Combined deficiencies of endosomal ganglioside neuraminidases 3 and 4 in mice cause lysosomal GM3 gangliosidosis
Bibliographic record
Abstract
By regulating recognition, signaling and physiology of neurons, gangliosides are essential to CNS function.The composition of gangliosides in the brain changes during development and aging being regulated by neuraminidases presumably, which cleave their terminal sialic acid residues.Two mammalian neuraminidases, Neu3 and Neu4 are major candidates for processing brain gangliosides, however, the corresponding knockout mice showed no changes in brain ganglioside metabolism or deficits in brain function.To elucidate the physiological functions of Neu4 and Neu3 in the brain, we generated a gene-targeted mouse strain devoid of both enzymes.At the age of 10 months the mice showed deficits in spatial and short-term memory, whereas neuraminidase activity against gangliosides in their brain tissues was below detection levels.GM3 ganglioside was stored in lysosomes of neurons, microglia and vascular pericytes and GM1-ganglioside decreased in the axons.The number of astrocytes and activated microglia was increased, consistent with neuroinflammation.Cultured hippocampal and cortical neurons also showed reduced levels of GM1 ganglioside in the axons and impaired neuritogenesis.Our data provide evidence that Neu3 and Neu4 have unique roles in the regulation of brain ganglioside composition essential for CNS function: Neu4 generates the neuronal GM1 necessary for axon growth whereas Neu3 catabolizes GM3.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.003 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.004 | 0.001 |
| Science and technology studies | 0.001 | 0.002 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 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".