Seed structure and phosphorylation in the fuzzy coat impact tau seeding competency
Bibliographic record
Abstract
ABSTRACT Tau is a pathogenic protein in Alzheimer’s (AD) and other neurodegenerative diseases. The misfolding of tau into β-sheet rich elongated filaments is thought to be a key event in disease pathogenesis, followed by subsequent templated recruitment of monomeric tau into this pathogenic form. Cryo-electron microscopy has revealed that specific tau conformations characterize different diseases. In this study, we explored how tau filament core structure and post-translational modifications in its disordered fuzzy coat influence its seeding capacity in primary neurons and mice. We show that the structure of the seeds affects seeding capacity, but that the AD tau core structure alone is insufficient to capture the full seeding capacity of AD tau. Proteolytic cleavage of AD tau which removes the fuzzy coat causes a loss in seeding capacity, as does removal of phosphorylation from the fuzzy coat by phosphatase treatment. Re-phosphorylation of phosphatase-treated AD tau by kinase treatment partially restores seeding activity. Finally, we find that filaments of recombinant tau with twelve phospho-mimetic residues (PAD12 tau) with the AD fold are able to recapitulate the seeding capacity of AD tau. Combined, these results suggest that the structure of the ordered core, together with phosphorylation in the fuzzy coat, confers the seeding capacity of tau filaments.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".