Inhibition of cathepsin B blocks amyloidogenesis in the mouse models of neurological lysosomal diseases mucopolysaccharidosis type IIIC and sialidosis
Bibliographic record
Abstract
Abstract Neuronal accumulation of amyloid aggregates is a hallmark of brain pathology in neurological lysosomal storage diseases (LSDs) including mucopolysaccharidoses (MPS), however, the molecular mechanism underlaying this pathology has not been understood. We demonstrate that elevated lysosomal cathepsin B (CTSB) levels and CTSB leakage to the cytoplasm triggers amyloidogenesis in two neurological LSDs. CTSB levels were elevated 3-5-fold in the cortices of mouse models of MPS IIIC ( Hgsnat-Geo and Hgsnat P304L ) and sialidosis ( Neu1 ΔEx3 ), as well as in cortical samples of MPS I, IIIA, IIIC and IIID patients. CTSB was found in the cytoplasm of pyramidal layer IV-V cortical neurons containing Thioflavin-S-positive, β-amyloid-positive aggregates consistent with pro-senile phenotype. In contrast, CTSB-deficient MPS IIIC ( Hgsnat P304L /Ctsb -/- ) mice as well as Hgsnat P304L and Neu1 ΔEx3 mice chronically treated with irreversible brain-penetrable CTSB inhibitor, E64, showed a drastic reduction of neuronal Thioflavin-S-positive/APP-positive deposits. Neurons of Hgsnat P304L /Ctsb -/- mice and E64-treated Hgsnat P304L mice also showed reduced levels of P62/LC3-positive puncta, G M2 ganglioside and misfolded subunit C of mitochondrial ATP synthase (SCMAS) consistent with restored autophagy. E64 treatment also rescued hyperactivity and reduced anxiety in Hgsnat P304L mice implying that CTSB may become a novel pharmacological target for MPS III and similar LSDs.
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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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 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".