S2‐01‐01: Localization of tau in rough endoplasmic reticulum and the mechanism of neurodegeneration
Bibliographic record
Abstract
In Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD), the neuronal microtubule-associated protein (MAP), tau becomes hyperphosphorylated, accumulates in the somato-dendritic compartment and aggregates into insoluble filaments. The consequences of the accumulation of hyperphosphorylated tau in the somato-dendritic compartment remain poorly characterized at the early stage of disease before the formation of tau insoluble filaments. We investigated the ultrastructural changes induced by this accumulation in the neuronal soma of motor neurons in JNPL3 mice overexpressing mutant tau, P301L before the formation of tau insoluble filaments. Immunogold labeling as well as subcellular fractionation were employed to examine the subcellular localization of hyperphosphorylated tau in the spinal cord and brain of JNPL3 mice and in AD brain. A significant higher number of contacts between rough endoplasmic reticulum (RER) membranes and mitochondria was observed in motor neurons of the spinal cord in JNLP3 mice than in wild-type mice. This correlated with a preferential increase of the amount of tau at the surface of RER membranes but not at the surface of mitochondria as revealed by tau immunogold labeling in motor neurons where insoluble tau filaments form. Using a subcellular fractionation procedure, an increased amount of phosphorylated tau was noted in the RM (rough microsomes) subfraction where the RER marker, ribophorin was enriched in brain of JNPL3 mice. A similar observation was noted in subfractions isolated from AD brain. The association of hyperphosphorylated tau with ER membranes was confirmed by double immunogold labeling of the subfraction enriched in ER membranes isolated from AD brain. The interaction between RER/mitochondria regulates calcium homeostasis which is perturbed in AD. The present study suggests that the increased number of contacts between RER membranes and mitochondria that could result from the accumulation of tau at the surface of RER membranes might contribute to tau-induced neurodegeneration by perturbing calcium homeostasis.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 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".