P4‐524: PROTEOLYTIC CLEAVAGE OF TAU IN CORTICOBASAL DEGENERATION AND PROGRESSIVE SUPRANUCLEAR PALSY PATHOGENESIS
Bibliographic record
Abstract
During the pathogenesis of tauopathies, such as corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), proteases cleave tau into fragments which have an altered propensity to be phosphorylated, to spread, to aggregate and propagate aggregation. One protease responsible to produce neurotoxic tauopathy-specific tau fragments and its potential role in tauopathy pathogenesis was investigated. The MEROPS database was used to identify the programmed cell death activating protease granzyme A as a candidate to cleave tau in a region known to produce tauopathy-specific tau fragments. The cleavage specificity was assayed in vitro using recombinant proteins, analysed by gel electrophoresis, western blotting with epitope-specific tau antibodies and mass spectrometry. HEK-293 cells expressing granzyme A and tau were employed to identify whether these cleavage events occur intracellularly. Cleavage sites identified by mass spectrometry were inhibited by site-directed mutagenesis. Granzyme A-cleaved tau fragments were expressed in HEK-293 and CHO-K1 cells to analyse transcellular spreading mechanisms, phosphorylation status, aggregation propensity and templated-seeded aggregation. Finally, the tau phosphorylation and fragmentation pattern were analysed in CBD and PSP patient brains. Through a series of experiments, we confirmed that full-length tau1-441 is cleaved by granzyme A at R194-S195 and R209-S210 to produce tauopathy-specific tau fragments. Granzyme A-cleaved C-terminal tau fragments have increased levels of phosphorylation, are more prone to aggregate and propagate aggregation compared to tau1-441, while these phenotypes are decreased in the granzyme A-cleaved N-terminal tau fragments. However, the latter demonstrate an increased propensity to undergo transcellular spreading compared to granzyme A-cleaved C-terminal tau fragments and full-length tau1-441. Furthermore, increased amounts of cleaved, phosphorylated and aggregated tau were identified in CBD and PSP patient brains compared to age-matched controls. Cleavage sites within tau to produce granzyme A-cleaved tau fragments were identified by mass spectrometry in CBD and PSP patient brains. Our results show that (i) granzyme A cleaves tau to produce tauopathy-specific tau fragments, and (ii) granzyme A-cleaved tau fragments have distinct cellular effects which could play an important role in tauopathy pathogenesis. Elucidating granzyme A-cleavage of tau is crucial in unravelling tauopathy pathogenesis to identify potential therapeutic targets and diagnostic biomarkers.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.002 |
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".