O1‐04–06: Glycogen synthase kinase‐3β and the p25 activator of cyclin‐dependent kinase‐5 regulate axoplasmic transport of mitochondria by increasing their stationary behavior
Bibliographic record
Abstract
The activities of glycogen synthase kinase-3β (GSK-3β) and cyclin dependent kinase-5 (cdk-5) have been reported to be increased in Alzheimer's disease, resulting in change in the biological activity of several substrates. Objectives: To further study the involvement of GSK-3β and cdk-5 in neuronal dysfunction, we have investigated in PC12 and in neurons the effects of increased expression of GSK-3β and of the p25 activator of cdk5 on axoplasmic transport of mitochondria. Differentiated PC12 cells and primary culture of neurons were co-transfected with DsRed-Mito and EGFP, EGFP-GSK-3β, EGFP-GSK-3β (S9A), or EGFP-p25. Axoplasmic transport of mitochondria in living neuronal cells was studied by time-lapse imaging and several kinetic parameters were measured. The frequency of mitochondrial stationary phases was significantly increased in p25, GSK-3β and GSK-3β (S9A) transfected neurons and PC12. The frequency of anterograde movements was proportionally more decreased than the frequency of retrograde movements. However, the mean instantaneous velocities of mitochondria in both anterograde and retrograde directions were not affected in PC12 or neurons transfected with p25, GSK-3β and GSK-3β (S9A). Mean anterograde and retrograde run were reduced resulting in a dramatic decrease of net transport of mitochondria. Nocodazole, but not cytochalasin D, decreased the mean velocity of mitochondria in the different conditions, and still reduced the frequency of residual movements in p25, GSK-3β and GSK-3β (S9A) transfected neurons. Our results indicate that increased activity of GSK-3β and of cdk5 increases the pausing behaviour of mitochondria in neurons, and affects preferentially their fast anterograde transport. We suggest that GSK-3β and p25 act primarily by reducing the pool of active molecular motors involved in fast transport, with a preferential, but not unique, action on anterograde motors such as kinesin. This mechanism might play a role in intracellular transport disturbances in neurons in Alzheimer's disease.
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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 | 0.000 |
| 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".