Title | High-throughput behavioral screen in C. elegans reveals Parkinson's disease drug candidates. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Sohrabi, S, Mor, DE, Kaletsky, R, Keyes, W, Murphy, CT |
Journal | Commun Biol |
Volume | 4 |
Issue | 1 |
Pagination | 203 |
Date Published | 2021 Feb 15 |
ISSN | 2399-3642 |
Keywords | Animals, Antiparkinson Agents, Behavior, Animal, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Drug Repositioning, High-Throughput Screening Assays, Image Interpretation, Computer-Assisted, Machine Learning, Neural Networks, Computer, Posture, Proof of Concept Study, RNA Interference, Transaminases, Workflow |
Abstract | <p>We recently linked branched-chain amino acid transferase 1 (BCAT1) dysfunction with the movement disorder Parkinson's disease (PD), and found that RNAi-mediated knockdown of neuronal bcat-1 in C. elegans causes abnormal spasm-like 'curling' behavior with age. Here we report the development of a machine learning-based workflow and its application to the discovery of potentially new therapeutics for PD. In addition to simplifying quantification and maintaining a low data overhead, our simple segment-train-quantify platform enables fully automated scoring of image stills upon training of a convolutional neural network. We have trained a highly reliable neural network for the detection and classification of worm postures in order to carry out high-throughput curling analysis without the need for user intervention or post-inspection. In a proof-of-concept screen of 50 FDA-approved drugs, enasidenib, ethosuximide, metformin, and nitisinone were identified as candidates for potential late-in-life intervention in PD. These findings point to the utility of our high-throughput platform for automated scoring of worm postures and in particular, the discovery of potential candidate treatments for PD.</p> |
DOI | 10.1038/s42003-021-01731-z |
Alternate Journal | Commun Biol |
PubMed ID | 33589689 |
PubMed Central ID | PMC7884385 |
Grant List | RF1 AG057341 / AG / NIA NIH HHS / United States P40 OD010440 / OD / NIH HHS / United States F32 AG062036 / AG / NIA NIH HHS / United States R01 AG034446 / AG / NIA NIH HHS / United States DP1 GM119167 / GM / NIGMS NIH HHS / United States |