Discovery of levodopa-induced dyskinesia-associated genes using genomic studies in patients and Drosophila behavioral analyses
Bibliographic record
Abstract
Although levodopa is the most effective medication for Parkinson's disease, long-term levodopa treatment is largely compromised due to late motor complications, including levodopa-induced dyskinesia (LID). However, the genetic basis of LID pathogenesis has not been fully understood. Here, we discover genes pathogenic for LID using Drosophila genetics and behavioral analyses combined with genome-wide association studies on 578 patients clinically diagnosed with LID. Similar to the therapeutic effect of levodopa in patients, acute levodopa treatments restore the motor defect of Parkinson's disease model flies, while prolonged treatments cause LID-related symptoms, such as increased yawing, freezing and abrupt acceleration of locomotion. These symptoms require dopamine 1-like receptor 1 and are induced by neuronal overexpression of the receptor. Among genes selected from our analyses in the patient genome, neuronal knockdown of adenylyl cyclase 2 suppresses the levodopa-induced phenotypes and the receptor overexpression-induced symptoms in Drosophila. Together, our study provides genetic insights for LID pathogenesis through the D1-like receptor-adenylyl cyclase 2 signaling axis.
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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 | 0.001 |
| 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".