P3–377: Abeta (1–42) peptide regulates phosphorylation of nuclear choline acetyltransferase at threonine–456 by p38 kinase
Bibliographic record
Abstract
Choline acetyltransferase (ChAT), a principal phenotypic marker of cholinergic neurons, synthesizes the neurotransmitter acetylcholine (ACh). Lower specific activities of ChAT and decrease of physiological concentrations of ACh in cholinergic neurons are one of the characteristic pathological features of Alzheimer disease (AD). ChAT is phosphorylated in vitro and in vivo at multiple sites by serine/threonine kinases, including protein kinase C (PKC), calcium/calmodulin protein kinase (alpha–CaMII), and protein kinase CK2. Previous studies show that phosphorylation of ChAT regulates its catalytic activity, subcellular distribution and interaction with cellular proteins. Well–studied regulators of PKC–dependent phosphorylation of ChAT include phorbol esters and the toxic fragment of beta–amyloid peptide (Abeta) 1–42. Treatment of IMR32 neuroblastoma cells expressing ChAT with Abeta(1–42) results in biphasic activation of the enzyme in a hierarchical manner. This includes an initial phosphorylation of ChAT by PKC (maximal at 30 min treatment), followed by phosphorylation of ChAT by alpha–CaMII at threonine–456 (Thr–456) (maximal at 10h treatment). Here, we demonstrate that an important fraction of ChAT located in cellular nuclei is transiently phosphorylated at Thr–456 when IMR32 cells are treated with Abeta(1–42) for 5 min. Using site–directed mutagenesis, we demonstrated that ChAT is phosphorylated by p38–kinase at Thr–456 only after being previously phosphorylated by PKC. ChAT phosphorylation at Thr–456 was abolished when cells were treated with the p38–inhibitor SB202190. In subcellular fractionation studies, we found that cell nuclei contained ChAT phosphorylated on a proline–directed threonine residue using an antibody that recognizes this motif; this corresponds to the consensus sequence 456pT–P457in ChAT. Abeta peptides can disrupt cellular Ca2+ homeostasis thus impacting function of Ca2+–dependent protein kinases, and are also involved in generation of reactive oxygen species leading to activation of stress–related protein kinases such as p38–kinase. These events can be transient and modulate regulatory signal transduction pathways in brain areas affected in AD, including in cholinergic neurons.
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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) | 0.001 | 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 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".