Cathepsin B inhibition blocks amyloidogenesis in the mouse models of neurological lysosomal diseases MPS IIIC and sialidosis
Bibliographic record
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 underlying 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- to 5-fold in the cortices of mouse models of MPS IIIC (<i>Hgsnat-Geo</i> and <i>Hgsnat</i><sup>P304L</sup>) and sialidosis (<i>Neu1</i><sup>ΔEx3</sup>), 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<sup>+</sup>, β-amyloid<sup>+</sup> aggregates consistent with a pro-senile phenotype. In contrast, CTSB-deficient MPS IIIC (<i>Hgsnat</i><sup>P304L</sup><i>/Ctsb</i><sup>−/−</sup>) mice as well as <i>Hgsnat</i><sup>P304L</sup> and <i>Neu1</i><sup>ΔEx3</sup> mice chronically treated with irreversible brain-penetrable CTSB inhibitor E64 showed a drastic reduction in neuronal thioflavin-S<sup>+</sup>/APP<sup>+</sup> deposits. Neurons of <i>Hgsnat</i><sup>P304L</sup><i>/Ctsb</i><sup>−/−</sup> mice and E64-treated <i>Hgsnat</i><sup>P304L</sup> mice also showed reduced levels of P62<sup>+</sup>, LC3<sup>+</sup> puncta, G<sub>M2</sub> ganglioside, and misfolded subunit C of mitochondrial ATP synthase, consistent with restored autophagy. E64 treatment also rescued hyperactivity and reduced anxiety in <i>Hgsnat</i><sup>P304L</sup> 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 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 | 0.003 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".