Cytosol-Exposed Lysine Residues Affect the Cytosol-Membrane Distribution and Serine-129 Phosphorylation of Alpha-Synuclein
Bibliographic record
Abstract
Familial Parkinson’s disease and other neurodegenerative diseases known as synucleinopathies are strongly associated with α-Synuclein (αS) missense mutations. One of these mutations, E46K, had been hypothesized to increase the electrostatic attraction of αS to neuronal vesicle membranes due to positively charged lysine that attracts negatively charged phospholipid head groups. Here, we confirm the biochemical mechanism of E46K through four compound mutants, each with three replacements with lysine on a cytosol-exposed position of the αS alpha helix. We show that the cytosolic αS to membrane-bound αS ratios are significantly lower, and that the phosphorylation rates of serine-129-a pathological marker-are pronouncedly higher for the mutants than for wild type. This experiment addresses the previous knowledge gap in the understanding of basic amino acid replacements in cytosol-exposed positions of αS. Importantly, the validated effect of cytosol-exposed lysine residues has implications for exploring the mechanism of pathogenesis of αS mutants in familial Parkinson’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 | 0.002 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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".