopathy: mass spectrometry analysis of the pathogenic prion protein provides a new perspective
Bibliographic record
Abstract
Variably protease-sensitive prionopathy (VPSPr) is a rare and complex prion disease that differs from sporadic Creutzfeldt-Jakob disease (sCJD) in its clinical and histopathological phenotypes. VPSPr also features a variety of fragments generated by the disease-causing prion protein (PrP D ). However, accurately determining the number and sequence of these fragments has been challenging when relying solely on epitope mapping with existing antibodies. To address these challenges, we performed mass spectrometry analyses and designed epitope mapping experiments to determine the primary structure and verify the presence or absence of the anchor in the VPSPr proteinase K-resistant and deglycosylated PrP D fragments. All three N-terminus fragments, with reported molecular weights of 20, 17, and 7 kDa, likely share Ser97 as the N-terminal amino acid. The C-terminus of the internal 7 kDa fragment is ragged, extending from Phe141 to Met154, while the 20 kDa and 17 kDa fragments differ only in the absence of the anchor in the latter. The three fragments belonging to the C-terminus group have previously been reported to have electrophoretic mobilities of 18, 12/13, and 8–9 kDa. After deglycosylation, the 18 kDa fragment was not detected. The 12 kDa component of the 12/13 kDa fragment was found to have a ragged N-terminus between Tyr162 and Asp181 and the anchor, while the 8 kDa fragment represented the anchorless version of the 12 kDa fragment. Unexpectedly, a second approximately 8 kDa fragment was identified that bore the anchor but had a shorter, ragged N-terminus ranging from Gly195 to Phe198. Calculation based on sequencing data revealed that the actual molecular masses of the 20, 17, and 12 kDa fragments are 1–2 kDa lighter. Moreover, the primary structures of the 20, 17, and 12 kDa fragments match those of the 19, 17, and 12 kDa fragments associated with sCJD type 2. Our findings provide new insights into the characteristics of the deglycosylated, PK-resistant fragments in VPSPr, which will likely assist in interpreting future high-resolution studies of amyloid fibrils in this disease.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".